Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

ERK signalling: a master regulator of cell behaviour, life and fate

Abstract

The proteins extracellular signal-regulated kinase 1 (ERK1) and ERK2 are the downstream components of a phosphorelay pathway that conveys growth and mitogenic signals largely channelled by the small RAS GTPases. By phosphorylating widely diverse substrates, ERK proteins govern a variety of evolutionarily conserved cellular processes in metazoans, the dysregulation of which contributes to the cause of distinct human diseases. The mechanisms underlying the regulation of ERK1 and ERK2, their mode of action and their impact on the development and homeostasis of various organisms have been the focus of much attention for nearly three decades. In this Review, we discuss the current understanding of this important class of kinases. We begin with a brief overview of the structure, regulation, substrate recognition and subcellular localization of ERK1 and ERK2. We then systematically discuss how ERK signalling regulates six fundamental cellular processes in response to extracellular cues. These processes are cell proliferation, cell survival, cell growth, cell metabolism, cell migration and cell differentiation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: ERK activation and subcellular localization.
Fig. 2: ERK regulation of cell proliferation.
Fig. 3: ERK regulation of cell survival.
Fig. 4: ERK regulation of cell growth.
Fig. 5: ERK regulation of cell metabolism.
Fig. 6: ERK regulation of cell motility through formation of lamellipodia and actomyosin contractility.
Fig. 7: ERK regulation of cell motility through focal adhesion turnover and transcriptional control.
Fig. 8: ERK regulation of embryonic stem cell self-renewal and differentiation.
Fig. 9: ERK regulation of cell differentiation and development.

Similar content being viewed by others

References

  1. Hoshi, M., Nishida, E. & Sakai, H. Activation of a Ca2+-inhibitable protein kinase that phosphorylates microtubule-associated protein 2 in vitro by growth factors, phorbol esters, and serum in quiescent cultured human fibroblasts. J. Biol. Chem. 263, 5396–5401 (1988).

    Article  CAS  PubMed  Google Scholar 

  2. Ray, L. B. & Sturgill, T. W. Rapid stimulation by insulin of a serine/threonine kinase in 3T3-L1 adipocytes that phosphorylates microtubule-associated protein 2 in vitro. Proc. Natl Acad. Sci. USA 84, 1502–1506 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Boulton, T. G. et al. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65, 663–675 https://doi.org/10.1016/0092-8674(91)90098-j (1991).

    Article  CAS  PubMed  Google Scholar 

  4. Boulton, T. G. et al. An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science 249, 64–67 https://doi.org/10.1126/science.2164259 (1990).

    Article  CAS  PubMed  Google Scholar 

  5. Cargnello, M. & Roux, P. P. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol. Mol. Biol. Rev. 75, 50–83 https://doi.org/10.1128/MMBR.00031-10 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lavoie, H. & Therrien, M. Regulation of RAF protein kinases in ERK signalling. Nat. Rev. Mol. Cell Biol. 16, 281–298 https://doi.org/10.1038/nrm3979 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Crews, C. M. & Erikson, R. L. Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product. Proc. Natl Acad. Sci. USA 89, 8205–8209 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Unal, E. B., Uhlitz, F. & Bluthgen, N. A compendium of ERK targets. FEBS Lett. 591, 2607–2615 https://doi.org/10.1002/1873-3468.12740 (2017).

    Article  CAS  PubMed  Google Scholar 

  9. Taylor, S. S. & Kornev, A. P. Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem. Sci. 36, 65–77 https://doi.org/10.1016/j.tibs.2010.09.006 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Zhang, J., Zhang, F., Ebert, D., Cobb, M. H. & Goldsmith, E. J. Activity of the MAP kinase ERK2 is controlled by a flexible surface loop. Structure 3, 299–307 https://doi.org/10.1016/s0969-2126(01)00160-5 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Canagarajah, B. J., Khokhlatchev, A., Cobb, M. H. & Goldsmith, E. J. Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell 90, 859–869 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Zhang, F., Strand, A., Robbins, D., Cobb, M. H. & Goldsmith, E. J. Atomic structure of the MAP kinase ERK2 at 2.3 Å resolution. Nature 367, 704–711 https://doi.org/10.1038/367704a0 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Bergeron, J. J., Di Guglielmo, G. M., Dahan, S., Dominguez, M. & Posner, B. I. Spatial and temporal regulation of receptor tyrosine kinase activation and intracellular signal transduction. Annu. Rev. Biochem. 85, 573–597 https://doi.org/10.1146/annurev-biochem-060815-014659 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Harding, A., Tian, T., Westbury, E., Frische, E. & Hancock, J. F. Subcellular localization determines MAP kinase signal output. Curr. Biol. 15, 869–873 https://doi.org/10.1016/j.cub.2005.04.020 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Prior, I. A. & Hancock, J. F. Ras trafficking, localization and compartmentalized signalling. Semin. Cell Dev. Biol. 23, 145–153 https://doi.org/10.1016/j.semcdb.2011.09.002 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Casar, B. & Crespo, P. ERK signals: scaffolding scaffolds? Front. Cell Dev. Biol. 4, 49 https://doi.org/10.3389/fcell.2016.00049 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sheikh, F. et al. An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice. J. Clin. Invest. 118, 3870–3880 https://doi.org/10.1172/JCI34472 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ogata, T. et al. MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced by alpha1-adrenergic receptors. Proc. Natl Acad. Sci. USA 111, 3811–3816 https://doi.org/10.1073/pnas.1315359111 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Good, M., Tang, G., Singleton, J., Remenyi, A. & Lim, W. A. The Ste5 scaffold directs mating signaling by catalytically unlocking the Fus3 MAP kinase for activation. Cell 136, 1085–1097 https://doi.org/10.1016/j.cell.2009.01.049 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lavoie, H. et al. MEK drives BRAF activation through allosteric control of KSR proteins. Nature 554, 549–553 https://doi.org/10.1038/nature25478 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Adachi, M., Fukuda, M. & Nishida, E. Nuclear export of MAP kinase (ERK) involves a MAP kinase kinase (MEK)-dependent active transport mechanism. J. Cell Biol. 148, 849–856 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Formstecher, E. et al. PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. Dev. Cell 1, 239–250 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Karlsson, M., Mathers, J., Dickinson, R. J., Mandl, M. & Keyse, S. M. Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal. J. Biol. Chem. 279, 41882–41891 https://doi.org/10.1074/jbc.M406720200 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Adachi, M., Fukuda, M. & Nishida, E. Two co-existing mechanisms for nuclear import of MAP kinase: passive diffusion of a monomer and active transport of a dimer. EMBO J. 18, 5347–5358 https://doi.org/10.1093/emboj/18.19.5347 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ranganathan, A., Yazicioglu, M. N. & Cobb, M. H. The nuclear localization of ERK2 occurs by mechanisms both independent of and dependent on energy. J. Biol. Chem. 281, 15645–15652 https://doi.org/10.1074/jbc.M513866200 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Lorenzen, J. A. et al. Nuclear import of activated D-ERK by DIM-7, an importin family member encoded by the gene moleskin. Development 128, 1403–1414 (2001).

    CAS  PubMed  Google Scholar 

  27. Whitehurst, A. W. et al. ERK2 enters the nucleus by a carrier-independent mechanism. Proc. Natl Acad. Sci. USA 99, 7496–7501 https://doi.org/10.1073/pnas.112495999 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Peleg, O. & Lim, R. Y. Converging on the function of intrinsically disordered nucleoporins in the nuclear pore complex. Biol. Chem. 391, 719–730 https://doi.org/10.1515/BC.2010.092 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Kosako, H. et al. Phosphoproteomics reveals new ERK MAP kinase targets and links ERK to nucleoporin-mediated nuclear transport. Nat. Struct. Mol. Biol. 16, 1026–1035 https://doi.org/10.1038/nsmb.1656 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Casar, B., Pinto, A. & Crespo, P. Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes. Mol. Cell 31, 708–721 https://doi.org/10.1016/j.molcel.2008.07.024 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Herrero, A. et al. Small molecule inhibition of ERK dimerization prevents tumorigenesis by RAS-ERK pathway oncogenes. Cancer Cell 28, 170–182 https://doi.org/10.1016/j.ccell.2015.07.001 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Lorenz, K., Schmitt, J. P., Schmitteckert, E. M. & Lohse, M. J. A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy. Nat. Med. 15, 75–83 https://doi.org/10.1038/nm.1893 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Lai, S. & Pelech, S. Regulatory roles of conserved phosphorylation sites in the activation T-loop of the MAP kinase ERK1. Mol. Biol. Cell 27, 1040–1050 https://doi.org/10.1091/mbc.E15-07-0527 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tee, W. W., Shen, S. S., Oksuz, O., Narendra, V. & Reinberg, D. Erk1/2 activity promotes chromatin features and RNAPII phosphorylation at developmental promoters in mouse ESCs. Cell 156, 678–690 https://doi.org/10.1016/j.cell.2014.01.009 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Goke, J., Chan, Y. S., Yan, J., Vingron, M. & Ng, H. H. Genome-wide kinase-chromatin interactions reveal the regulatory network of ERK signaling in human embryonic stem cells. Mol. Cell 50, 844–855 https://doi.org/10.1016/j.molcel.2013.04.030 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Hu, S. et al. Profiling the human protein-DNA interactome reveals ERK2 as a transcriptional repressor of interferon signaling. Cell 139, 610–622 https://doi.org/10.1016/j.cell.2009.08.037 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Peti, W. & Page, R. Molecular basis of MAP kinase regulation. Protein Sci. 22, 1698–1710 https://doi.org/10.1002/pro.2374 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lee, T. et al. Docking motif interactions in MAP kinases revealed by hydrogen exchange mass spectrometry. Mol. Cell 14, 43–55 https://doi.org/10.1016/s1097-2765(04)00161-3 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Jacobs, D., Glossip, D., Xing, H., Muslin, A. J. & Kornfeld, K. Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev. 13, 163–175 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Piserchio, A. et al. Solution NMR insights into docking interactions involving inactive ERK2. Biochemistry 50, 3660–3672 https://doi.org/10.1021/bi2000559 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Mace, P. D. et al. Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK. Nat. Commun. 4, 1681 https://doi.org/10.1038/ncomms2687 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Piserchio, A. et al. Local destabilization, rigid body, and fuzzy docking facilitate the phosphorylation of the transcription factor Ets-1 by the mitogen-activated protein kinase ERK2. Proc. Natl Acad. Sci. USA 114, E6287–E6296 https://doi.org/10.1073/pnas.1702973114 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Voisin, L., Saba-El-Leil, M. K., Julien, C., Fremin, C. & Meloche, S. Genetic demonstration of a redundant role of extracellular signal-regulated kinase 1 (ERK1) and ERK2 mitogen-activated protein kinases in promoting fibroblast proliferation. Mol. Cell Biol. 30, 2918–2932 https://doi.org/10.1128/MCB.00131-10 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Drosten, M. et al. Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J. 29, 1091–1104 https://doi.org/10.1038/emboj.2010.7 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Squires, M. S., Nixon, P. M. & Cook, S. J. Cell-cycle arrest by PD184352 requires inhibition of extracellular signal-regulated kinases (ERK) 1/2 but not ERK5/BMK1. Biochem. J. 366, 673–680 https://doi.org/10.1042/BJ20020372 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Stacey, D. W. & Kung, H. F. Transformation of NIH 3T3 cells by microinjection of Ha-ras p21 protein. Nature 310, 508–511 https://doi.org/10.1038/310508a0 (1984).

    Article  CAS  PubMed  Google Scholar 

  47. Jones, S. M. & Kazlauskas, A. Growth-factor-dependent mitogenesis requires two distinct phases of signalling. Nat. Cell Biol. 3, 165–172 https://doi.org/10.1038/35055073 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Vasjari, L., Bresan, S., Biskup, C., Pai, G. & Rubio, I. Ras signals principally via Erk in G1 but cooperates with PI3K/Akt for cyclin D induction and S-phase entry. Cell Cycle 18, 204–225 https://doi.org/10.1080/15384101.2018.1560205 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chambard, J. C., Lefloch, R., Pouyssegur, J. & Lenormand, P. ERK implication in cell cycle regulation. Biochim. Biophys. Acta 1773, 1299–1310 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Deschenes-Simard, X., Kottakis, F., Meloche, S. & Ferbeyre, G. ERKs in cancer: friends or foes? Cancer Res. 74, 412–419 https://doi.org/10.1158/0008-5472.CAN-13-2381 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Fowler, T., Sen, R. & Roy, A. L. Regulation of primary response genes. Mol. Cell 44, 348–360 https://doi.org/10.1016/j.molcel.2011.09.014 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rivera, V. M. et al. A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity. Mol. Cell Biol. 13, 6260–6273 https://doi.org/10.1128/mcb.13.10.6260 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hollenhorst, P. C., McIntosh, L. P. & Graves, B. J. Genomic and biochemical insights into the specificity of ETS transcription factors. Annu. Rev. Biochem. 80, 437–471 https://doi.org/10.1146/annurev.biochem.79.081507.103945 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Janknecht, R., Ernst, W. H., Pingoud, V. & Nordheim, A. Activation of ternary complex factor Elk-1 by MAP kinases. EMBO J. 12, 5097–5104 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mylona, A. et al. Opposing effects of Elk-1 multisite phosphorylation shape its response to ERK activation. Science 354, 233–237 https://doi.org/10.1126/science.aad1872 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Esnault, C. et al. ERK-induced activation of TCF family of SRF cofactors initiates a chromatin modification cascade associated with transcription. Mol. Cell 65, 1081–1095 e1085 https://doi.org/10.1016/j.molcel.2017.02.005 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Clark, J. P. & Cooper, C. S. ETS gene fusions in prostate cancer. Nat. Rev. Urol. 6, 429–439 https://doi.org/10.1038/nrurol.2009.127 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Renzi, S., Anderson, N. D., Light, N. & Gupta, A. Ewing-like sarcoma: An emerging family of round cell sarcomas. J. Cell. Physiol. 234, 7999–8007 https://doi.org/10.1002/jcp.27558 (2019).

    Article  CAS  PubMed  Google Scholar 

  59. Hollenhorst, P. C. et al. Oncogenic ETS proteins mimic activated RAS/MAPK signaling in prostate cells. Genes Dev. 25, 2147–2157 https://doi.org/10.1101/gad.17546311 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Verger, A. et al. Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation. J. Biol. Chem. 276, 17181–17189 https://doi.org/10.1074/jbc.M010208200 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Bettegowda, C. et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333, 1453–1455 https://doi.org/10.1126/science.1210557 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kawamura-Saito, M. et al. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum. Mol. Genet. 15, 2125–2137 https://doi.org/10.1093/hmg/ddl136 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Padul, V., Epari, S., Moiyadi, A., Shetty, P. & Shirsat, N. V. ETV/Pea3 family transcription factor-encoding genes are overexpressed in CIC-mutant oligodendrogliomas. Genes Chromosomes Cancer 54, 725–733 https://doi.org/10.1002/gcc.22283 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Le Gallic, L., Sgouras, D., Beal, G. Jr. & Mavrothalassitis, G. Transcriptional repressor ERF is a Ras/mitogen-activated protein kinase target that regulates cellular proliferation. Mol. Cell Biol. 19, 4121–4133 https://doi.org/10.1128/mcb.19.6.4121 (1999).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Sgouras, D. N. et al. ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation. EMBO J. 14, 4781–4793 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Le Gallic, L., Virgilio, L., Cohen, P., Biteau, B. & Mavrothalassitis, G. ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression. Mol. Cell Biol. 24, 1206–1218 https://doi.org/10.1128/mcb.24.3.1206-1218.2004 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Bose, R. et al. ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis. Nature 546, 671–675 https://doi.org/10.1038/nature22820 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lopez-Bergami, P., Lau, E. & Ronai, Z. Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nat. Rev. Cancer 10, 65–76 https://doi.org/10.1038/nrc2681 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dang, C. V. MYC on the path to cancer. Cell 149, 22–35 https://doi.org/10.1016/j.cell.2012.03.003 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gualdrini, F. et al. SRF Co-factors control the balance between cell proliferation and contractility. Mol. Cell 64, 1048–1061 https://doi.org/10.1016/j.molcel.2016.10.016 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zwang, Y. et al. Two phases of mitogenic signaling unveil roles for p53 and EGR1 in elimination of inconsistent growth signals. Mol. Cell 42, 524–535 https://doi.org/10.1016/j.molcel.2011.04.017 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bugaj, L. J. et al. Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway. Science 361, eaao3048 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Albeck, J. G., Mills, G. B. & Brugge, J. S. Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals. Mol. Cell 49, 249–261 https://doi.org/10.1016/j.molcel.2012.11.002 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Nakakuki, T. et al. Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics. Cell 141, 884–896 https://doi.org/10.1016/j.cell.2010.03.054 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Murphy, L. O., MacKeigan, J. P. & Blenis, J. A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration. Mol. Cell Biol. 24, 144–153 https://doi.org/10.1128/mcb.24.1.144-153.2004 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chen, R. H., Abate, C. & Blenis, J. Phosphorylation of the c-Fos transrepression domain by mitogen-activated protein kinase and 90-kDa ribosomal S6 kinase. Proc. Natl Acad. Sci. USA 90, 10952–10956 https://doi.org/10.1073/pnas.90.23.10952 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Murphy, L. O., Smith, S., Chen, R. H., Fingar, D. C. & Blenis, J. Molecular interpretation of ERK signal duration by immediate early gene products. Nat. Cell Biol. 4, 556–564 https://doi.org/10.1038/ncb822 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Wiggin, G. R. et al. MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts. Mol. Cell Biol. 22, 2871–2881 https://doi.org/10.1128/mcb.22.8.2871-2881.2002 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sears, R. et al. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 14, 2501–2514 https://doi.org/10.1101/gad.836800 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yeh, E. et al. A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat. Cell Biol. 6, 308–318 https://doi.org/10.1038/ncb1110 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Albanese, C. et al. Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J. Biol. Chem. 270, 23589–23597 https://doi.org/10.1074/jbc.270.40.23589 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Lavoie, J. N., L’Allemain, G., Brunet, A., Muller, R. & Pouyssegur, J. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J. Biol. Chem. 271, 20608–20616 https://doi.org/10.1074/jbc.271.34.20608 (1996).

    Article  CAS  PubMed  Google Scholar 

  83. Klein, E. A. & Assoian, R. K. Transcriptional regulation of the cyclin D1 gene at a glance. J. Cell Sci. 121, 3853–3857 https://doi.org/10.1242/jcs.039131 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Bertoli, C., Skotheim, J. M. & de Bruin, R. A. Control of cell cycle transcription during G1 and S phases. Nat. Rev. Mol. Cell Biol. 14, 518–528 https://doi.org/10.1038/nrm3629 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Villanueva, J., Yung, Y., Walker, J. L. & Assoian, R. K. ERK activity and G1 phase progression: identifying dispensable versus essential activities and primary versus secondary targets. Mol. Biol. Cell 18, 1457–1463 https://doi.org/10.1091/mbc.e06-10-0908 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Brown, J. R. et al. Fos family members induce cell cycle entry by activating cyclin D1. Mol. Cell Biol. 18, 5609–5619 https://doi.org/10.1128/mcb.18.9.5609 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kozar, K. et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 118, 477–491 https://doi.org/10.1016/j.cell.2004.07.025 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Yang, H. W., Chung, M., Kudo, T. & Meyer, T. Competing memories of mitogen and p53 signalling control cell-cycle entry. Nature 549, 404–408 https://doi.org/10.1038/nature23880 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Garcia-Gutierrez, L., Delgado, M. D. & Leon, J. MYC oncogene contributions to release of cell cycle brakes. Genes https://doi.org/10.3390/genes10030244 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Fujita, N., Sato, S. & Tsuruo, T. Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization. J. Biol. Chem. 278, 49254–49260 https://doi.org/10.1074/jbc.M306614200 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Hwang, C. Y., Lee, C. & Kwon, K. S. Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21Cip1. Mol. Cell Biol. 29, 3379–3389 https://doi.org/10.1128/MCB.01758-08 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Singh, R., Letai, A. & Sarosiek, K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 20, 175–193 https://doi.org/10.1038/s41580-018-0089-8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Berra, E., Diaz-Meco, M. T. & Moscat, J. The activation of p38 and apoptosis by the inhibition of Erk is antagonized by the phosphoinositide 3-kinase/Akt pathway. J. Biol. Chem. 273, 10792–10797 https://doi.org/10.1074/jbc.273.17.10792 (1998).

    Article  CAS  PubMed  Google Scholar 

  94. Edlich, F. BCL-2 proteins and apoptosis: Recent insights and unknowns. Biochem. Biophys. Res. Commun. 500, 26–34 https://doi.org/10.1016/j.bbrc.2017.06.190 (2018).

    Article  CAS  PubMed  Google Scholar 

  95. Kale, J., Osterlund, E. J. & Andrews, D. W. BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ. 25, 65–80 https://doi.org/10.1038/cdd.2017.186 (2018).

    Article  CAS  PubMed  Google Scholar 

  96. Chen, L. et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell 17, 393–403 https://doi.org/10.1016/j.molcel.2004.12.030 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Hubner, A., Barrett, T., Flavell, R. A. & Davis, R. J. Multisite phosphorylation regulates Bim stability and apoptotic activity. Mol. Cell 30, 415–425 https://doi.org/10.1016/j.molcel.2008.03.025 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ewings, K. E. et al. ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL. EMBO J. 26, 2856–2867 https://doi.org/10.1038/sj.emboj.7601723 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yang, J. Y. et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat. Cell Biol. 10, 138–148 https://doi.org/10.1038/ncb1676 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lopez, J. et al. Src tyrosine kinase inhibits apoptosis through the Erk1/2-dependent degradation of the death accelerator Bik. Cell Death Differ. 19, 1459–1469 https://doi.org/10.1038/cdd.2012.21 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Shao, Y. & Aplin, A. E. ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity. Cell Death Dis. 3, e253 https://doi.org/10.1038/cddis.2011.137 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Bonni, A. et al. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 1358–1362 https://doi.org/10.1126/science.286.5443.1358 (1999).

    Article  CAS  PubMed  Google Scholar 

  103. Shimamura, A., Ballif, B. A., Richards, S. A. & Blenis, J. Rsk1 mediates a MEK-MAP kinase cell survival signal. Curr. Biol. 10, 127–135 https://doi.org/10.1016/s0960-9822(00)00310-9 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Allan, L. A. et al. Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat. Cell Biol. 5, 647–654 https://doi.org/10.1038/ncb1005 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Domina, A. M., Vrana, J. A., Gregory, M. A., Hann, S. R. & Craig, R. W. MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene 23, 5301–5315 https://doi.org/10.1038/sj.onc.1207692 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Boucher, M. J. et al. MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J. Cell Biochem. 79, 355–369 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Subramanian, M. & Shaha, C. Up-regulation of Bcl-2 through ERK phosphorylation is associated with human macrophage survival in an estrogen microenvironment. J. Immunol. 179, 2330–2338 https://doi.org/10.4049/jimmunol.179.4.2330 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Ye, Q., Cai, W., Zheng, Y., Evers, B. M. & She, Q. B. ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer. Oncogene 33, 1828–1839 https://doi.org/10.1038/onc.2013.122 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Ginzberg, M. B., Kafri, R. & Kirschner, M. Cell biology. On being right size. Science 348, 1245075 https://doi.org/10.1126/science.1245075 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bywater, M. J., Pearson, R. B., McArthur, G. A. & Hannan, R. D. Dysregulation of the basal RNA polymerase transcription apparatus in cancer. Nat. Rev. Cancer 13, 299–314 https://doi.org/10.1038/nrc3496 (2013).

    Article  CAS  PubMed  Google Scholar 

  111. Stefanovsky, V. Y. et al. An immediate response of ribosomal transcription to growth factor stimulation in mammals is mediated by ERK phosphorylation of UBF. Mol. Cell 8, 1063–1073 https://doi.org/10.1016/s1097-2765(01)00384-7 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Stefanovsky, V., Langlois, F., Gagnon-Kugler, T., Rothblum, L. I. & Moss, T. Growth factor signaling regulates elongation of RNA polymerase I transcription in mammals via UBF phosphorylation and r-chromatin remodeling. Mol. Cell 21, 629–639 https://doi.org/10.1016/j.molcel.2006.01.023 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Zhao, J., Yuan, X., Frodin, M. & Grummt, I. ERK-dependent phosphorylation of the transcription initiation factor TIF-IA is required for RNA polymerase I transcription and cell growth. Mol. Cell 11, 405–413 https://doi.org/10.1016/s1097-2765(03)00036-4 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Felton-Edkins, Z. A. et al. The mitogen-activated protein (MAP) kinase ERK induces tRNA synthesis by phosphorylating TFIIIB. EMBO J. 22, 2422–2432 https://doi.org/10.1093/emboj/cdg240 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sriskanthadevan-Pirahas, S., Deshpande, R., Lee, B. & Grewal, S. S. Ras/ERK-signalling promotes tRNA synthesis and growth via the RNA polymerase III repressor Maf1 in Drosophila. PLoS Genet. 14, e1007202 https://doi.org/10.1371/journal.pgen.1007202 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Johnston, L. A., Prober, D. A., Edgar, B. A., Eisenman, R. N. & Gallant, P. Drosophila myc regulates cellular growth during development. Cell 98, 779–790 https://doi.org/10.1016/s0092-8674(00)81512-3 (1999).

    Article  CAS  PubMed  Google Scholar 

  117. Sriskanthadevan-Pirahas, S., Lee, J. & Grewal, S. S. The EGF/Ras pathway controls growth in Drosophila via ribosomal RNA synthesis. Dev.Biol. 439, 19–29 https://doi.org/10.1016/j.ydbio.2018.04.006 (2018).

    Article  CAS  PubMed  Google Scholar 

  118. Iritani, B. M. & Eisenman, R. N. c-Myc enhances protein synthesis and cell size during B lymphocyte development. Proc. Natl Acad. Sci. USA 96, 13180–13185 https://doi.org/10.1073/pnas.96.23.13180 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Iritani, B. M. et al. Modulation of T-lymphocyte development, growth and cell size by the Myc antagonist and transcriptional repressor Mad1. EMBO J. 21, 4820–4830 https://doi.org/10.1093/emboj/cdf492 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Poortinga, G. et al. MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation. EMBO J. 23, 3325–3335 https://doi.org/10.1038/sj.emboj.7600335 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Poortinga, G. et al. c-MYC coordinately regulates ribosomal gene chromatin remodeling and Pol I availability during granulocyte differentiation. Nucleic Acids Res. 39, 3267–3281 https://doi.org/10.1093/nar/gkq1205 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Arabi, A. et al. c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription. Nat. Cell Biol. 7, 303–310 https://doi.org/10.1038/ncb1225 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Grandori, C. et al. c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat. Cell Biol. 7, 311–318 https://doi.org/10.1038/ncb1224 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Grewal, S. S., Li, L., Orian, A., Eisenman, R. N. & Edgar, B. A. Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nat. Cell Biol. 7, 295–302 https://doi.org/10.1038/ncb1223 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Ueda, T., Watanabe-Fukunaga, R., Fukuyama, H., Nagata, S. & Fukunaga, R. Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. Mol. Cell Biol. 24, 6539–6549 https://doi.org/10.1128/MCB.24.15.6539-6549.2004 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Pelletier, J., Graff, J., Ruggero, D. & Sonenberg, N. Targeting the eIF4F translation initiation complex: a critical nexus for cancer development. Cancer Res. 75, 250–263 https://doi.org/10.1158/0008-5472.CAN-14-2789 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ueda, T. et al. Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development. Proc. Natl Acad. Sci. USA 107, 13984–13990 https://doi.org/10.1073/pnas.1008136107 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Furic, L. et al. eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc. Natl Acad. Sci. USA 107, 14134–14139 https://doi.org/10.1073/pnas.1005320107 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Aguilar-Valles, A. et al. Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E. Nat. Commun. 9, 2459 https://doi.org/10.1038/s41467-018-04883-5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 https://doi.org/10.1016/j.cell.2017.02.004 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P. & Pandolfi, P. P. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179–193 https://doi.org/10.1016/j.cell.2005.02.031 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Roux, P. P., Ballif, B. A., Anjum, R., Gygi, S. P. & Blenis, J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl Acad. Sci. USA 101, 13489–13494 https://doi.org/10.1073/pnas.0405659101 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648–657 https://doi.org/10.1038/ncb839 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Carriere, A. et al. ERK1/2 phosphorylate Raptor to promote Ras-dependent activation of mTOR complex 1 (mTORC1). J. Biol. Chem. 286, 567–577 https://doi.org/10.1074/jbc.M110.159046 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Carriere, A. et al. Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr. Biol. 18, 1269–1277 https://doi.org/10.1016/j.cub.2008.07.078 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Galan, J. A. et al. Phosphoproteomic analysis identifies the tumor suppressor PDCD4 as a RSK substrate negatively regulated by 14-3-3. Proc. Natl Acad. Sci. U S A 111, E2918–E2927 https://doi.org/10.1073/pnas.1405601111 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Dorrello, N. V. et al. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314, 467–471 https://doi.org/10.1126/science.1130276 (2006).

    Article  CAS  PubMed  Google Scholar 

  138. Shahbazian, D. et al. The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO J. 25, 2781–2791 https://doi.org/10.1038/sj.emboj.7601166 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Dayton, T. L., Jacks, T. & Vander Heiden, M. G. PKM2, cancer metabolism, and the road ahead. EMBO Rep. 17, 1721–1730 https://doi.org/10.15252/embr.201643300 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    Article  CAS  PubMed  Google Scholar 

  141. Ito, K. & Suda, T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat. Rev. Mol. Cell Biol. 15, 243–256 https://doi.org/10.1038/nrm3772 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Scott, D. A. et al. Comparative metabolic flux profiling of melanoma cell lines: beyond the Warburg effect. J. Biol. Chem. 286, 42626–42634 https://doi.org/10.1074/jbc.M111.282046 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 https://doi.org/10.1016/j.cell.2012.01.058 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Kerr, E. M., Gaude, E., Turrell, F. K., Frezza, C. & Martins, C. P. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 531, 110–113 https://doi.org/10.1038/nature16967 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Hall, A. et al. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the V600EBRAF oncogene. Oncotarget 4, 584–599 https://doi.org/10.18632/oncotarget.965 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Tanner, L. B. et al. Four key steps control glycolytic flux in mammalian cells. Cell Syst. 7, 49–62 e48 https://doi.org/10.1016/j.cels.2018.06.003 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Falck Miniotis, M. et al. MEK1/2 inhibition decreases lactate in BRAF-driven human cancer cells. Cancer Res. 73, 4039–4049 https://doi.org/10.1158/0008-5472.CAN-12-1969 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Theodosakis, N. et al. BRAF inhibition decreases cellular glucose uptake in melanoma in association with reduction in cell volume. Mol. Cancer Ther. 14, 1680–1692 https://doi.org/10.1158/1535-7163.MCT-15-0080 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Parmenter, T. J. et al. Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov. 4, 423–433 https://doi.org/10.1158/2159-8290.CD-13-0440 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Kim, J. W., Gao, P., Liu, Y. C., Semenza, G. L. & Dang, C. V. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol. Cell Biol. 27, 7381–7393 https://doi.org/10.1128/MCB.00440-07 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Richard, D. E., Berra, E., Gothie, E., Roux, D. & Pouyssegur, J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J. Biol. Chem. 274, 32631–32637 https://doi.org/10.1074/jbc.274.46.32631 (1999).

    Article  CAS  PubMed  Google Scholar 

  152. Mylonis, I. et al. Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1alpha. J. Biol. Chem. 281, 33095–33106 https://doi.org/10.1074/jbc.M605058200 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Shim, H. et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl Acad. Sci. USA 94, 6658–6663 https://doi.org/10.1073/pnas.94.13.6658 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Schodel, J. et al. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood 117, e207–e217 https://doi.org/10.1182/blood-2010-10-314427 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Osthus, R. C. et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J. Biol. Chem. 275, 21797–21800 https://doi.org/10.1074/jbc.C000023200 (2000).

    Article  CAS  PubMed  Google Scholar 

  156. Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3, 187–197 https://doi.org/10.1016/j.cmet.2006.01.012 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 https://doi.org/10.1016/j.cmet.2006.02.002 (2006).

    Article  CAS  PubMed  Google Scholar 

  158. Yang, W. et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat. Cell Biol. 14, 1295–1304 https://doi.org/10.1038/ncb2629 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Houles, T. et al. RSK Regulates PFK-2 Activity to Promote Metabolic Rewiring in Melanoma. Cancer Res. 78, 2191–2204 https://doi.org/10.1158/0008-5472.CAN-17-2215 (2018).

    Article  CAS  PubMed  Google Scholar 

  160. Austin, S. & St-Pierre, J. PGC1alpha and mitochondrial metabolism-emerging concepts and relevance in ageing and neurodegenerative disorders. J. Cell Sci. 125, 4963–4971 https://doi.org/10.1242/jcs.113662 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Haq, R. et al. Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell 23, 302–315 https://doi.org/10.1016/j.ccr.2013.02.003 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Vazquez, F. et al. PGC1alpha expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23, 287–301 https://doi.org/10.1016/j.ccr.2012.11.020 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Wellbrock, C. & Arozarena, I. Microphthalmia-associated transcription factor in melanoma development and MAP-kinase pathway targeted therapy. Pigment Cell Melanoma Res. 28, 390–406 https://doi.org/10.1111/pcmr.12370 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Wu, M. et al. c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev. 14, 301–312 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Hemesath, T. J., Price, E. R., Takemoto, C., Badalian, T. & Fisher, D. E. MAP kinase links the transcription factor microphthalmia to c-Kit signalling in melanocytes. Nature 391, 298–301 https://doi.org/10.1038/34681 (1998).

    Article  CAS  PubMed  Google Scholar 

  166. Luo, C. et al. A PGC1alpha-mediated transcriptional axis suppresses melanoma metastasis. Nature 537, 422–426 https://doi.org/10.1038/nature19347 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Frederick, D. T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 https://doi.org/10.1158/1078-0432.CCR-12-1630 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Viale, A. et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628–632 https://doi.org/10.1038/nature13611 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Serasinghe, M. N. et al. Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol. Cell 57, 521–536 https://doi.org/10.1016/j.molcel.2015.01.003 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Kashatus, J. A. et al. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol. Cell 57, 537–551 https://doi.org/10.1016/j.molcel.2015.01.002 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Prieto, J. et al. Early ERK1/2 activation promotes DRP1-dependent mitochondrial fission necessary for cell reprogramming. Nat. Commun. 7, 11124 https://doi.org/10.1038/ncomms11124 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Smith, B. et al. Addiction to coupling of the Warburg effect with glutamine catabolism in Cancer Cells. Cell Rep. 17, 821–836 https://doi.org/10.1016/j.celrep.2016.09.045 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 https://doi.org/10.1038/nature12040 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Gaglio, D. et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol. Syst. Biol. 7, 523 https://doi.org/10.1038/msb.2011.56 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Romero, R. et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat. Med. 23, 1362–1368 https://doi.org/10.1038/nm.4407 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Hernandez-Davies, J. E. et al. Vemurafenib resistance reprograms melanoma cells towards glutamine dependence. J. Transl. Med. 13, 210 https://doi.org/10.1186/s12967-015-0581-2 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Wise, D. R. et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. USA 105, 18782–18787 https://doi.org/10.1073/pnas.0810199105 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Yang, R. et al. EGFR activates GDH1 transcription to promote glutamine metabolism through MEK/ERK/ELK1 pathway in glioblastoma. Oncogene 39, 2975–2986 (2020).

    Article  CAS  PubMed  Google Scholar 

  179. Santana-Codina, N. et al. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nat. Commun. 9, 4945 https://doi.org/10.1038/s41467-018-07472-8 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Graves, L. M. et al. Regulation of carbamoyl phosphate synthetase by MAP kinase. Nature 403, 328–332 https://doi.org/10.1038/35002111 (2000).

    Article  CAS  PubMed  Google Scholar 

  181. Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 https://doi.org/10.1038/nrm.2017.95 (2018).

    Article  CAS  PubMed  Google Scholar 

  182. Zheng, B. et al. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol. Cell 33, 237–247, https://doi.org/10.1016/j.molcel.2008.12.026 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Shen, C. H. et al. Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Mol. Cell 52, 161–172 https://doi.org/10.1016/j.molcel.2013.08.044 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Tanimura, S. & Takeda, K. ERK signalling as a regulator of cell motility. J. Biochem. 162, 145–154 https://doi.org/10.1093/jb/mvx048 (2017).

    Article  CAS  PubMed  Google Scholar 

  185. Hiratsuka, T. et al. Intercellular propagation of extracellular signal-regulated kinase activation revealed by in vivo imaging of mouse skin. eLife 4, e05178 https://doi.org/10.7554/eLife.05178 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Aoki, K. et al. Propagating wave of ERK activation orients collective cell migration. Dev. Cell 43, 305–317 e305 https://doi.org/10.1016/j.devcel.2017.10.016 (2017).

    Article  CAS  PubMed  Google Scholar 

  187. Mendoza, M. C., Vilela, M., Juarez, J. E., Blenis, J. & Danuser, G. ERK reinforces actin polymerization to power persistent edge protrusion during motility. Sci. Signal. 8, ra47 https://doi.org/10.1126/scisignal.aaa8859 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Brahmbhatt, A. A. & Klemke, R. L. ERK and RhoA differentially regulate pseudopodia growth and retraction during chemotaxis. J. Biol. Chem. 278, 13016–13025 https://doi.org/10.1074/jbc.M211873200 (2003).

    Article  CAS  PubMed  Google Scholar 

  189. Choi, C. & Helfman, D. M. The Ras-ERK pathway modulates cytoskeleton organization, cell motility and lung metastasis signature genes in MDA-MB-231 LM2. Oncogene 33, 3668–3676 (2014).

    Article  CAS  PubMed  Google Scholar 

  190. Te Boekhorst, V., Preziosi, L. & Friedl, P. Plasticity of cell migration in vivo and in silico. Annu. Rev. Cell Dev. Biol. 32, 491–526 https://doi.org/10.1146/annurev-cellbio-111315-125201 (2016).

    Article  CAS  Google Scholar 

  191. Lawson, C. D. & Ridley, A. J. Rho GTPase signaling complexes in cell migration and invasion. J. Cell Biol. 217, 447–457 https://doi.org/10.1083/jcb.201612069 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Fincham, V. J., James, M., Frame, M. C. & Winder, S. J. Active ERK/MAP kinase is targeted to newly forming cell-matrix adhesions by integrin engagement and v-Src. EMBO J. 19, 2911–2923 https://doi.org/10.1093/emboj/19.12.2911 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Case, L. B. & Waterman, C. M. Integration of actin dynamics and cell adhesion by a three-dimensional, mechanosensitive molecular clutch. Nat. Cell Biol. 17, 955–963 https://doi.org/10.1038/ncb3191 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Miki, H., Fukuda, M., Nishida, E. & Takenawa, T. Phosphorylation of WAVE downstream of mitogen-activated protein kinase signaling. J. Biol. Chem. 274, 27605–27609 https://doi.org/10.1074/jbc.274.39.27605 (1999).

    Article  CAS  PubMed  Google Scholar 

  195. Mendoza, M. C. et al. ERK-MAPK drives lamellipodia protrusion by activating the WAVE2 regulatory complex. Mol. Cell 41, 661–671 https://doi.org/10.1016/j.molcel.2011.02.031 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Danson, C. M., Pocha, S. M., Bloomberg, G. B. & Cory, G. O. Phosphorylation of WAVE2 by MAP kinases regulates persistent cell migration and polarity. J. Cell Sci. 120, 4144–4154 https://doi.org/10.1242/jcs.013714 (2007).

    Article  CAS  PubMed  Google Scholar 

  197. Martinez-Quiles, N., Ho, H. Y., Kirschner, M. W., Ramesh, N. & Geha, R. S. Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP. Mol. Cell Biol. 24, 5269–5280 https://doi.org/10.1128/MCB.24.12.5269-5280.2004 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Woo, M. S., Ohta, Y., Rabinovitz, I., Stossel, T. P. & Blenis, J. Ribosomal S6 kinase (RSK) regulates phosphorylation of filamin A on an important regulatory site. Mol. Cell Biol. 24, 3025–3035 https://doi.org/10.1128/mcb.24.7.3025-3035.2004 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Vicente-Manzanares, M., Ma, X., Adelstein, R. S. & Horwitz, A. R. Non-muscle myosin II takes centre stage in cell adhesion and migration. Nat. Rev. Mol. Cell Biol. 10, 778–790 https://doi.org/10.1038/nrm2786 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Klemke, R. L. et al. Regulation of cell motility by mitogen-activated protein kinase. J. Cell Biol. 137, 481–492 https://doi.org/10.1083/jcb.137.2.481 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Webb, D. J. et al. FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nat. Cell Biol. 6, 154–161 https://doi.org/10.1038/ncb1094 (2004).

    Article  CAS  PubMed  Google Scholar 

  202. Samson, S. C. et al. p90 ribosomal S6 kinase (RSK) phosphorylates myosin phosphatase and thereby controls edge dynamics during cell migration. J. Biol. Chem. 294, 10846–10862 https://doi.org/10.1074/jbc.RA119.007431 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Tanimura, S. et al. ERK signaling promotes cell motility by inducing the localization of myosin 1E to lamellipodial tips. J. Cell Biol. 214, 475–489 https://doi.org/10.1083/jcb.201503123 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Parsons, J. T., Horwitz, A. R. & Schwartz, M. A. Cell adhesion: integrating cytoskeletal dynamics and cellular tension. Nat. Rev. Mol. Cell Biol. 11, 633–643 https://doi.org/10.1038/nrm2957 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Klein, R. M., Spofford, L. S., Abel, E. V., Ortiz, A. & Aplin, A. E. B-RAF regulation of Rnd3 participates in actin cytoskeletal and focal adhesion organization. Mol. Biol. Cell 19, 498–508 https://doi.org/10.1091/mbc.E07-09-0895 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Ishibe, S., Joly, D., Zhu, X. & Cantley, L. G. Phosphorylation-dependent paxillin-ERK association mediates hepatocyte growth factor-stimulated epithelial morphogenesis. Mol. Cell 12, 1275–1285 https://doi.org/10.1016/s1097-2765(03)00406-4 (2003).

    Article  CAS  PubMed  Google Scholar 

  207. Slack-Davis, J. K. et al. PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J. Cell Biol. 162, 281–291 https://doi.org/10.1083/jcb.200212141 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Ishibe, S., Joly, D., Liu, Z. X. & Cantley, L. G. Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis. Mol. Cell 16, 257–267 https://doi.org/10.1016/j.molcel.2004.10.006 (2004).

    Article  CAS  PubMed  Google Scholar 

  209. Woodrow, M. A., Woods, D., Cherwinski, H. M., Stokoe, D. & McMahon, M. Ras-induced serine phosphorylation of the focal adhesion protein paxillin is mediated by the Raf–>MEK–>ERK pathway. Exp. Cell Res. 287, 325–338 https://doi.org/10.1016/s0014-4827(03)00122-8 (2003).

    Article  CAS  PubMed  Google Scholar 

  210. Zheng, Y. et al. FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST. Mol. Cell 35, 11–25 https://doi.org/10.1016/j.molcel.2009.06.013 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Eblen, S. T. et al. Mitogen-activated protein kinase feedback phosphorylation regulates MEK1 complex formation and activation during cellular adhesion. Mol. Cell Biol. 24, 2308–2317 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Coles, L. C. & Shaw, P. E. PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway. Oncogene 21, 2236–2244 https://doi.org/10.1038/sj.onc.1205302 (2002).

    Article  CAS  PubMed  Google Scholar 

  213. King, A. J. et al. The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature 396, 180–183 https://doi.org/10.1038/24184 (1998).

    Article  CAS  PubMed  Google Scholar 

  214. Nayal, A. et al. Paxillin phosphorylation at Ser273 localizes a GIT1-PIX-PAK complex and regulates adhesion and protrusion dynamics. J. Cell Biol. 173, 587–589 https://doi.org/10.1083/jcb.200509075 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Sundberg-Smith, L. J., Doherty, J. T., Mack, C. P. & Taylor, J. M. Adhesion stimulates direct PAK1/ERK2 association and leads to ERK-dependent PAK1 Thr212 phosphorylation. J. Biol. Chem. 280, 2055–2064 https://doi.org/10.1074/jbc.M406013200 (2005).

    Article  CAS  PubMed  Google Scholar 

  216. Kubiniok, P., Lavoie, H., Therrien, M. & Thibault, P. Time-resolved phosphoproteome analysis of paradoxical RAF activation reveals novel targets of ERK. Mol. Cell Proteom. 16, 663–679 https://doi.org/10.1074/mcp.M116.065128 (2017).

    Article  CAS  Google Scholar 

  217. Pullikuth, A. K. & Catling, A. D. Extracellular signal-regulated kinase promotes Rho-dependent focal adhesion formation by suppressing p190A RhoGAP. Mol. Cell Biol. 30, 3233–3248 https://doi.org/10.1128/MCB.01178-09 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Shi, G. X., Yang, W. S., Jin, L., Matter, M. L. & Ramos, J. W. RSK2 drives cell motility by serine phosphorylation of LARG and activation of Rho GTPases. Proc. Natl Acad. Sci. USA 115, E190–E199 https://doi.org/10.1073/pnas.1708584115 (2018).

    Article  CAS  PubMed  Google Scholar 

  219. Fujishiro, S. H. et al. ERK1/2 phosphorylate GEF-H1 to enhance its guanine nucleotide exchange activity toward RhoA. Biochem. Biophys. Res. Commun. 368, 162–167 https://doi.org/10.1016/j.bbrc.2008.01.066 (2008).

    Article  CAS  PubMed  Google Scholar 

  220. Olson, E. N. & Nordheim, A. Linking actin dynamics and gene transcription to drive cellular motile functions. Nat. Rev. Mol. Cell Biol. 11, 353–365 https://doi.org/10.1038/nrm2890 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Mouilleron, S., Guettler, S., Langer, C. A., Treisman, R. & McDonald, N. Q. Molecular basis for G-actin binding to RPEL motifs from the serum response factor coactivator MAL. EMBO J. 27, 3198–3208 https://doi.org/10.1038/emboj.2008.235 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Panayiotou, R. et al. Phosphorylation acts positively and negatively to regulate MRTF-A subcellular localisation and activity. eLife 5, e15460 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Muehlich, S. et al. Serum-induced phosphorylation of the serum response factor coactivator MKL1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. Mol. Cell Biol. 28, 6302–6313 https://doi.org/10.1128/MCB.00427-08 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Salvany, L., Muller, J., Guccione, E. & Rorth, P. The core and conserved role of MAL is homeostatic regulation of actin levels. Genes Dev. 28, 1048–1053 https://doi.org/10.1101/gad.237743.114 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Esnault, C. et al. Rho-actin signaling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts. Genes Dev. 28, 943–958 https://doi.org/10.1101/gad.239327.114 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Patel, A. L. & Shvartsman, S. Y. Outstanding questions in developmental ERK signaling. Development 145, dev143818 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Busca, R., Pouyssegur, J. & Lenormand, P. ERK1 and ERK2 map kinases: specific roles or functional redundancy? Front. Cell Dev. Biol. 4, 53 https://doi.org/10.3389/fcell.2016.00053 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Saba-El-Leil, M. K., Fremin, C. & Meloche, S. Redundancy in the world of MAP kinases: all for one. Front. Cell Dev. Biol. 4, 67 https://doi.org/10.3389/fcell.2016.00067 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Martello, G. & Smith, A. The nature of embryonic stem cells. Annu. Rev. Cell Dev. Biol. 30, 647–675 https://doi.org/10.1146/annurev-cellbio-100913-013116 (2014).

    Article  CAS  PubMed  Google Scholar 

  230. Kunath, T. et al. FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development 134, 2895–2902 https://doi.org/10.1242/dev.02880 (2007).

    Article  CAS  PubMed  Google Scholar 

  231. Burdon, T., Stracey, C., Chambers, I., Nichols, J. & Smith, A. Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. Dev. Biol. 210, 30–43 https://doi.org/10.1006/dbio.1999.9265 (1999).

    Article  CAS  PubMed  Google Scholar 

  232. Ying, Q. L. et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 https://doi.org/10.1038/nature06968 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Chen, H. et al. Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 112, E5936–E5943 https://doi.org/10.1073/pnas.1516319112 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Mayor-Ruiz, C. et al. ERF deletion rescues RAS deficiency in mouse embryonic stem cells. Genes Dev. 32, 568–576 https://doi.org/10.1101/gad.310086.117 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Ng, H. H. & Surani, M. A. The transcriptional and signalling networks of pluripotency. Nat. Cell Biol. 13, 490–496 https://doi.org/10.1038/ncb0511-490 (2011).

    Article  CAS  PubMed  Google Scholar 

  236. Hamilton, W. B. et al. Dynamic lineage priming is driven via direct enhancer regulation by ERK. Nature 575, 355–360 https://doi.org/10.1038/s41586-019-1732-z (2019).

    Article  CAS  PubMed  Google Scholar 

  237. Brumbaugh, J. et al. NANOG is multiply phosphorylated and directly modified by ERK2 and CDK1 in vitro. Stem Cell Rep. 2, 18–25 https://doi.org/10.1016/j.stemcr.2013.12.005 (2014).

    Article  CAS  Google Scholar 

  238. Dhaliwal, N. K., Miri, K., Davidson, S., Tamim El Jarkass, H. & Mitchell, J. A. KLF4 nuclear export requires ERK activation and initiates exit from naive pluripotency. Stem Cell Rep. 10, 1308–1323 https://doi.org/10.1016/j.stemcr.2018.02.007 (2018).

    Article  CAS  Google Scholar 

  239. Kim, M. O. et al. ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4. Nat. Struct. Mol. Biol. 19, 283–290 https://doi.org/10.1038/nsmb.2217 (2012).

    Article  CAS  PubMed  Google Scholar 

  240. Spelat, R., Ferro, F. & Curcio, F. Serine 111 phosphorylation regulates OCT4A protein subcellular distribution and degradation. J. Biol. Chem. 287, 38279–38288 https://doi.org/10.1074/jbc.M112.386755 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Yeo, J. C. et al. Klf2 is an essential factor that sustains ground state pluripotency. Cell Stem Cell 14, 864–872 https://doi.org/10.1016/j.stem.2014.04.015 (2014).

    Article  CAS  PubMed  Google Scholar 

  242. Nett, I. R., Mulas, C., Gatto, L., Lilley, K. S. & Smith, A. Negative feedback via RSK modulates Erk-dependent progression from naive pluripotency. EMBO Rep. 19, e45642 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  243. Chung, J., Uchida, E., Grammer, T. C. & Blenis, J. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol. Cell Biol. 17, 6508–6516 https://doi.org/10.1128/mcb.17.11.6508 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Sengupta, T. K., Talbot, E. S., Scherle, P. A. & Ivashkiv, L. B. Rapid inhibition of interleukin-6 signaling and Stat3 activation mediated by mitogen-activated protein kinases. Proc. Natl Acad. Sci. USA 95, 11107–11112 https://doi.org/10.1073/pnas.95.19.11107 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Huang, G., Yan, H., Ye, S., Tong, C. & Ying, Q. L. STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ESC fates. Stem Cell 32, 1149–1160 https://doi.org/10.1002/stem.1609 (2014).

    Article  CAS  Google Scholar 

  246. Kretzschmar, M., Doody, J. & Massague, J. Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 389, 618–622 https://doi.org/10.1038/39348 (1997).

    Article  CAS  PubMed  Google Scholar 

  247. Sapkota, G. et al. Signaling through integrated inputs into the Smad1 linker. Mol. Cell 25, 441–454 https://doi.org/10.1016/j.molcel.2007.01.006 (2007).

    Article  CAS  PubMed  Google Scholar 

  248. Fuentealba, L. C. et al. Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 131, 980–993 https://doi.org/10.1016/j.cell.2007.09.027 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Li, Z. et al. BMP4 signaling acts via dual-specificity phosphatase 9 to control ERK activity in mouse embryonic stem cells. Cell Stem Cell 10, 171–182 https://doi.org/10.1016/j.stem.2011.12.016 (2012).

    Article  CAS  PubMed  Google Scholar 

  250. Qi, X. et al. BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways. Proc. Natl Acad. Sci. USA 101, 6027–6032 https://doi.org/10.1073/pnas.0401367101 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Rauen, K. A. The RASopathies. Annu. Rev. Genomics Hum. Genet. 14, 355–369 https://doi.org/10.1146/annurev-genom-091212-153523 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Nowaczyk, M. J. et al. Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy? Clin. Genet. 85, 138–146 https://doi.org/10.1111/cge.12116 (2014).

    Article  CAS  PubMed  Google Scholar 

  253. Dinsmore, C. J. & Soriano, P. MAPK and PI3K signaling: at the crossroads of neural crest development. Dev. Biol. 444, S79–S97 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Nakamura, T., Gulick, J., Pratt, R. & Robbins, J. Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations. Proc. Natl Acad. Sci. USA 106, 15436–15441 https://doi.org/10.1073/pnas.0903302106 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  255. Newbern, J. et al. Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development. Proc. Natl Acad. Sci. USA 105, 17115–17120 https://doi.org/10.1073/pnas.0805239105 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  256. Nakamura, T., Gulick, J., Colbert, M. C. & Robbins, J. Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development. Proc. Natl Acad. Sci. USA 106, 11270–11275 https://doi.org/10.1073/pnas.0902230106 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  257. Vasudevan, H. N. & Soriano, P. SRF regulates craniofacial development through selective recruitment of MRTF cofactors by PDGF signaling. Dev. Cell 31, 332–344 https://doi.org/10.1016/j.devcel.2014.10.005 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Minoux, M. & Rijli, F. M. Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development. Development 137, 2605–2621 https://doi.org/10.1242/dev.040048 (2010).

    Article  CAS  PubMed  Google Scholar 

  259. Shukla, V., Coumoul, X., Wang, R. H., Kim, H. S. & Deng, C. X. RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nat. Genet. 39, 1145–1150 https://doi.org/10.1038/ng2096 (2007).

    Article  CAS  PubMed  Google Scholar 

  260. Ueda, K., Yaoita, M., Niihori, T., Aoki, Y. & Okamoto, N. Craniosynostosis in patients with RASopathies: accumulating clinical evidence for expanding the phenotype. Am. J. Med. Genet. A 173, 2346–2352 https://doi.org/10.1002/ajmg.a.38337 (2017).

    Article  CAS  PubMed  Google Scholar 

  261. Twigg, S. R. et al. Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis. Nat. Genet. 45, 308–313 https://doi.org/10.1038/ng.2539 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Lee, B. et al. Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat. Genet. 16, 307–310 https://doi.org/10.1038/ng0797-307 (1997).

    Article  CAS  PubMed  Google Scholar 

  263. Xiao, G. et al. MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1. J. Biol. Chem. 275, 4453–4459 https://doi.org/10.1074/jbc.275.6.4453 (2000).

    Article  CAS  PubMed  Google Scholar 

  264. Ge, C. et al. Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. J. Biol. Chem. 284, 32533–32543, https://doi.org/10.1074/jbc.M109.040980 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Pandit, B. et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat. Genet. 39, 1007–1012 https://doi.org/10.1038/ng2073 (2007).

    Article  CAS  PubMed  Google Scholar 

  266. Pierpont, M. E. et al. Cardio-facio-cutaneous syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 134, e1149–e1162 https://doi.org/10.1542/peds.2013-3189 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  267. Yin, J. C. et al. Cellular interplay via cytokine hierarchy causes pathological cardiac hypertrophy in RAF1-mutant Noonan syndrome. Nat. Commun. 8, 15518 https://doi.org/10.1038/ncomms15518 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Lauriol, J. et al. Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines. J. Clin. Invest. 126, 2989–3005 https://doi.org/10.1172/JCI80396 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  269. Carvajal-Vergara, X. et al. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 465, 808–812 https://doi.org/10.1038/nature09005 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Ruppert, C. et al. Interference with ERK(Thr188) phosphorylation impairs pathological but not physiological cardiac hypertrophy. Proc. Natl Acad. Sci. USA 110, 7440–7445 https://doi.org/10.1073/pnas.1221999110 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  271. Bouveret, R. et al. NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets. eLife 4, e06942 (2015).

    Article  PubMed Central  Google Scholar 

  272. Dorn, T. et al. Interplay of cell-cell contacts and RhoA/MRTF-A signaling regulates cardiomyocyte identity. EMBO J. 37, e98133 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  273. Liang, Q. et al. The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes. Mol. Cell Biol. 21, 7460–7469 https://doi.org/10.1128/MCB.21.21.7460-7469.2001 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. van Berlo, J. H., Elrod, J. W., Aronow, B. J., Pu, W. T. & Molkentin, J. D. Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo. Proc. Natl Acad. Sci. USA 108, 12331–12336 https://doi.org/10.1073/pnas.1104499108 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  275. Atkins, C. M., Selcher, J. C., Petraitis, J. J., Trzaskos, J. M. & Sweatt, J. D. The MAPK cascade is required for mammalian associative learning. Nat. Neurosci. 1, 602–609 https://doi.org/10.1038/2836 (1998).

    Article  CAS  PubMed  Google Scholar 

  276. Brambilla, R. et al. A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390, 281–286 https://doi.org/10.1038/36849 (1997).

    Article  CAS  PubMed  Google Scholar 

  277. Cui, Y. et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 135, 549–560 https://doi.org/10.1016/j.cell.2008.09.060 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Wang, Y. et al. ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities. Cell 150, 816–830 https://doi.org/10.1016/j.cell.2012.06.034 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Hashimoto, S. et al. MED23 mutation links intellectual disability to dysregulation of immediate early gene expression. Science 333, 1161–1163 https://doi.org/10.1126/science.1206638 (2011).

    Article  CAS  PubMed  Google Scholar 

  280. Bozon, B., Davis, S. & Laroche, S. A requirement for the immediate early gene zif268 in reconsolidation of recognition memory after retrieval. Neuron 40, 695–701 https://doi.org/10.1016/s0896-6273(03)00674-3 (2003).

    Article  CAS  PubMed  Google Scholar 

  281. Jones, M. W. et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat. Neurosci. 4, 289–296 https://doi.org/10.1038/85138 (2001).

    Article  CAS  PubMed  Google Scholar 

  282. Lu, H. C. et al. Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nat. Genet. 49, 527–536 https://doi.org/10.1038/ng.3808 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Tan, Q. et al. Loss of capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma. Proc. Natl Acad. Sci. USA 115, E1511–E1519 https://doi.org/10.1073/pnas.1716452115 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Napoli, I. et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134, 1042–1054 https://doi.org/10.1016/j.cell.2008.07.031 (2008).

    Article  CAS  PubMed  Google Scholar 

  285. Panja, D. et al. Two-stage translational control of dentate gyrus LTP consolidation is mediated by sustained BDNF-TrkB signaling to MNK. Cell Rep. 9, 1430–1445 https://doi.org/10.1016/j.celrep.2014.10.016 (2014).

    Article  CAS  PubMed  Google Scholar 

  286. Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 https://doi.org/10.1016/j.cell.2011.06.013 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Zalfa, F. et al. The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 112, 317–327 https://doi.org/10.1016/s0092-8674(03)00079-5 (2003).

    Article  CAS  PubMed  Google Scholar 

  288. McCormick, J. W., Pincus, D., Resnekov, O. & Reynolds, K. A. Strategies for engineering and rewiring kinase regulation. Trends Biochem. Sci. 45, 259–271 https://doi.org/10.1016/j.tibs.2019.11.005 (2020).

    Article  CAS  PubMed  Google Scholar 

  289. Muhlhauser, W. W., Fischer, A., Weber, W. & Radziwill, G. Optogenetics - bringing light into the darkness of mammalian signal transduction. Biochim. Biophys. Acta Mol. Cell Res. 1864, 280–292 (2017).

    Article  PubMed  Google Scholar 

  290. Pargett, M., Gillies, T. E., Teragawa, C. K., Sparta, B. & Albeck, J. G. Single-cell imaging of ERK signaling using fluorescent biosensors. Methods Mol. Biol. 1636, 35–59 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Lake, D., Correa, S. A. & Muller, J. Negative feedback regulation of the ERK1/2 MAPK pathway. Cell Mol. Life Sci. 73, 4397–4413 https://doi.org/10.1007/s00018-016-2297-8 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank C. Baril and D. Kachaner for critical reading of the manuscript. J.G. was supported by a scholarship from the Fonds de Recherche du Québec – Santé. M.T holds an Impact Grant from the Canadian Cancer Society (706165), a Foundation Grant from the Canadian Institutes for Health Research (FDN388023) and a Canada Research Chair in Intracellular Signalling.

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Marc Therrien.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Molecular Cell Biology thanks Piero Crespo, Benjamin Turk and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Regulon

Group of genes that are regulated as a single unit, generally under the control of a common regulatory transcription factor that acts as a repressor or activator of gene expression.

Mediator complex

Multiprotein transcription co-activator conserved in all eukaryotes that transmits signals between transcription factors and the RNA polymerase II machinery through direct physical interactions.

ETS family

Transcription activators and inhibitors that share the E26 transformation-specific DNA-binding domain, which associates with DNA motifs encompassing the consensus sequence GGA(A/T).

TPA response element

DNA motif with the consensus sequence TGA(G/C)TCA that serves as a binding site for the AP-1 transcription factor dimers JUN–JUN and JUN–FOS.

cAMP response element

DNA motif with the consensus sequence TGACGTCA that serves as a binding site for the AP-1 transcription factor dimers JUN–ATF2 and ATF2–ATF2 and for ATF1 and CREB family dimers.

Intrinsic apoptosis pathway

Signalling pathway activated by environmental stresses and sensed by BCL-2 family proteins; leads to apoptosis through mitochondrial membrane permeabilization and release of cytochrome c.

Extrinsic apoptosis pathways

Signalling pathways activated by agonists of cell death receptors such as FAS, tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF, which lead to apoptosis through formation of death-inducing signalling complexes.

12-O-Tetradecanoylphorbol-13-acetate

(TPA). Synthetic phorbol ester analogue with potent oncogenic properties that stimulates protein kinase C and multiple downstream events, including hyperactivation of the RAS–ERK signalling cascade.

Oxidative phosphorylation

(OXPHOS). Metabolic process by which an electron transport chain in the inner membrane of mitochondria generates ATP through oxidation of tricarboxylic acid cycle intermediates (NADH or FADH2).

Glycolytic flux

Series of ten metabolic reactions within the glycolysis pathway that lead to the conversion of glucose into pyruvate and that generate the free energy required to form the high-energy molecules ATP and NADH.

Mechanotransduction

Process by which cells sense and transmit mechanical cues from their immediate environment through a series of signalling relays that trigger biological responses.

Focal adhesions

Adhesive contacts between the cell and the extracellular matrix that sense and transmit mechanical forces between integrins and the actin cytoskeleton on engagement of the cell with the extracellular matrix.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lavoie, H., Gagnon, J. & Therrien, M. ERK signalling: a master regulator of cell behaviour, life and fate. Nat Rev Mol Cell Biol 21, 607–632 (2020). https://doi.org/10.1038/s41580-020-0255-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-020-0255-7

This article is cited by

Search

Quick links