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Feedback regulation of EGFR signalling: decision making by early and delayed loops

Key Points

  • The epidermal growth factor receptor (EGFR)/ERBB family has evolved from a primordial, simple pathway of a single ligand receptor pair to a complex signalling network. Studies in invertebrates and in mammalian systems have unveiled a web of activity-dependent regulatory loops, which fall into early and late groups.

  • In the early phase, ubiquitylation and other covalent modifications that control receptor degradation, as well as primary and secondary (backward) phosphorylation, have major roles in the immediate regulation of receptor signalling. This phase also includes very rapid turnover of a group of microRNAs (miRNAs).

  • Late regulatory mechanisms of the network comprise newly induced mRNAs, miRNAs and proteins, which account for the specificity of the response to external stimuli.

  • The dynamic behaviour of the EGFR network and similar signalling systems identifies feedback and feedforward loops as a computational core able to perform complex tasks, such as digitalization of graded signals, filtration of noise, calculation of fold induction and fixation of output. This leads to stable phenotypes.

  • Cancer and other hyperproliferation diseases harness the regulatory mechanisms of the network by weakening negative feedback and enhancing positive feedback, thereby manipulating critical time constants of the network.

Abstract

Human-made information relay systems invariably incorporate central regulatory components, which are mirrored in biological systems by dense feedback and feedforward loops. This type of system control is exemplified by positive and negative feedback loops (for example, receptor endocytosis and dephosphorylation) that enable growth factors and receptor Tyr kinases of the epidermal growth factor receptor (EGFR)/ERBB family to regulate cellular function. Recent studies show that the collection of feedback regulatory loops can perform computational tasks — such as decoding ligand specificity, transforming graded input signals into a digital output and regulating response kinetics. Aberrant signal processing and feedback regulation can lead to defects associated with pathologies such as cancer.

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Figure 1: Early regulatory loops — the 'all out war'.
Figure 2: Wave-like regulation of mrNas and microrNas by egF.
Figure 3: Late regulatory loops.
Figure 4: Decision making by PC-12 cells.
Figure 5: Examples of network motifs in mammalian signalling systems.

References

  1. 1

    Levi-Montalcini, R. & Cohen, S. Effects of the extract of the mouse submaxillary salivary glands on the sympathetic system of mammals. Ann. N. Y. Acad. Sci. 85, 324–341 (1960).

    CAS  PubMed  Google Scholar 

  2. 2

    Cohen, S., Carpenter, G. & King, L. Jr. Epidermal growth factor-receptor-protein kinase interactions. Co-purification of receptor and epidermal growth factor-enhanced phosphorylation activity. J. Biol. Chem. 255, 4834–4842 (1980).

    CAS  PubMed  Google Scholar 

  3. 3

    Ullrich, A. et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309, 418–425 (1984).

    CAS  PubMed  Google Scholar 

  4. 4

    Hunter, T. Tyrosine phosphorylation: thirty years and counting. Curr. Opin. Cell Biol. 21, 140–146 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Pawson, T. & Scott, J. D. Signaling through scaffold, anchoring, and adaptor proteins. Science 278, 2075–2080 (1997).

    CAS  PubMed  Google Scholar 

  6. 6

    Citri, A. & Yarden, Y. EGF-ERBB signalling: towards the systems level. Nature Rev. Mol. Cell Biol. 7, 505–516 (2006).

    CAS  Google Scholar 

  7. 7

    Kholodenko, B. N. Cell-signalling dynamics in time and space. Nature Rev. Mol. Cell Biol. 7, 165–176 (2006).

    CAS  Google Scholar 

  8. 8

    Oda, K., Matsuoka, Y., Funahashi, A. & Kitano, H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol. Syst. Biol. 1, 20050010 (2005). Presents a comprehensive pathway map of EGFR signalling. The map reveals that the overall architecture of the pathway is a bow-tie structure with several feedback loops.

    Google Scholar 

  9. 9

    Freeman, M. Feedback control of intercellular signalling in development. Nature 408, 313–319 (2000).

    CAS  PubMed  Google Scholar 

  10. 10

    Xiong, W. & Ferrell, J. E. Jr. A positive-feedback-based bistable 'memory module' that governs a cell fate decision. Nature 426, 460–465 (2003). Shows that a brief exposure of frog oocytes to progesterone irreversibly triggers their maturation through a positive-feedback loop involving the MAPK cascade. However, the response becomes transient when positive feedback is blocked.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Kitano, H. Biological robustness. Nature Rev. Genet. 5, 826–837 (2004).

    CAS  Google Scholar 

  12. 12

    Kholodenko, B. N., Hancock, J. F. & Kolch, W. Signalling ballet in space and time. Nature Rev. Mol. Cell Biol. 11, 414–426 (2010).

    CAS  Google Scholar 

  13. 13

    Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Jacob, F. & Monod, J. Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3, 318–356 (1961).

    CAS  Google Scholar 

  15. 15

    Waddington, C. H. Canalization of development and the inheritance of acquired characters. Nature 150, 563–565 (1942).

    Google Scholar 

  16. 16

    Carpenter, G. & Cohen, S. 125I-labeled human epidermal growth factor. Binding, internalization, and degradation in human fibroblasts. J. Cell Biol. 71, 159–171 (1976).

    CAS  PubMed  Google Scholar 

  17. 17

    Grimes, M. L., Beattie, E. & Mobley, W. C. A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA. Proc. Natl Acad. Sci. USA 94, 9909–9914 (1997).

    CAS  PubMed  Google Scholar 

  18. 18

    Vieira, A. V., Lamaze, C. & Schmid, S. L. Control of EGF receptor signaling by clathrin-mediated endocytosis. Science 274, 2086–2089 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Fehrenbacher, N., Bar-Sagi, D. & Philips, M. Ras/MAPK signaling from endomembranes. Mol. Oncol. 3, 297–307 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Goh, L. K., Huang, F., Kim, W., Gygi, S. & Sorkin, A. Multiple mechanisms collectively regulate clathrin-mediated endocytosis of the epidermal growth factor receptor. J. Cell Biol. 189, 871–883 (2010). Demonstrates, using receptor mutagenesis, that clathrin-dependent internalization of EGFR is regulated by four mechanisms: ubiquitylation of the receptor kinase domain, the clathrin adaptor complex AP2, the GRB2 adaptor protein and acetylation of three C-terminal Lys residues.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Sigismund, S. et al. Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation. Dev. Cell 15, 209–219 (2008). Reports that EGFRs internalized via clathrin-mediated endocytosis are recycled to the cell surface and their signalling is prolonged. By contrast, clathrin-independent internalization preferentially commits the receptor to degradation.

    CAS  Google Scholar 

  22. 22

    Huang, F., Kirkpatrick, D., Jiang, X., Gygi, S. & Sorkin, A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol. Cell 21, 737–748 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Levkowitz, G. et al. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol. Cell 4, 1029–1040 (1999).

    CAS  PubMed  Google Scholar 

  24. 24

    Frosi, Y. et al. A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation. J. Cell Biol. 189, 557–571 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Joazeiro, C. A. et al. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science 286, 309–312 (1999).

    CAS  PubMed  Google Scholar 

  26. 26

    Oved, S. et al. Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases. J. Biol. Chem. 281, 21640–21651 (2006).

    CAS  PubMed  Google Scholar 

  27. 27

    Mosesson, Y. et al. Endocytosis of receptor tyrosine kinases is driven by monoubiquitylation, not polyubiquitylation. J. Biol. Chem. 278, 21323–21326 (2003).

    CAS  PubMed  Google Scholar 

  28. 28

    Haglund, K. et al. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nature Cell Biol. 5, 461–466 (2003).

    CAS  PubMed  Google Scholar 

  29. 29

    Katzmann, D. J., Odorizzi, G. & Emr, S. D. Receptor downregulation and multivesicular-body sorting. Nature Rev. Mol. Cell Biol. 3, 893–905 (2002).

    CAS  Google Scholar 

  30. 30

    Polo, S. et al. A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 416, 451–455 (2002).

    CAS  PubMed  Google Scholar 

  31. 31

    Roepstorff, K. et al. Differential effects of EGFR ligands on endocytic sorting of the receptor. Traffic 10, 1115–1127 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Abella, J. V. & Park, M. Breakdown of endocytosis in the oncogenic activation of receptor tyrosine kinases. Am. J. Physiol. Endocrinol. Metab. 296, E973–E984 (2009).

    CAS  PubMed  Google Scholar 

  33. 33

    Wang, Y. et al. Regulation of endocytosis via the oxygen-sensing pathway. Nature Med. 15, 319–324 (2009).

    CAS  PubMed  Google Scholar 

  34. 34

    McMahon, H. T. & Gallop, J. L. Membrane curvature and mechanisms of dynamic cell membrane remodelling. Nature 438, 590–596 (2005).

    CAS  Google Scholar 

  35. 35

    Merrifield, C. J., Feldman, M. E., Wan, L. & Almers, W. Imaging actin and dynamin recruitment during invagination of single clathrin-coated pits. Nature Cell Biol. 4, 691–698 (2002).

    CAS  PubMed  Google Scholar 

  36. 36

    Deribe, Y. L. et al. Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6. Sci. Signal. 2, ra84 (2009). Reports that HDAC6 negatively regulates EGFR endocytosis and degradation by controlling the acetylation of α-tubulin. A negative-feedback loop consisting of EGFR-mediated phosphorylation of HDAC6 resulted in reduced deacetylase activity.

    PubMed  Google Scholar 

  37. 37

    Jozic, D. et al. Cbl promotes clustering of endocytic adaptor proteins. Nature Struct. Mol. Biol. 12, 972–979 (2005).

    CAS  Google Scholar 

  38. 38

    Clague, M. J. & Urbe, S. Endocytosis: the DUB version. Trends Cell Biol. 16, 551–559 (2006).

    CAS  PubMed  Google Scholar 

  39. 39

    McCullough, J. et al. Activation of the endosome-associated ubiquitin isopeptidase AMSH by STAM, a component of the multivesicular body-sorting machinery. Curr. Biol. 16, 160–165 (2006).

    CAS  Google Scholar 

  40. 40

    Niendorf, S. et al. Essential role of ubiquitin-specific protease 8 for receptor tyrosine kinase stability and endocytic trafficking in vivo. Mol. Cell Biol. 27, 5029–5039 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Haj, F. G., Verveer, P. J., Squire, A., Neel, B. G. & Bastiaens, P. I. Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science 295, 1708–1711 (2002).

    CAS  PubMed  Google Scholar 

  42. 42

    Eden, E. R., White, I. J., Tsapara, A. & Futter, C. E. Membrane contacts between endosomes and ER provide sites for PTP1B-epidermal growth factor receptor interaction. Nature Cell Biol. 12, 267–272 (2010). Shows that the EGFR–PTP1B interaction occurs at sites of direct contact between the perimeter membrane of multivesicular bodies and the ER. This population of EGFR undergoes ESCRT- mediated sorting within MVBs, and PTP1B activity promotes EGFR sequestration into internal vesicles of the MVB.

    CAS  PubMed  Google Scholar 

  43. 43

    Stuible, M. et al. PTP1B targets the endosomal sorting machinery: dephosphorylation of regulatory sites on the endosomal sorting complex required for transport component STAM2. J. Biol. Chem. 285, 23899–23907 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Mattila, E. et al. Negative regulation of EGFR signalling through integrin-α1β1-mediated activation of protein tyrosine phosphatase TCPTP. Nature Cell Biol. 7, 78–85 (2005).

    CAS  PubMed  Google Scholar 

  45. 45

    Xu, Y., Tan, L. J., Grachtchouk, V., Voorhees, J. J. & Fisher, G. J. Receptor-type protein-tyrosine phosphatase-κ regulates epidermal growth factor receptor function. J. Biol. Chem. 280, 42694–42700 (2005).

    CAS  PubMed  Google Scholar 

  46. 46

    Berset, T. A., Hoier, E. F. & Hajnal, A. The C. elegans homolog of the mammalian tumor suppressor Dep-1/Scc1 inhibits EGFR signaling to regulate binary cell fate decisions. Genes Dev. 19, 1328–1340 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Tarcic, G. et al. An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase controlling EGFR endocytosis. Curr. Biol. 19, 1788–1798 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Ruivenkamp, C. A. et al. Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nature Genet. 31, 295–300 (2002).

    CAS  PubMed  Google Scholar 

  49. 49

    Hoepfner, S. et al. Modulation of receptor recycling and degradation by the endosomal kinesin KIF16B. Cell 121, 437–50 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Carlucci, A. et al. PTPD1 supports receptor stability and mitogenic signaling in bladder cancer cells. J. Biol. Chem. 285, 39260–39270 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888 (1999).

    CAS  PubMed  Google Scholar 

  52. 52

    Biscardi, J. S. et al. c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J. Biol. Chem. 274, 8335–8343 (1999).

    CAS  PubMed  Google Scholar 

  53. 53

    Zwang, Y. & Yarden, Y. p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy. EMBO J. 25, 4195–4206 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Zimmermann, S. & Moelling, K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286, 1741–1744 (1999).

    CAS  Google Scholar 

  55. 55

    Dhillon, A. S., Meikle, S., Yazici, Z., Eulitz, M. & Kolch, W. Regulation of Raf-1 activation and signalling by dephosphorylation. EMBO J. 21, 64–71 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Dougherty, M. K. et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol. Cell 17, 215–224 (2005).

    CAS  PubMed  Google Scholar 

  57. 57

    Cloughesy, T. F. et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 5, e8 (2008). Results of a Phase I clinical trial of rapamycin, an inhibitor of mTOR, in patients with recurrent glioblastoma. Rapamycin treatment led to AKT activation in seven out of 14 patients, presumably owing to loss of negative feedback.

    PubMed  PubMed Central  Google Scholar 

  58. 58

    Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    CAS  PubMed  Google Scholar 

  59. 59

    Li, X. & Carthew, R. W. A microRNA mediates EGF receptor signaling and promotes photoreceptor differentiation in the Drosophila eye. Cell 123, 1267–1277 (2005).

    CAS  Google Scholar 

  60. 60

    Davis, B. N., Hilyard, A. C., Lagna, G. & Hata, A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454, 56–61 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Avraham, R. et al. EGF decreases the abundance of microRNAs that restrain oncogenic transcription factors. Sci. Signal. 3, ra43 (2010). Reported EGF-induced rapid turnover of a group of microRNAs, termed ID-miRs, which regulate transcription of oncogenic transcription factors.

  62. 62

    Herschman, H. R. Primary response genes induced by growth factors and tumor promoters. Annu. Rev. Biochem. 60, 281–319 (1991).

    CAS  PubMed  Google Scholar 

  63. 63

    Amit, I. et al. A module of negative feedback regulators defines growth factor signaling. Nature Genet. 39, 503–512 (2007). Uncovered transcription-dependent feedback loops, which inactivate the early response genes which are collectively upregulated in response to growth factors.

    CAS  Google Scholar 

  64. 64

    Lau, L. F. & Nathans, D. Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc. Proc. Natl Acad. Sci. USA 84, 1182–1186 (1987).

    CAS  PubMed  Google Scholar 

  65. 65

    Hargreaves, D. C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129–145 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Fujita, T., Piuz, I. & Schlegel, W. Negative elongation factor NELF controls transcription of immediate early genes in a stimulus-specific manner. Exp. Cell Res. 315, 274–284 (2009).

    CAS  PubMed  Google Scholar 

  67. 67

    Ramirez-Carrozzi, V. R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019–1031 (2009). References 65–68 demonstrated permissive structures of the promoters of IEGs, which enable rapid induction of transcription, and also uncovered novel mechanisms that suppress IEG expression at the basal state.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Bluthgen, N. et al. A systems biological approach suggests that transcriptional feedback regulation by dual-specificity phosphatase 6 shapes extracellular signal-related kinase activity in RAS-transformed fibroblasts. FEBS J. 276, 1024–1035 (2009).

    PubMed  Google Scholar 

  70. 70

    Carballo, E., Lai, W. S. & Blackshear, P. J. Feedback inhibition of macrophage tumor necrosis factor-α production by tristetraprolin. Science 281, 1001–1005 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Jing, Q. et al. Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120, 623–634 (2005).

    CAS  PubMed  Google Scholar 

  72. 72

    Yilmaz, M. & Christofori, G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 28, 15–33 (2009).

    PubMed  Google Scholar 

  73. 73

    Nieman, M. T., Prudoff, R. S., Johnson, K. R. & Wheelock, M. J. N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J. Cell Biol. 147, 631–644 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Katz, M. et al. A reciprocal tensin-3-cten switch mediates EGF-driven mammary cell migration. Nature Cell Biol. 9, 961–969 (2007).

    CAS  PubMed  Google Scholar 

  75. 75

    Sporn, M. B. & Todaro, G. J. Autocrine secretion and malignant transformation of cells. N. Engl. J. Med. 303, 878–880 (1980).

    CAS  PubMed  Google Scholar 

  76. 76

    Joslin, E. J., Opresko, L. K., Wells, A., Wiley, H. S. & Lauffenburger, D. A. EGF-receptor-mediated mammary epithelial cell migration is driven by sustained ERK signaling from autocrine stimulation. J. Cell Sci. 120, 3688–3699 (2007).

    CAS  PubMed  Google Scholar 

  77. 77

    Goswami, S. et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 65, 5278–5283 (2005).

    CAS  PubMed  Google Scholar 

  78. 78

    Janes, K. A. et al. The response of human epithelial cells to TNF involves an inducible autocrine cascade. Cell 124, 1225–1239 (2006). Shows that challenging cells with multiple extracellular signals induces an autocrine cascade involving the release of, and response to, additional, newly secreted factors.

    CAS  Google Scholar 

  79. 79

    Sheng, Q. et al. An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell 17, 298–310 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Khambata-Ford, S. et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J. Clin. Oncol. 25, 3230–3237 (2007).

    CAS  PubMed  Google Scholar 

  81. 81

    Alon, U. Network motifs: theory and experimental approaches. Nature Rev. Genet. 8, 450–461 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Bruggeman, F. J., Westerhoff, H. V., Hoek, J. B. & Kholodenko, B. N. Modular response analysis of cellular regulatory networks. J. Theor. Biol. 218, 507–520 (2002).

    CAS  PubMed  Google Scholar 

  83. 83

    Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).

    CAS  PubMed  Google Scholar 

  84. 84

    Heasley, L. E. & Johnson, G. L. The β-PDGF receptor induces neuronal differentiation of PC12 cells. Mol. Biol. Cell 3, 545–553 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Nagashima, T. et al. Quantitative transcriptional control of ErbB receptor signaling undergoes graded to biphasic response for cell differentiation. J. Biol. Chem. 282, 4045–4056 (2007).

    CAS  PubMed  Google Scholar 

  86. 86

    Santos, S. D., Verveer, P. J. & Bastiaens, P. I. Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nature Cell Biol. 9, 324–330 (2007). Modular-response analysis was applied to PC-12 cells activated with EGF or NGF. On EGF stimulation, the network exhibited negative feedback, whereas a positive feedback was observed on NGF stimulation.

    CAS  PubMed  Google Scholar 

  87. 87

    Murphy, L. O., Smith, S., Chen, R. H., Fingar, D. C. & Blenis, J. Molecular interpretation of ERK signal duration by immediate early gene products. Nature Cell Biol. 4, 556–564 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Sasagawa, S., Ozaki, Y., Fujita, K. & Kuroda, S. Prediction and validation of the distinct dynamics of transient and sustained ERK activation. Nature Cell Biol. 7, 365–373 (2005).

    CAS  PubMed  Google Scholar 

  89. 89

    von Kriegsheim, A. et al. Cell fate decisions are specified by the dynamic ERK interactome. Nature Cell Biol. 11, 1458–1464 (2009). Using proteomics and GF-stimulated PC-12 cells, this report identified 60 proteins that changed their binding to ERK during differentiation, including effectors of signal duration, ERK localization and crosstalk with the AKT pathway.

    CAS  PubMed  Google Scholar 

  90. 90

    Shankaran, H., Wiley, H. S. & Resat, H. Receptor downregulation and desensitization enhance the information processing ability of signalling receptors. BMC Syst. Biol. 1, 48 (2007).

    PubMed  PubMed Central  Google Scholar 

  91. 91

    Aquino, G. & Endres, R. G. Increased accuracy of ligand sensing by receptor internalization. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 81, 021909 (2010).

    PubMed  Google Scholar 

  92. 92

    Yeung, K. et al. Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 401, 173–177 (1999).

    CAS  PubMed  Google Scholar 

  93. 93

    Corbit, K. C. et al. Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein. J. Biol. Chem. 278, 13061–13068 (2003).

    CAS  PubMed  Google Scholar 

  94. 94

    Bhalla, U. S., Ram, P. T. & Iyengar, R. MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science 297, 1018–1023 (2002).

    CAS  PubMed  Google Scholar 

  95. 95

    Lahav, G. et al. Dynamics of the p53-Mdm2 feedback loop in individual cells. Nature Genet. 36, 147–150 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Kholodenko, B. N. Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. Eur. J. Biochem. 267, 1583–1588 (2000).

    CAS  Google Scholar 

  97. 97

    Dong, C., Waters, S. B., Holt, K. H. & Pessin, J. E. SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signaling pathways. J. Biol. Chem. 271, 6328–6332 (1996).

    Google Scholar 

  98. 98

    Waters, S. B. et al. Insulin and epidermal growth factor receptors regulate distinct pools of Grb2-SOS in the control of Ras activation. J. Biol. Chem. 271, 18224–18230 (1996).

    CAS  PubMed  Google Scholar 

  99. 99

    Shin, S. Y. et al. Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway. J. Cell Sci. 122, 425–435 (2009).

    CAS  PubMed  Google Scholar 

  100. 100

    Shankaran, H. et al. Rapid and sustained nuclear-cytoplasmic ERK oscillations induced by epidermal growth factor. Mol. Syst. Biol. 5, 332 (2009).

    PubMed  PubMed Central  Google Scholar 

  101. 101

    Cohen-Saidon, C., Cohen, A. A., Sigal, A., Liron, Y. & Alon, U. Dynamics and variability of ERK2 response to EGF in individual living cells. Mol. Cell 36, 885–893 (2009). References 99–101 observed oscillatory nucleo- cytoplasmic translocations of ERK in EGF-treated cells, and combined the data with mathematical models. A fold-change response, along with negative-feedback loops (for example, from ERK to SOS) and other mechanisms were found to have crucial roles in generating oscillatory behaviour.

    CAS  Google Scholar 

  102. 102

    Ashall, L. et al. Pulsatile stimulation determines timing and specificity of NF-κB-dependent transcription. Science 324, 242–246 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Barabasi, A. L. & Oltvai, Z. N. Network biology: understanding the cell's functional organization. Nature Rev. Genet. 5, 101–113 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Behar, M., Hao, N., Dohlman, H. G. & Elston, T. C. Mathematical and computational analysis of adaptation via feedback inhibition in signal transduction pathways. Biophys. J. 93, 806–821 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Ma, W., Trusina, A., El-Samad, H., Lim, W. A. & Tang, C. Defining network topologies that can achieve biochemical adaptation. Cell 138, 760–773 (2009). The authors searched all possible three-node enzyme topologies to identify those that could perform adaptation. Only two core topologies emerged: a negative-feedback loop with a buffering node and an incoherent feedforward loop with a proportioner node.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Goentoro, L. & Kirschner, M. W. Evidence that fold-change, and not absolute level, of β-catenin dictates Wnt signaling. Mol. Cell 36, 872–884 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Ekstrand, A. J. et al. Genes for epidermal growth factor receptor, transforming growth factor α, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res. 51, 2164–2172 (1991).

    CAS  PubMed  Google Scholar 

  108. 108

    Slamon, D. J. et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707–712 (1989).

    CAS  Google Scholar 

  109. 109

    Prickett, T. D. et al. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nature Genet. 41, 1127–1132 (2009).

    CAS  PubMed  Google Scholar 

  110. 110

    Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).

    CAS  PubMed  Google Scholar 

  111. 111

    Shtiegman, K. et al. Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling. Oncogene 26, 6968–6978 (2007).

    CAS  PubMed  Google Scholar 

  112. 112

    Tzahar, E. et al. Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network. EMBO J. 17, 5948–5963 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Reddy, C. C., Niyogi, S. K., Wells, A., Wiley, H. S. & Lauffenburger, D. A. Engineering epidermal growth factor for enhanced mitogenic potency. Nature Biotech. 14, 1696–1699 (1996).

    CAS  Google Scholar 

  114. 114

    Schulze, A., Lehmann, K., Jefferies, H. B., McMahon, M. & Downward, J. Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev. 15, 981–994 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Barozzi, C. et al. Relevance of biologic markers in colorectal carcinoma: a comparative study of a broad panel. Cancer 94, 647–657 (2002).

    CAS  PubMed  Google Scholar 

  116. 116

    Yi, W. et al. Expression of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins in human ependymoma relates to tumor location, WHO grade, and patient age. Clin. Neuropathol. 28, 21–27 (2009).

    CAS  PubMed  Google Scholar 

  117. 117

    Ying, H. et al. Mig-6 controls EGFR trafficking and suppresses gliomagenesis. Proc. Natl Acad. Sci. USA 107, 6912–6917 (2010).

    CAS  PubMed  Google Scholar 

  118. 118

    Sargin, B. et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood 110, 1004–1012 (2007).

    CAS  PubMed  Google Scholar 

  119. 119

    Rao, D. S. et al. Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival. J. Clin. Invest. 110, 351–360 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Goentoro, L. A. et al. Quantifying the Gurken morphogen gradient in Drosophila oogenesis. Dev. Cell 11, 263–272 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Yeger-Lotem, E. et al. Network motifs in integrated cellular networks of transcription-regulation and protein-protein interaction. Proc. Natl Acad. Sci. USA 101, 5934–5939 (2004).

    CAS  Google Scholar 

  122. 122

    French, A. R., Sudlow, G. P., Wiley, H. S. & Lauffenburger, D. A. Postendocytic trafficking of epidermal growth factor-receptor complexes is mediated through saturable and specific endosomal interactions. J. Biol. Chem. 269, 15749–15755 (1994).

    CAS  PubMed  Google Scholar 

  123. 123

    Traverse, S. et al. EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Curr. Biol. 4, 694–701 (1994).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R. Milo and members of our laboratory for comments. Our laboratory is supported by research grants from the National Cancer Institute, the Seventh Framework Program (FP7) of the European Commission, the German Research Foundation (DFG), M. Adelson and S. G. Adelson of the Medical Research Foundation, the Kekst Family Institute for Medical Genetics, the Kirk Center for Childhood Cancer and Immunological Disorders, the Women's Health Research Center funded by Bennett-Pritzker Endowment Fund, the Marvelle Koffler Program for Breast Cancer Research and the M.D. Moross Institute for Cancer Research. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair.

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S1 (box)

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Glossary

Extracellular signal-related kinase pathway

A three-tiered kinase module in which the first kinase, RAF, phosphorylates and activates the second kinase, mitogen-activated protein kinase kinase (MEK), which phosphorylates the third kinase, extracellular signal- regulated kinase (ERK), in a two-step, non-processive reaction.

Sub-functionalization

Concurrent partial loss of function of the protein product of duplicated genes, such that collaboration between respective gene products reconstitutes the full set of sub-functions attributed to the original ancestor.

Redundancy

Coexistence of functionally similar components offering an alternative route for signal propagation if one of the components is inactivated.

Feedback loop

A composite two-arm loop in which a protein, X, activates a downstream protein, Y, or transcriptionally induces a gene encoding Y. On activation, Y regulates X (positively or negatively).

Endocytosis

The intake of material from the extracellular matrix or the membrane into vesicles that arise from the inward folding of the plasma membrane.

Binary switching

When a system's output can transit between two states: 'on' and 'off', with (almost) no intermediate states.

Analogue signal

A continuous signal that changes quantitatively in amplitude or concentration.

E3 ubiquitin ligase

A protein that induces the attachment of ubiquitin, a small, highly conserved regulatory protein, to a Lys on a target protein and thus targets specific protein substrates for degradation.

14-3-3 chaperone

Adaptor/scaffold proteins that form homo- and heterodimers and bind, through specialized phosphorylated peptide motifs, to various proteins that are involved in signal transduction and in cell-cycle control.

Immediate early genes

(IEGs). Genes that are induced rapidly and do not require new protein synthesis for their transcription.

RNA polymerase II

(Pol II). An enzyme that catalyses the transcription of DNA to synthesize precursors of mRNA and most known small RNAs.

Histone acetylation

Addition of an acetyl group to Lys amino acids on histone proteins, which renders DNA more accessible to transcription factors, and thus is linked to transcriptional activation.

CpG island

A genomic region that contains a relatively high content of cytosine (C) and guanine (G) dinucleotides (the 'p' refers to the phosphodiester bond linking the two bases). CpG islands are found in many mammalian promoters and unlike scattered CpGs throughout the genome, which are usually hypermethylated, promoter CpG islands are normally hypomethylated.

Epithelial–mesenchymal transition

(EMT). A phenotypic transformation of a highly polarized epithelial sheet of densely packed cells into sparse, motile cells resembling connective tissue cells. This transition involves a series of molecular switches, which are dependent on newly induced mRNAs and microRNAs.

Hysteresis

A mode in which it is easier to maintain the system in its 'on' state than to toggle the system between 'on' and 'off'.

Network motifs

A pattern of interactions that recurs in cellular networks significantly more often than in randomized networks.

Pheochromocytoma

An adrenal gland tumour that originates from neural crest cells.

Feedforward loop

A regulatory pattern in which a stimulus (X) feeds into a response (Y) via more than one route: directly into Y or indirectly via Z (which interacts with Y). In a coherent feedforward loop the sign of the leg from X to Y equals the summation of the alternative leg (X-to-Z-to-Y). In any other case, the design is referred to as an incoherent feedforward loop.

Scale-free network

A non-uniform network whose connectivity (the number of edges of each of the nodes) follows a power law. Scale-free biological networks are mostly comprised of nodes with one to two edges, and several highly linked hubs with six or more edges.

Network hubs

Richly linked nodes of the network that account for most of the vulnerability of scale-free networks, as damage to one of the hubs of a network can break it up into segregated sub-graphs.

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Avraham, R., Yarden, Y. Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat Rev Mol Cell Biol 12, 104–117 (2011). https://doi.org/10.1038/nrm3048

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