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AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade

Nature Cell Biology volume 12, pages 1242–1249 (2010)Cite this article

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Abstract

Mitogen-activated protein kinase (MAPK) cascades propagate a variety of cellular activities1. Processive relay of signals through RAF–MEK–ERK modulates cell growth and proliferation2,3. Signalling through this ERK cascade is frequently amplified in cancers, and drugs such as sorafenib (which is prescribed to treat renal and hepatic carcinomas) and PLX4720 (which targets melanomas) inhibit RAF kinases4,5. Natural factors that influence ERK1/2 signalling include the second messenger cyclic AMP6,7. However, the mechanisms underlying this cascade have been difficult to elucidate. We demonstrate that the A-kinase-anchoring protein AKAP-Lbc and the scaffolding protein kinase suppressor of Ras (KSR-1) form the core of a signalling network that efficiently relay signals from RAF, through MEK, and on to ERK1/2. AKAP-Lbc functions as an enhancer of ERK signalling by securing RAF in the vicinity of MEK1 and synchronizing protein kinase A (PKA)-mediated phosphorylation of Ser 838 on KSR-1. This offers mechanistic insight into cAMP-responsive control of ERK signalling events.

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Figure 1: Characterization of AKAP-Lbc–KSR-1 interactions.
Figure 2: AKAP-Lbc anchors RAF.
Figure 3: AKAP-Lbc enhances signal relay through the ERK kinase cascade.
Figure 4: PKA phosphorylation of KSR-1.
Figure 5: Phosphorylation of KSR-1 on Ser 838 controls ERK1/2 signalling.

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References

  1. Raman, M., Chen, W. & Cobb, M. H. Differential regulation and properties of MAPKs. Oncogene 26, 3100–3112 (2007).

    CAS  PubMed  Google Scholar 

  2. Mansour, S. J. et al. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265, 966–970 (1994).

    Article  CAS  Google Scholar 

  3. Wan, P. T. et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855–867 (2004).

    Article  CAS  Google Scholar 

  4. Wilhelm, S. M. et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther. 7, 3129–3140 (2008).

    Article  CAS  Google Scholar 

  5. Tsai, J. et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl Acad. Sci. USA 105, 3041–3046 (2008).

    Article  CAS  Google Scholar 

  6. Wu, J. et al. Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3', 5'-monophosphate. Science 262, 1065–1072 (1993).

    Article  CAS  Google Scholar 

  7. Cook, S. J. & McCormick, F. Inhibition by cAMP of ras-dependent activation of raf. Science 262, 1069–1072 (1993).

    Article  CAS  Google Scholar 

  8. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 3, 11–22 (2003).

    Article  CAS  Google Scholar 

  9. Stork, P. J. & Schmitt, J. M. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol. 12, 258–266 (2002).

    Article  CAS  Google Scholar 

  10. Bos, J. L. Epac: a new cAMP target and new avenues in cAMP research. Nat. Rev. Mol. Cell Biol. 4, 733–738 (2003).

    Article  CAS  Google Scholar 

  11. Dumaz, N. & Marais, R. Integrating signals between cAMP and the RAS/RAF/MEK/ERK signalling pathways. FEBS J. 272, 3491–3504 (2005).

    Article  CAS  Google Scholar 

  12. Dodge-Kafka, K. L. et al. The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 437, 574–578 (2005).

    Article  CAS  Google Scholar 

  13. Diviani, D., Soderling, J. & Scott, J. D. AKAP-Lbc anchors protein kinase A and nucleates Gα12-selective Rho-mediated stress fiber formation. J. Biol. Chem. 276, 44247–44257 (2001).

    Article  CAS  Google Scholar 

  14. Carnegie, G. K., Smith, F. D., McConnachie, G., Langeberg, L. K. & Scott, J. D. AKAP-Lbc nucleates a protein kinase D activation scaffold. Mol. Cell 15, 889–899 (2004).

    Article  CAS  Google Scholar 

  15. Therrien, M., Michaud, N. R., Rubin, G. M. & Morrison, D. K. KSR modulates signal propagation within the MAPK cascade. Genes Dev. 10, 2684–2695 (1996).

    Article  CAS  Google Scholar 

  16. Harvey, C. D. et al. A genetically encoded fluorescent sensor of ERK activity. Proc. Natl Acad. Sci. USA 105, 19264–19269 (2008).

    Article  CAS  Google Scholar 

  17. Leevers, S. J., Paterson, H. F. & Marshall, C. J. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 369, 411–414 (1994).

    Article  CAS  Google Scholar 

  18. Muller, J., Ory, S., Copeland, T., Piwnica-Worms, H. & Morrison, D. K. C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Mol. Cell 8, 983–993 (2001).

    Article  CAS  Google Scholar 

  19. Scott, J. D. & Pawson, T. Cell signaling in space and time: where proteins come together and when they're apart. Science 326, 1220–1224 (2009).

    Article  CAS  Google Scholar 

  20. Morrison, D. K. & Davis, R. J. Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu. Rev. Cell Dev. Biol. 19, 91–118 (2003).

    Article  CAS  Google Scholar 

  21. Bhattacharyya, R. P., Remenyi, A., Yeh, B. J. & Lim, W. A. Domains, motifs and scaffolds: the role of modular interactions in the evolution and wiring of cell signaling circuits. Annu. Rev. Biochem. 75, 655–680 (2006).

    Article  CAS  Google Scholar 

  22. Matheny, S. A. et al. Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature 427, 256–260 (2004).

    Article  CAS  Google Scholar 

  23. Smith, F. D., Langeberg, L. K. & Scott, J. D. The where's and when's of kinase anchoring. Trends Biochem. Sci. 31, 316–323 (2006).

    Article  CAS  Google Scholar 

  24. Nguyen, A. et al. Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo. Mol. Cell Biol. 22, 3035–3045 (2002).

    Article  CAS  Google Scholar 

  25. Dumaz, N. & Marais, R. Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. J. Biol. Chem. 278, 29819–29823 (2003).

    Article  CAS  Google Scholar 

  26. Dhillon, A. S. et al. Cyclic AMP-dependent kinase regulates Raf-1 kinase mainly by phosphorylation of serine 259. Mol. Cell Biol. 22, 3237–3246 (2002).

    Article  CAS  Google Scholar 

  27. Jin, J. et al. Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Curr. Biol. 14, 1436–1450 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors wish to thank members of the Scott lab for critical evaluation of this work, M. Milnes for assistance in preparation of the manuscript, and K.L. Guan (UCSD) and R. Marais (ICR, London) for plasmids encoding KSR-1 and Flag–B-Raf. J.D.S. was supported in part by HL088366.

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Authors and Affiliations

  1. Department of Pharmacology, Howard Hughes Medical Institute, University of Washington School of Medicine, 1959 Pacific Avenue NE, Seattle, 98195, WA, USA

    F. Donelson Smith, Lorene K. Langeberg & John D. Scott

  2. Howard Hughes Medical Institute, University of Massachusetts, Program in Molecular Medicine, 373 Plantation Street, Worcester, 01605, MA, USA

    Cristina Cellurale & Roger J. Davis

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 1084-600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Tony Pawson

  4. Laboratory of Cell and Developmental Signalling, NCI-Frederick, Building 560, Room 22-90B, Frederick, 21702, MD, USA

    Deborah K. Morrison

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Contributions

F.D.S and L.K.L performed all experiments. F.D.S., L.K.L and J.D.S. designed and analysed all experiments and wrote the manuscript. T.P. performed mass spectrometry. D.K.M. generated KSR-1 rescue MEFs. R.J.D. and C.C. developed and characterized the FRET reporters.

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Correspondence to John D. Scott.

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The authors declare no competing financial interests.

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Smith, F., Langeberg, L., Cellurale, C. et al. AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade. Nat Cell Biol 12, 1242–1249 (2010). https://doi.org/10.1038/ncb2130

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