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Transactivation joins multiple tracks to the ERK/MAPK cascade

Nature Reviews Molecular Cell Biology volume 4, pages 651–657 (2003)Cite this article

Abstract

Many agonists of G-protein-coupled receptors (GPCRs) can stimulate receptor tyrosine kinases and the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. A 'transactivation' mechanism, which links these events in one signalling chain, inspired many researchers, but inevitably raised new questions. A 'multi-track' model for GPCR signalling to the ERK/MAPK pathway might resolve some of the puzzles in the transactivation field.

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Figure 1: Signal transduction of GPCRs and RTKs.
Figure 2: The 'triple-membrane-passing-signalling' model.
Figure 3: Alternative mechanisms for GPCR–RTK transactivation.
Figure 4: Activation of ERK/MAPK through parallel tracks.

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References

  1. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000).

    CAS  PubMed  Google Scholar 

  2. Pierce, K. L., Premont, R. T. & Lefkowitz, R. J. Seven-transmembrane receptors. Nature Rev. Mol. Cell Biol. 3, 639–650 (2002).

    Article  CAS  Google Scholar 

  3. Faure, M., Voyno-Yasenetskaya, T. A. & Bourne, H. R. cAMP and βγ subunits of heterotrimeric G proteins stimulate the mitogen-activated protein kinase pathway in COS-7 cells. J. Biol. Chem. 269, 7851–7854 (1994).

    CAS  PubMed  Google Scholar 

  4. Knebel, A., Rahmsdorf, H. J., Ullrich, A. & Herrlich, P. Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents. EMBO J. 15, 5314–5325 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Goldkorn, T., Balaban, N., Shannon, M. & Matsukuma, K. EGF receptor phosphorylation is affected by ionizing radiation. Biochim. Biophys. Acta 1358, 289–299 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Daub, H., Weiss, F. U., Wallasch, C. & Ullrich, A. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379, 557–560 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Gutkind, J. S. Regulation of mitogen-activated protein kinase signaling networks by G protein-coupled receptors. Sci. STKE 2000, re1 (2000).

  8. Kranenburg, O. & Moolenaar, W. H. Ras-MAP kinase signaling by lysophosphatidic acid and other G protein-coupled receptor agonists. Oncogene 20, 1540–1546 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Pierce, K. L., Luttrell, L. M. & Lefkowitz, R. J. New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades. Oncogene 20, 1532–1539 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Gschwind, A., Zwick, E., Prenzel, N., Leserer, M. & Ullrich, A. Cell communication networks: epidermal growth factor receptor transactivation as the paradigm for interreceptor signal transmission. Oncogene 20, 1594–1600 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Lowes, V. L., Ip, N. Y. & Wong, Y. H. Integration of signals from receptor tyrosine kinases and G protein-coupled receptors. Neurosignals 11, 5 19 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Carpenter, G. EGF receptor tra–nsactivation mediated by the proteolytic production of EGF-like agonists. Sci. STKE 2000, pe1 (2000).

  13. Daub, H., Wallasch, C., Lankenau, A., Herrlich, A. & Ullrich, A. Signal characteristics of G protein-transactivated EGF receptor. EMBO J. 16, 7032–7044 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Asakura, M. et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nature Med. 8, 35–40 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Gschwind, A., Prenzel, N. & Ullrich, A. Lysophosphatidic acid-induced squamous cell carcinoma cell proliferation and motility involves epidermal growth factor receptor signal transactivation. Cancer Res. 62, 6329–6336 (2002).

    CAS  PubMed  Google Scholar 

  16. Pai, R. et al. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nature Med. 8, 289–293 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Pierce, K. L. et al. Epidermal growth factor (EGF) receptor-dependent ERK activation by G-protein-coupled receptors: a co-culture system for identifying intermediates upstream and downstream of heparin-binding EGF shedding. J. Biol. Chem. 276, 23155–23160 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Fujiyama, S. et al. Angiotensin AT(1) and AT(2) receptors differentially regulate angiopoietin-2 and vascular endothelial growth factor expression and angiogenesis by modulating heparin binding-epidermal growth factor (EGF)-mediated EGF receptor transactivation. Circ. Res. 88, 22–29 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Wallasch, C. et al. Helicobacter pylori-stimulated EGF receptor transactivation requires metalloprotease cleavage of HB-EGF. Biochem. Biophys. Res. Commun. 295, 695–701 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Dent, P. et al. Radiation-induced release of transforming growth factor α activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol. Biol. Cell 10, 2493–2506 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Luttrell, L. M. et al. Role of c-Src tyrosine kinase in G protein-coupled receptor- and Gβγ subunit-mediated activation of mitogen-activated protein kinases. J. Biol. Chem. 271, 19443–19450 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. Keely, S. J., Calandrella, S. O. & Barrett, K. E. Carbachol-stimulated transactivation of epidermal growth factor receptor and mitogen-activated protein kinase in T(84) cells is mediated by intracellular Ca2+, PYK-2, and p60(src). J. Biol. Chem. 275, 12619–12625 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Heldin, C. H., Eriksson, U. & Ostman, A. New members of the platelet-derived growth factor family of mitogens. Arch. Biochem. Biophys. 398, 284–290 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Rao, G. N., Delafontaine, P. & Runge, M. S. Thrombin stimulates phosphorylation of insulin-like growth factor-1 receptor, insulin receptor substrate-1, and phospholipase C-γ-1 in rat aortic smooth muscle cells. J. Biol. Chem. 270, 27871–27875 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Lee, F. S. & Chao, M. V. Activation of Trk neurotrophin receptors in the absence of neurotrophins. Proc. Natl Acad. Sci. USA. 98, 3555–3560 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Peng, H. et al. Integrative nuclear FGFR1 signaling (INFS) pathway mediates activation of the tyrosine hydroxylase gene by angiotensin II, depolarization and protein kinase C. J. Neurochem. 81, 506–524 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Östman, A. & Böhmer, F. D. Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell. Biol. 11, 258–266 (2001).

    Article  PubMed  Google Scholar 

  30. Meng, T. C., Fukada, T. & Tonks, N. K. Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol. Cell 9, 387–399 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K. & Finkel, T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296–299 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Rhee, S. G., Bae, Y. S., Lee, S. R. & Kwon, J. Hydrogen peroxide: a key messenger that modulates protein phosphorylation through cysteine oxidation. Sci. STKE 2000, pe1 (2000).

  33. Chen, Q., Olashaw, N. & Wu, J. Participation of reactive oxygen species in the lysophosphatidic acid-stimulated mitogen-activated protein kinase kinase activation pathway. J. Biol. Chem. 270, 28499–28502 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Patterson, C. et al. Stimulation of a vascular smooth muscle cell NAD(P)H oxidase by thrombin. Evidence that p47(phox) may participate in forming this oxidase in vitro and in vivo. J. Biol. Chem. 274, 19814–19822 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Liebmann, C. Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity. Cell. Signal. 13, 777–785 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Lopez-Ilasaca, M., Crespo, P., Pellici, P. G., Gutkind, J. S. & Wetzker, R. Linkage of G protein-coupled receptors to the MAPK signaling pathway through PI 3-kinase γ. Science 275, 394–397 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Schmitt, J. M. & Stork, P. J. β2-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein rap1 and the serine/threonine kinase B-Raf. J. Biol. Chem. 275, 25342–25350 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Andreev, J. et al. Src and Pyk2 mediate G-protein-coupled receptor activation of epidermal growth factor receptor (EGFR) but are not required for coupling to the mitogen-activated protein (MAP) kinase signaling cascade. J. Biol. Chem. 276, 20130–20135 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Yart, A. et al. A function for phosphoinositide 3-kinase β lipid products in coupling βγ to Ras activation in response to lysophosphatidic acid. J. Biol. Chem. 277, 21167–21178 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Della Rocca, G. J., Maudsley, S., Daaka, Y., Lefkowitz, R. J. & Luttrell, L. M. Pleiotropic coupling of G protein-coupled receptors to the mitogen-activated protein kinase cascade. Role of focal adhesions and receptor tyrosine kinases. J. Biol. Chem. 274, 13978–13984 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Adomeit, A. et al. Bradykinin B(2) receptor-mediated mitogen-activated protein kinase activation in COS-7 cells requires dual signaling via both protein kinase C pathway and epidermal growth factor receptor transactivation. Mol. Cell. Biol. 19, 5289–5297 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sabri, A., Short, J., Guo, J. & Steinberg, S. F. Protease-activated receptor-1-mediated DNA synthesis in cardiac fibroblast is via epidermal growth factor receptor transactivation: distinct PAR-1 signaling pathways in cardiac fibroblasts and cardiomyocytes. Circ. Res. 91, 532–539 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Brummer, T., Shaw, P. E., Reth, M. & Misawa, Y. Inducible gene deletion reveals different roles for B-Raf and Raf-1 in B-cell antigen receptor signalling. EMBO J. 21, 5611–5622 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hanke, S., Nürnberg, B., Groll, D. H. & Liebmann, C. Cross talk between β-adrenergic and bradykinin B(2) receptors results in cooperative regulation of cyclic AMP accumulation and mitogen-activated protein kinase activity. Mol. Cell. Biol. 21, 8452–8460 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sabri, A. et al. Mechanisms of protease-activated receptor-4 actions in cardiomyocytes: role of Src tyrosine kinase. J. Biol. Chem. 278, 11714–11720 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Siekhaus, D. E. & Drubin, D. G. Spontaneous receptor-independent heterotrimeric G-protein signalling in an RGS mutant. Nature Cell Biol. 5, 231–235 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Wennström, S. & Downward, J. Role of phosphoinositide 3-kinase in activation of ras and mitogen-activated protein kinase by epidermal growth factor. Mol. Cell Biol. 19, 4279–4288 (1999).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Rubio, I. & Wetzker, R. A permissive function of phosphoinositide 3-kinase in Ras activation mediated by inhibition of GTPase-activating proteins. Curr. Biol. 10, 1225–1228 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Piiper, A. et al. Cholecystokinin stimulates extracellular signal-regulated kinase through activation of the epidermal growth factor receptor, Yes, and protein kinase C. Signal amplification at the level of Raf by activation of protein kinase Cε. J. Biol. Chem. 278, 7065–7072 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Thuringer, D., Maulon, L. & Frelin, C. Rapid transactivation of the vascular endothelial growth factor receptor KDR/Flk-1 by the bradykinin B2 receptor contributes to endothelial nitric-oxide synthase activation in cardiac capillary endothelial cells. J. Biol. Chem. 277, 2028–2032 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Gilmore, A. P. et al. Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor. J. Biol. Chem. 277, 27643–27650 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Zwick, E. et al. Critical role of calcium-dependent epidermal growth factor receptor transactivation in PC12 cell membrane depolarization and bradykinin signaling. J. Biol. Chem. 272, 24767–24770 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Moro, L. et al. Integrins induce activation of EGF receptor: role in MAP kinase induction and adhesion-dependent cell survival. EMBO J. 17, 6622–6632 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen, N. et al. Transactivation of the epidermal growth factor receptor is involved in 12-O-tetradecanoylphorbol-13-acetate-induced signal transduction. J. Biol. Chem. 276, 46722–46728 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Delafontaine, P., Anwar, A., Lou, H. & Ku, L. G-protein coupled and tyrosine kinase receptors: evidence that activation of the insulin-like growth factor I receptor is required for thrombin-induced mitogenesis of rat aortic smooth muscle cells. J. Clin. Invest. 97, 139–145 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Herrlich, A. et al. Ligand-independent activation of platelet-derived growth factor receptor is a necessary intermediate in lysophosphatidic acid-stimulated mitogenic activity in L cells. Proc. Natl Acad. Sci. USA 95, 8985–8990 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Linseman, D. A., Benjamin, C. W. & Jones, D. A. Convergence of angiotensin II and platelet-derived growth factor receptor signaling cascades in vascular smooth muscle cells. J. Biol. Chem. 270, 12563–12568 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Zhang, Y., Jiang, J., Black, R. A., Baumann, G. & Frank, S. J. Tumor necrosis factor-α converting enzyme (TACE) is a growth hormone binding protein (GHBP) sheddase: the metalloprotease TACE/ADAM-17 is critical for (PMA-induced) GH receptor proteolysis and GHBP generation. Endocrinology 141, 4342–4348 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Yan, Y., Shirakabe, K. & Werb, Z. The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors. J. Cell. Biol. 158, 221–226 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lemjabbar, H. & Basbaum, C. Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nature Med. 8, 41–46 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Gschwind, A. Hart, S. Fischer, O. M. & Ullrich, A. TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells. EMBO J. 22, 2411–2421 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Salmeen et al. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 423, 769–773 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. van Montfort, R. L., Congreve, M., Tisi, D., Carr, R. & Jhoti, H. Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. Nature 423, 773–777 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank several colleagues who made data available ahead of press. We gratefully acknowledge critical reading of this manuscript by I. Rubio, C. Liebmann, A. Östman, S. Hsieh and A. Uecker. Work in the authors' laboratories is supported by grants from the Deutsche Forschungsgemeinschaft, Human Frontiers in Science (to R.W.), the European Union (to R.W and F.D.B.) and Deutsche Krebshilfe (to F.D.B.).

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Wetzker, R., Böhmer, FD. Transactivation joins multiple tracks to the ERK/MAPK cascade. Nat Rev Mol Cell Biol 4, 651–657 (2003). https://doi.org/10.1038/nrm1173

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