The Docking Protein Gab1 is the Primary Mediator of EGF-stimulated Activation of the PI-3K/Akt Cell Survival Pathway

Overview

Journal BMC Biol

Publisher Biomed Central

Specialty Biology

Date 2004 Nov 20

PMID 15550174

Citations 86

Authors

Dawn R Mattoon

Betty Lamothe

Irit Lax

Joseph Schlessinger

Affiliations

Soon will be listed here.

Abstract

Background: Gab1 is a docking protein that recruits phosphatidylinositol-3 kinase (PI-3 kinase) and other effector proteins in response to the activation of many receptor tyrosine kinases (RTKs). As the autophosphorylation sites on EGF-receptor (EGFR) do not include canonical PI-3 kinase binding sites, it is thought that EGF stimulation of PI-3 kinase and its downstream effector Akt is mediated by an indirect mechanism.

Results: We used fibroblasts isolated from Gab1-/- mouse embryos to explore the mechanism of EGF stimulation of the PI-3 kinase/Akt anti-apoptotic cell signaling pathway. We demonstrate that Gab1 is essential for EGF stimulation of PI-3 kinase and Akt in these cells and that these responses are mediated by complex formation between p85, the regulatory subunit of PI-3 kinase, and three canonical tyrosine phosphorylation sites on Gab1. Furthermore, complex formation between Gab1 and the protein tyrosine phosphatase Shp2 negatively regulates Gab1 mediated PI-3 kinase and Akt activation following EGF-receptor stimulation. We also demonstrate that tyrosine phosphorylation of ErbB3 may lead to recruitment and activation of PI-3 kinase and Akt in Gab1-/- MEFs.

Conclusions: The primary mechanism of EGF-induced stimulation of the PI-3 kinase/Akt anti-apoptotic pathway occurs via the docking protein Gab1. However, in cells expressing ErbB3, EGF and neuroregulin can stimulate PI-3 kinase and Akt activation in a Gab1-dependent or Gab1-independent manner.

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References

Shi Z, Yu D, Park M, Marshall M, Feng G . Molecular mechanism for the Shp-2 tyrosine phosphatase function in promoting growth factor stimulation of Erk activity. Mol Cell Biol. 2000; 20(5):1526-36. PMC: 85329. DOI: 10.1128/MCB.20.5.1526-1536.2000. View

Rodrigues G, Falasca M, Zhang Z, Ong S, Schlessinger J . A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling. Mol Cell Biol. 2000; 20(4):1448-59. PMC: 85307. DOI: 10.1128/MCB.20.4.1448-1459.2000. View

Lock L, Royal I, Naujokas M, Park M . Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases. J Biol Chem. 2000; 275(40):31536-45. DOI: 10.1074/jbc.M003597200. View

Yart A, Laffargue M, Mayeux P, Chretien S, Peres C, Tonks N . A critical role for phosphoinositide 3-kinase upstream of Gab1 and SHP2 in the activation of ras and mitogen-activated protein kinases by epidermal growth factor. J Biol Chem. 2001; 276(12):8856-64. DOI: 10.1074/jbc.M006966200. View

Saxton T, Cheng A, Ong S, Lu Y, Sakai R, CROSS J . Gene dosage-dependent functions for phosphotyrosine-Grb2 signaling during mammalian tissue morphogenesis. Curr Biol. 2001; 11(9):662-70. DOI: 10.1016/s0960-9822(01)00198-1. View

Ong S, Hadari Y, Gotoh N, Guy G, Schlessinger J, Lax I . Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc Natl Acad Sci U S A. 2001; 98(11):6074-9. PMC: 33424. DOI: 10.1073/pnas.111114298. View

Cunnick J, Mei L, Doupnik C, Wu J . Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2. J Biol Chem. 2001; 276(26):24380-7. DOI: 10.1074/jbc.M010275200. View

Liu Y, Rohrschneider L . The gift of Gab. FEBS Lett. 2002; 515(1-3):1-7. DOI: 10.1016/s0014-5793(02)02425-0. View

Zhang S, Tsiaras W, Araki T, Wen G, Minichiello L, Klein R . Receptor-specific regulation of phosphatidylinositol 3'-kinase activation by the protein tyrosine phosphatase Shp2. Mol Cell Biol. 2002; 22(12):4062-72. PMC: 133866. DOI: 10.1128/MCB.22.12.4062-4072.2002. View

10.

Prigent S, Gullick W . Identification of c-erbB-3 binding sites for phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J. 1994; 13(12):2831-41. PMC: 395164. DOI: 10.1002/j.1460-2075.1994.tb06577.x. View

11.

Soltoff S, Carraway 3rd K, Prigent S, Gullick W, Cantley L . ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol. 1994; 14(6):3550-8. PMC: 358722. DOI: 10.1128/mcb.14.6.3550-3558.1994. View

12.

Yu C, Liu Z, Cantley L . ERK negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase. J Biol Chem. 2002; 277(22):19382-8. DOI: 10.1074/jbc.M200732200. View

13.

Schlessinger J . Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell. 2002; 110(6):669-72. DOI: 10.1016/s0092-8674(02)00966-2. View

14.

Yamasaki S, Nishida K, Yoshida Y, Itoh M, Hibi M, Hirano T . Gab1 is required for EGF receptor signaling and the transformation by activated ErbB2. Oncogene. 2003; 22(10):1546-56. DOI: 10.1038/sj.onc.1206284. View

15.

Jorissen R, Walker F, Pouliot N, Garrett T, Ward C, Burgess A . Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003; 284(1):31-53. DOI: 10.1016/s0014-4827(02)00098-8. View

16.

Lamothe B, Yamada M, Schaeper U, Birchmeier W, Lax I, Schlessinger J . The docking protein Gab1 is an essential component of an indirect mechanism for fibroblast growth factor stimulation of the phosphatidylinositol 3-kinase/Akt antiapoptotic pathway. Mol Cell Biol. 2004; 24(13):5657-66. PMC: 480891. DOI: 10.1128/MCB.24.13.5657-5666.2004. View

17.

Whitman M, Kaplan D, Schaffhausen B, Cantley L, Roberts T . Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature. 1985; 315(6016):239-42. DOI: 10.1038/315239a0. View

18.

Bjorge J, Chan T, Antczak M, Kung H, Fujita D . Activated type I phosphatidylinositol kinase is associated with the epidermal growth factor (EGF) receptor following EGF stimulation. Proc Natl Acad Sci U S A. 1990; 87(10):3816-20. PMC: 53994. DOI: 10.1073/pnas.87.10.3816. View

19.

Batzer A, Rotin D, Urena J, Skolnik E, Schlessinger J . Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Mol Cell Biol. 1994; 14(8):5192-201. PMC: 359038. DOI: 10.1128/mcb.14.8.5192-5201.1994. View

20.

Hellyer N, Kim H, Greaves C, Sierke S, Koland J . Cloning of the rat ErbB3 cDNA and characterization of the recombinant protein. Gene. 1995; 165(2):279-84. DOI: 10.1016/0378-1119(95)00436-a. View