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Sci. STKE, 15 February 2000
Vol. 2000, Issue 19, p. tw4
[DOI: 10.1126/stke.2000.19.tw4]

EDITORS' CHOICE

Receptors New Adaptor Protein for EGF Receptor

The epidermal growth factor receptor (EGFR) can stimulate phosphatidylinositol 3-kinase (PI3K) even though it lacks a direct binding site for the enzyme. Although the EGFR could accomplish this by forming a heterodimer with another family member, ErbB3, which does bind to PI3K, Rodrigues et al. now show that the EGFR can activate PI3K through an adaptor protein called Grb 2-associated protein 1 (Gab1). Gab1 binds directly to two tyrosine residues in the EGFR tail and overexpression of Gab1 increased EGF-induced stimulation of mitogen-activated protein kinase (MAPK) and Jun kinase (JNK) in a PI3K-dependent manner. In addition, PI3K appears to be an upstream activator of Gab1. Like many other adaptor proteins, Gab1 has a pleckstrin homology (PH) domain that binds to phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P3], a membrane lipid that is generated by PI3K. Blocking PH domain-mediated translocation of Gab1 to the plasma membrane inhibited EGF-induced activation of MAPK and JNK. The authors propose a positive feedback model in which Gab1 is recruited to, and becomes phosphorylated by, the activated EGFR. Gab1 could then bind to and activate PI3K. Increased production of PI(3,4,5)P3 could further promote membrane recruitment of Gab1 and enhance PI3K signaling through the EGFR. It is not yet clear how this loop might be terminated.

Rodrigues, G.A., Falasca, M., Zhang, Z., Ong, S.H., and Schlessinger, J. (2000) A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling. Mol. Cell. Biol. 20: 1448-1459. [Abstract] [Full Text]

Citation: New Adaptor Protein for EGF Receptor. Sci. STKE 2000, tw4 (2000).


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