Abstract
Grb2-associated binder 1 (GAB1) is a scaffold protein involved in numerous interactions that propagate signaling by growth factor and cytokine receptors. Here we explore in silico and validate in vivo the role of GAB1 in the control of mitogenic (Ras/MAPK) and survival (phosphatidylinositol 3-kinase (PI3K)/Akt) signaling stimulated by epidermal growth factor (EGF). We built a comprehensive mechanistic model that allows for reliable predictions of temporal patterns of cellular responses to EGF under diverse perturbations, including different EGF doses, GAB1 suppression, expression of mutant proteins, and pharmacological inhibitors. We show that the temporal dynamics of GAB1 tyrosine phosphorylation is significantly controlled by positive GAB1-PI3K feedback and negative MAPK-GAB1 feedback. Our experimental and computational results demonstrate that the essential function of GAB1 is to enhance PI3K/Akt activation and extend the duration of Ras/MAPK signaling. By amplifying positive interactions between survival and mitogenic pathways, GAB1 plays the critical role in cell proliferation and tumorigenesis.
Highlights
JULY 21, 2006 VOLUME 281 NUMBER 29 dimerization of EGFR monomers and activates their intrinsic tyrosine kinase activity
All members of Grb2associated binder (GAB) family contain the N-terminal pleckstrin homology (PH) domain that mediates membrane targeting, several proline-rich motifs serving as binding sites for SH3 domain-containing proteins, such as Grb2 and the soluble tyrosine kinase Src, and multiple tyrosine phosphorylation sites that recruit a variety of effectors, including phosphatidylinositol 3-kinase (PI3K), RasGAP, and JOURNAL OF BIOLOGICAL CHEMISTRY 19925
This positive effect is related to the formation of the GAB11⁄7SHP2 complexes and subsequent dephosphorylation of the docking sites on Grb2-associated binder 1 (GAB1) involved in RasGAP binding [27], which results in an elevation of active Ras into its active GTP-bound form (Ras-GTP)
Summary
JULY 21, 2006 VOLUME 281 NUMBER 29 dimerization of EGFR monomers and activates their intrinsic tyrosine kinase activity. EGFR-mediated phosphorylation and activation of multiple binding partners initiates signal propagation through a number of interacting branches, including the mitogen-activated protein kinase (MAPK) cascade and the phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway (see Fig. 1). All members of GAB family contain the N-terminal pleckstrin homology (PH) domain that mediates membrane targeting, several proline-rich motifs serving as binding sites for SH3 domain-containing proteins, such as Grb and the soluble tyrosine kinase Src, and multiple tyrosine phosphorylation sites that recruit a variety of effectors, including PI3K, RasGAP, and JOURNAL OF BIOLOGICAL CHEMISTRY 19925. Protein phosphatase SHP2, which binds to GAB1, was reported to be a positive regulator of the MAPK pathway (20, 22, 24 –27) This positive effect is related to the formation of the GAB11⁄7SHP2 complexes and subsequent dephosphorylation of the docking sites on GAB1 involved in RasGAP binding [27], which results in an elevation of active Ras-GTP
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