Scaffolding protein Grb2-associated binder 1 sustains epidermal growth factor-induced mitogenic and survival signaling by multiple positive feedback loops

J Biol Chem. 2006 Jul 21;281(29):19925-38. doi: 10.1074/jbc.M600482200. Epub 2006 May 9.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Carcinoma, Squamous Cell
  • Cell Division / drug effects*
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects*
  • Epidermal Growth Factor / pharmacology*
  • Feedback
  • Guanosine Diphosphate / metabolism
  • Guanosine Triphosphate / metabolism
  • Humans
  • Models, Biological
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • GAB1 protein, human
  • Guanosine Diphosphate
  • Epidermal Growth Factor
  • Guanosine Triphosphate