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 May 22;98(11):6074-9. doi: 10.1073/pnas.111114298. Epub 2001 May 15.

Abstract

The docking protein FRS2 is a major downstream effector that links fibroblast growth factor (FGF) and nerve growth factor receptors with the Ras/mitogen-activated protein kinase signaling cascade. In this report, we demonstrate that FRS2 also plays a pivotal role in FGF-induced recruitment and activation of phosphatidylinositol 3-kinase (PI3-kinase). We demonstrate that tyrosine phosphorylation of FRS2alpha leads to Grb2-mediated complex formation with the docking protein Gab1 and its tyrosine phosphorylation, resulting in the recruitment and activation of PI3-kinase. Furthermore, Grb2 bound to tyrosine-phosphorylated FRS2 through its SH2 domain interacts primarily via its carboxyl-terminal SH3 domain with a proline-rich region in Gab1 and via its amino-terminal SH3 domain with the nucleotide exchange factor Sos1. Assembly of FRS2alpha:Grb2:Gab1 complex induced by FGF stimulation results in activation of PI3-kinase and downstream effector proteins such as the S/T kinase Akt, whose cellular localization and activity are regulated by products of PI3-kinase. These experiments reveal a unique mechanism for generation of signal diversity by growth factor-induced coordinated assembly of a multidocking protein complex that can activate the Ras/mitogen-activated protein kinase cascade to induce cell proliferation and differentiation, and PI3-kinase to activate a mediator of a cell survival pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing*
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Enzyme Activation
  • Fibroblast Growth Factors / metabolism
  • Fibroblast Growth Factors / pharmacology
  • GRB2 Adaptor Protein
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Membrane Proteins / physiology
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphoproteins / physiology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism*
  • src Homology Domains*

Substances

  • Adaptor Proteins, Signal Transducing
  • FRS2 protein, human
  • GAB1 protein, human
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Gab1 protein, mouse
  • Grb2 protein, mouse
  • Membrane Proteins
  • Phosphoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Fibroblast Growth Factor
  • Fibroblast Growth Factors
  • FGFR1 protein, human
  • Fgfr1 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt