Stimulation of Phosphatidylinositol 3-Kinase by Fibroblast Growth Factor Receptors is Mediated by Coordinated Recruitment of Multiple Docking Proteins

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 activ...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-05, Vol.98 (11), p.6074-6079
Main Authors: Ong, S. H., Hadari, Y. R., Gotoh, N., Guy, G. R., Schlessinger, J., Lax, I.
Format: Article
Language:English
Subjects:
3T3 Cells
Adaptor Proteins, Signal Transducing
Animals
Antibodies
Biochemistry
Biological Sciences
Cell growth
Cercopithecus aethiops
COS Cells
Enzyme Activation
Enzymes
Fibroblast growth factor receptors
Fibroblast growth factors
Fibroblast Growth Factors - metabolism
Fibroblast Growth Factors - pharmacology
GRB2 Adaptor Protein
Humans
Immunoblotting
Insulin
Membrane Proteins - genetics
Membrane Proteins - metabolism
Membrane Proteins - physiology
Mice
PC12 cells
Phosphatidylinositol 3-Kinases - metabolism
Phosphoproteins - genetics
Phosphoproteins - metabolism
Phosphoproteins - physiology
Phosphorylation
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Proteins
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
Receptors, Fibroblast Growth Factor - genetics
Receptors, Fibroblast Growth Factor - metabolism
src Homology Domains
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Summary: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 FRS2α 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 FRS2α: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.111114298