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PMID: 9632781 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation.

Molecular and cellular biology ·Vol. 18 ·No. 7 ·1998-07-00 ·Pages 3966-73

Hadari YR, Kouhara H, Lax I, Schlessinger J

Abstract

FRS2 is a lipid-anchored docking protein that plays an important role in linking fibroblast growth factor (FGF) and nerve growth factor receptors with the Ras/mitogen-activated protein (MAP) kinase signaling pathway. In this report, we demonstrate that FRS2 forms a complex with the N-terminal SH2 domain of the protein tyrosine phosphatase Shp2 in response to FGF stimulation. FGF stimulation induces tyrosine phosphorylation of Shp2, leading to the formation of a complex containing Grb2 and Sos1 molecules. In addition, a mutant FRS2 deficient in both Grb2 and Shp2 binding induces a weak and transient MAP kinase response and fails to induce PC12 cell differentiation in response to FGF stimulation. Furthermore, FGF is unable to induce differentiation of PC12 cells expressing an FRS2 point mutant deficient in Shp2 binding. Finally, we demonstrate that the catalytic activity of Shp2 is essential for sustained activation of MAP kinase and for potentiation of FGF-induced PC12 cell differentiation. These experiments demonstrate that FRS2 recruits Grb2 molecules both directly and indirectly via complex formation with Shp2 and that Shp2 plays an important role in FGF-induced PC12 cell differentiation.

MeSH Terms
3T3 Cells Adaptor Proteins, Signal Transducing Animals Binding Sites Calcium-Calmodulin-Dependent Protein Kinases/metabolism Catalysis Cell Differentiation Cell Line Enzyme Activation Fibroblast Growth Factors/pharmacology GRB2 Adaptor Protein Humans Intracellular Signaling Peptides and Proteins Membrane Proteins/metabolism Mice Mutagenesis Neurites PC12 Cells Phosphoproteins/metabolism Phosphorylation Phosphotyrosine/metabolism Protein Tyrosine Phosphatase, Non-Receptor Type 11 Protein Tyrosine Phosphatase, Non-Receptor Type 6 Protein Tyrosine Phosphatases/metabolism Proteins/metabolism Rats Recombinant Fusion Proteins/metabolism SH2 Domain-Containing Protein Tyrosine Phosphatases src Homology Domains
Chemicals
Adaptor Proteins, Signal Transducing FRS2 protein, human GRB2 Adaptor Protein GRB2 protein, human Grb2 protein, mouse Grb2 protein, rat Intracellular Signaling Peptides and Proteins Membrane Proteins Phosphoproteins Proteins Recombinant Fusion Proteins Phosphotyrosine Fibroblast Growth Factors Calcium-Calmodulin-Dependent Protein Kinases PTPN11 protein, human PTPN6 protein, human Protein Tyrosine Phosphatase, Non-Receptor Type 11 Protein Tyrosine Phosphatase, Non-Receptor Type 6 Protein Tyrosine Phosphatases Ptpn11 protein, mouse Ptpn11 protein, rat Ptpn6 protein, mouse Ptpn6 protein, rat SH2 Domain-Containing Protein Tyrosine Phosphatases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Hadari Y R
Department of Pharmacology, New York University Medical Center, New York, New York 10016, USA.
Kouhara H
Lax I
Schlessinger J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.18.7.3966
Published
1998-07-00
Pages
3966-73
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC108981
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.18.7.3966 PMC Full Text View journal details
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