The tyrosine phosphatase SHP-2 is required for mediating phosphatidylinositol 3-kinase/Akt activation by growth factors.
SHP-2 is a ubiquitously expressed non-transmembrane tyrosine phosphatase with two SH2 domains. Multiple reverse-genetic studies have indicated that SHP-2 is a required component for organ and animal development. SHP-2 wild-type and homozygous mutant mouse fibroblast cells in which the N-terminal SH2 domain was target-deleted were used to examine the function ... of SHP-2 in regulating Phosphatidylinositol 3-Kinase (PI3K) activation by growth factors. In addition, SHP-2 and various mutants were introduced into human glioblastoma cells as well as SHP-2(-/-) mouse fibroblasts. We found that EGF stimulation and EGFR oncoprotein (DeltaEGFR) expression independently induced the co-immunoprecipitation of the p85 subunit of PI3K with SHP-2. Targeted deletion of the N-terminal SH2 domain of SHP-2 severely impaired PDGF- and IGF-induced Akt phosphorylation. Ectopic expression of SHP-2 in U87MG gliobastoma cells elevated EGF-induced Akt phosphorylation, and the effect was abolished by mutation of its N-terminal SH2 domain. Likewise, the reconstitution of SHP-2 expression in the SHP-2(-/-) cells enhanced Akt phosphorylation induced by EGF while rescuing that induced by PDGF and IGF. Further lipid kinase activity assays confirmed that SHP-2 modulation of Akt phosphorylation correlated with its regulation of PI3K activation. Based on these results, we conclude that SHP-2 is required for mediating PI3K/Akt activation, and the N-terminal SH2 domain is critically important for a "positive" role of SHP-2 in regulating PI3K pathway activation.
Mesh Terms:
Animals, Cell Line, Enzyme Activation, Epidermal Growth Factor, Glioblastoma, Growth Substances, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mutation, Phosphatidylinositol 3-Kinases, Phosphorylation, Platelet-Derived Growth Factor, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Receptor, Epidermal Growth Factor, SH2 Domain-Containing Protein Tyrosine Phosphatases, Signal Transduction, Somatomedins, Transfection, Tumor Cells, Cultured, src Homology Domains
Animals, Cell Line, Enzyme Activation, Epidermal Growth Factor, Glioblastoma, Growth Substances, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mutation, Phosphatidylinositol 3-Kinases, Phosphorylation, Platelet-Derived Growth Factor, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Receptor, Epidermal Growth Factor, SH2 Domain-Containing Protein Tyrosine Phosphatases, Signal Transduction, Somatomedins, Transfection, Tumor Cells, Cultured, src Homology Domains
Oncogene
Date: Sep. 20, 2001
PubMed ID: 11593409
View in: Pubmed Google Scholar
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