Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility.
The coordinated interplay of substrate adhesion and deadhesion is necessary for cell motility. Using MCF-7 cells, we found that insulin-like growth factor I (IGF-I) induces the adhesion of MCF-7 to vitronectin and collagen in a dose- and time-dependent manner, suggesting that IGF-I triggers the activation of different integrins. On the ... other hand, IGF-I promotes the association of insulin receptor substrate 1 with the focal adhesion kinase (FAK), paxillin, and the tyrosine phosphatase SHP-2, resulting in FAK and paxillin dephosphorylation. Abrogation of SHP-2 catalytic activity with a dominant-negative mutant (SHP2-C>S) abolishes IGF-I-induced FAK dephosphorylation, and cells expressing SHP2-C>S show reduced IGF-I-stimulated chemotaxis compared with either mock- or SHP-2 wild-type-transfected cells. This impairment of cell migration is recovered by reintroduction of a catalytically active SHP-2. Interestingly, SHP-2-C>S cells show a larger number of focal adhesion contacts than wild-type cells, suggesting that SHP-2 activity participates in the integrin deactivation process. Although SHP-2 regulates mitogen-activated protein kinase activity, the mitogen-activated protein kinase kinase inhibitor PD-98059 has only a marginal effect on MCF-7 cell migration. The role of SHP-2 as a general regulator of cell chemotaxis induced by other chemotactic agents and integrins is discussed.
Mesh Terms:
Cell Adhesion, Cell Adhesion Molecules, Cell Movement, Chemokine CCL5, Chemotactic Factors, Chemotaxis, Cytoskeletal Proteins, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Humans, Insulin Receptor Substrate Proteins, Insulin-Like Growth Factor I, Integrins, Intracellular Signaling Peptides and Proteins, Models, Biological, Neoplasm Invasiveness, Paxillin, Phosphoproteins, Phosphorylation, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Receptor Cross-Talk, Receptor, IGF Type 1, Signal Transduction, Tumor Cells, Cultured
Cell Adhesion, Cell Adhesion Molecules, Cell Movement, Chemokine CCL5, Chemotactic Factors, Chemotaxis, Cytoskeletal Proteins, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Humans, Insulin Receptor Substrate Proteins, Insulin-Like Growth Factor I, Integrins, Intracellular Signaling Peptides and Proteins, Models, Biological, Neoplasm Invasiveness, Paxillin, Phosphoproteins, Phosphorylation, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Receptor Cross-Talk, Receptor, IGF Type 1, Signal Transduction, Tumor Cells, Cultured
Mol. Cell. Biol.
Date: Apr. 01, 1999
PubMed ID: 10082579
View in: Pubmed Google Scholar
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