Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Adhesion / physiology
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Cell Adhesion Molecules / metabolism*
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Cell Movement / physiology*
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Chemokine CCL5 / pharmacology
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Chemotactic Factors / metabolism
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Chemotaxis / physiology
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Cytoskeletal Proteins / metabolism
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Humans
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Insulin Receptor Substrate Proteins
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Insulin-Like Growth Factor I / pharmacology*
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Integrins / metabolism
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Intracellular Signaling Peptides and Proteins
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Models, Biological
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Neoplasm Invasiveness
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Paxillin
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Binding
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Protein-Tyrosine Kinases / metabolism*
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Receptor Cross-Talk / physiology*
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Receptor, IGF Type 1 / metabolism
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Signal Transduction
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Tumor Cells, Cultured
Substances
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Cell Adhesion Molecules
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Chemokine CCL5
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Chemotactic Factors
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Cytoskeletal Proteins
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IRS1 protein, human
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Insulin Receptor Substrate Proteins
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Integrins
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Intracellular Signaling Peptides and Proteins
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PXN protein, human
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Paxillin
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Phosphoproteins
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Insulin-Like Growth Factor I
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Protein-Tyrosine Kinases
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Receptor, IGF Type 1
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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PTK2 protein, human
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PTPN11 protein, human
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases