A beta 1 integrin signaling pathway involving Src-family kinases, Cbl and PI-3 kinase is required for macrophage spreading and migration.
We have used mutant macrophages which are deficient in expression of Src-family kinases to define an integrin signaling pathway that is required for macrophage adhesion and migration. Following ligation of surface integrins by fibronectin, the p120(c-cbl) (Cbl) protein rapidly becomes tyrosine phosphorylated and associated with the Src-family kinases Fgr and ... Lyn. In hck-/-fgr-/-lyn-/- triple mutant cells, which are defective in spreading on fibronectin-coated surfaces in vitro and show impaired migration in vivo, Cbl tyrosine phosphorylation is blocked, Cbl protein levels are low, adhesion-dependent translocation of Cbl to the membrane is impaired and Cbl-associated, membrane-localized phosphatidylinositol 3 (PI-3)-kinase activity is dramatically reduced. In contrast, adhesion-dependent activation of total cellular PI-3 kinase activity is normal in mutant cells, demonstrating that it is the membrane-associated fraction of PI-3 kinase which is most critical in regulating actin cytoskeletal rearrangements that lead to cell spreading. Treatment of wild-type cells with the Src-family-specific inhibitor PP1, Cbl antisense oligonucleotides or pharmacological inhibitors of PI-3 kinase blocks cell spreading on fibronectin surfaces. These data provide a molecular description for the role of Src-family kinases Hck, Fgr and Lyn in beta 1-integrin signal transduction in macrophages.
Mesh Terms:
Animals, Antigens, CD29, Calcium-Calmodulin-Dependent Protein Kinases, Cell Adhesion, Cell Migration Inhibition, Cell Movement, DNA, Enzyme Activation, Fibronectins, Inflammation, Macrophages, Peritoneal, Mice, Mice, Knockout, Mutation, NF-kappa B, Oligonucleotides, Antisense, Oncogene Protein v-cbl, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-hck, Retroviridae Proteins, Oncogenic, Signal Transduction, Tyrosine, src-Family Kinases
Animals, Antigens, CD29, Calcium-Calmodulin-Dependent Protein Kinases, Cell Adhesion, Cell Migration Inhibition, Cell Movement, DNA, Enzyme Activation, Fibronectins, Inflammation, Macrophages, Peritoneal, Mice, Mice, Knockout, Mutation, NF-kappa B, Oligonucleotides, Antisense, Oncogene Protein v-cbl, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-hck, Retroviridae Proteins, Oncogenic, Signal Transduction, Tyrosine, src-Family Kinases
EMBO J.
Date: Aug. 03, 1998
PubMed ID: 9687507
View in: Pubmed Google Scholar
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