A Conserved Inositol Phospholipid Binding Site within the Pleckstrin Homology Domain of the Gab1 Docking Protein Is Required for Epithelial Morphogenesis
| Autor: | David K. Moscatello, Morag Park, Monica A. Naujokas, Marina Holgado-Madruga, Christiane R. Maroun, Albert J. Wong |
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| Rok vydání: | 1999 |
| Předmět: |
Biology
Arginine Biochemistry chemistry.chemical_compound Phosphatidylinositol Phosphates EVH1 domain Morphogenesis Amino Acid Sequence Phosphatidylinositol Phosphorylation Molecular Biology Conserved Sequence Binding Sites Sequence Homology Amino Acid Binding protein Tryptophan Epithelial Cells Blood Proteins Cell Biology Proto-Oncogene Proteins c-met Phosphoproteins IRS1 Pleckstrin homology domain chemistry Hepatocyte Growth Factor Receptor Mutagenesis Site-Directed Phospholipid Binding Protein Binding |
| Zdroj: | Journal of Biological Chemistry. 274:31719-31726 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.274.44.31719 |
| Popis: | Stimulation of the hepatocyte growth factor receptor tyrosine kinase, Met, induces the inherent morphogenic program of epithelial cells. The multisubstrate binding protein Gab1 (Grb2-associated binder-1) is the major phosphorylated protein in epithelial cells following activation of Met. Gab1 contains a pleckstrin homology domain and multiple tyrosine residues that act to couple Met with multiple signaling proteins. Met receptor mutants that are impaired in their association with Gab1 fail to induce a morphogenic program in epithelial cells, which is rescued by overexpression of Gab1. The Gab1 pleckstrin homology domain binds to phosphatidylinositol 3,4, 5-trisphosphate and contains conserved residues, shown from studies of other pleckstrin homology domains to be crucial for phospholipid binding. Mutation of conserved phospholipid binding residues tryptophan 26 and arginine 29, generates Gab1 proteins with decreased phosphatidylinositol 3,4,5-trisphosphate binding, decreased localization at sites of cell-cell contact, and reduced ability to rescue Met-dependent morphogenesis. We conclude that the ability of the Gab1 pleckstrin homology domain to bind phosphatidylinositol 3,4,5-trisphosphate is critical for subcellular localization of Gab1 and for efficient morphogenesis downstream from the Met receptor. |
| Databáze: | OpenAIRE |
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