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The Multisubstrate Adapter Gab1 Regulates Hepatocyte Growth Factor (Scatter Factor)–c-Met Signaling for Cell Survival and DNA Repair
- Source :
- Molecular and Cellular Biology. 21:4968-4984
- Publication Year :
- 2001
- Publisher :
- Informa UK Limited, 2001.
-
Abstract
- Hepatocyte growth factor (scatter factor) (HGF/SF) is a pleiotrophic mediator of epithelial cell motility, morphogenesis, angiogenesis, and tumorigenesis. HGF/SF protects cells against DNA damage by a pathway from its receptor c-Met to phosphatidylinositol 3-kinase (PI3K) to c-Akt, resulting in enhanced DNA repair and decreased apoptosis. We now show that protection against the DNA-damaging agent adriamycin (ADR; topoisomerase IIalpha inhibitor) requires the Grb2-binding site of c-Met, and overexpression of the Grb2-associated binder Gab1 (a multisubstrate adapter required for epithelial morphogenesis) inhibits the ability of HGF/SF to protect MDCK epithelial cells against ADR. In contrast to Gab1 and its homolog Gab2, overexpression of c-Cb1, another multisubstrate adapter that associates with c-Met, did not affect protection. Gab1 blocked the ability of HGF/SF to cause the sustained activation of c-Akt and c-Akt signaling (FKHR phosphorylation). The Gab1 inhibition of sustained c-Akt activation and of cell protection did not require the Gab1 pleckstrin homology or SHP2 phosphatase-binding domain but did require the PI3K-binding domain. HGF/SF protection of parental MDCK cells was blocked by wortmannin, expression of PTEN, and dominant negative mutants of p85 (regulatory subunit of PI3K), Akt, and Pak1; the protection of cells overexpressing Gab1 was restored by wild-type or activated mutants of p85, Akt, and Pak1. These findings suggest that the adapter Gab1 may redirect c-Met signaling through PI3K away from a c-Akt/Pak1 cell survival pathway.
- Subjects :
- Time Factors
DNA Repair
Tetrazolium Salts
Apoptosis
Wortmannin
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Cell Movement
Enzyme Inhibitors
Phosphorylation
Cell Growth and Development
Caspase 3
Hepatocyte Growth Factor
Proto-Oncogene Proteins c-met
Recombinant Proteins
Pleckstrin homology domain
Caspases
Hepatocyte growth factor
Signal transduction
Cell Division
Protein Binding
Signal Transduction
medicine.drug
C-Met
Cell Survival
DNA repair
Blotting, Western
Genetic Vectors
DNA Fragmentation
Protein Serine-Threonine Kinases
Biology
Transfection
Models, Biological
Cell Line
Dogs
Proto-Oncogene Proteins
medicine
Animals
Humans
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Adaptor Proteins, Signal Transducing
GRB2 Adaptor Protein
Binding Sites
Proteins
Epithelial Cells
DNA
Cell Biology
Phosphoproteins
Precipitin Tests
Protein Structure, Tertiary
Androstadienes
Thiazoles
p21-Activated Kinases
chemistry
Doxorubicin
Mutation
Cancer research
Proto-Oncogene Proteins c-akt
DNA Damage
Subjects
Details
- ISSN :
- 10985549
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Molecular and Cellular Biology
- Accession number :
- edsair.doi.dedup.....3b836ef76d2122aea6261f36014612bc