PMID- 11438654
OWN - NLM
STAT- MEDLINE
DCOM- 20010816
LR  - 20211203
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 21
IP  - 15
DP  - 2001 Aug
TI  - The multisubstrate adapter Gab1 regulates hepatocyte growth factor (scatter 
      factor)-c-Met signaling for cell survival and DNA repair.
PG  - 4968-84
AB  - 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.
FAU - Fan, S
AU  - Fan S
AD  - Department of Radiation Oncology, Long Island Jewish Medical Center, The Long 
      Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New 
      York 11040, USA.
FAU - Ma, Y X
AU  - Ma YX
FAU - Gao, M
AU  - Gao M
FAU - Yuan, R Q
AU  - Yuan RQ
FAU - Meng, Q
AU  - Meng Q
FAU - Goldberg, I D
AU  - Goldberg ID
FAU - Rosen, E M
AU  - Rosen EM
LA  - eng
GR  - R01-CA80000/CA/NCI NIH HHS/United States
GR  - R01-CA82599/CA/NCI NIH HHS/United States
GR  - R01-ES09169/ES/NIEHS NIH HHS/United States
GR  - R01 CA082599/CA/NCI NIH HHS/United States
GR  - R01 ES009169/ES/NIEHS NIH HHS/United States
GR  - R01 CA080000/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Androstadienes)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (GAB1 protein, human)
RN  - 0 (GAB2 protein, human)
RN  - 0 (GRB2 Adaptor Protein)
RN  - 0 (GRB2 protein, human)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tetrazolium Salts)
RN  - 0 (Thiazoles)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - 80168379AG (Doxorubicin)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (PAK1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (p21-Activated Kinases)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
RN  - EUY85H477I (thiazolyl blue)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - *Adaptor Proteins, Signal Transducing
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Apoptosis
MH  - Binding Sites
MH  - Blotting, Western
MH  - Caspase 3
MH  - Caspases/metabolism/physiology
MH  - Cell Division
MH  - Cell Line
MH  - Cell Movement
MH  - Cell Survival
MH  - DNA/metabolism
MH  - DNA Damage
MH  - DNA Fragmentation
MH  - DNA Repair
MH  - Dogs
MH  - Doxorubicin/pharmacology
MH  - Enzyme Inhibitors/pharmacology
MH  - Epithelial Cells/metabolism
MH  - GRB2 Adaptor Protein
MH  - Genetic Vectors
MH  - Hepatocyte Growth Factor/*metabolism
MH  - Humans
MH  - Models, Biological
MH  - Mutation
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoproteins/*metabolism/*physiology
MH  - Phosphorylation
MH  - Precipitin Tests
MH  - Protein Binding
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Protein Structure, Tertiary
MH  - Proteins/metabolism
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Proto-Oncogene Proteins c-met/*metabolism
MH  - Recombinant Proteins/metabolism
MH  - Signal Transduction
MH  - Tetrazolium Salts/pharmacology
MH  - Thiazoles/pharmacology
MH  - Time Factors
MH  - Transfection
MH  - Wortmannin
MH  - p21-Activated Kinases
PMC - PMC87224
EDAT- 2001/07/05 10:00
MHDA- 2001/08/17 10:01
PMCR- 2001/08/01
CRDT- 2001/07/05 10:00
PHST- 2001/07/05 10:00 [pubmed]
PHST- 2001/08/17 10:01 [medline]
PHST- 2001/07/05 10:00 [entrez]
PHST- 2001/08/01 00:00 [pmc-release]
AID - 1577 [pii]
AID - 10.1128/MCB.21.15.4968-4984.2001 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2001 Aug;21(15):4968-84. doi: 10.1128/MCB.21.15.4968-4984.2001.