HGF receptor associates with the anti-apoptotic protein BAG-1 and prevents cell death.
The mechanisms by which apoptosis is prevented by survival factors are largely unknown. Using an interaction cloning approach, we identified a protein that binds to the intracellular domain of the hepatocyte growth factor (HGF) receptor. This protein was identified as BAG-1, a recently characterized Bcl-2 functional partner, which prolongs cell survival through unknown mechanisms. Overexpression of BAG-1 in liver progenitor cells enhances protection from apoptosis by HGF. Association of the receptor with BAG-1 occurs in intact cells, is mediated by the C-terminal region of BAG-1 and is independent from tyrosine phosphorylation of the receptor. Formation of the complex is increased rapidly following induction of apoptosis. BAG-1 also enhances platelet-derived growth factor (PDGF)-mediated protection from apoptosis and associates with the PDGF receptor. Microinjection or transient expression of BAG-1 deletion mutants shows that both the N- and the C-terminal domains are required for protection from apoptosis. The finding of a link between growth factor receptors and the anti-apoptotic machinery fills a gap in the understanding of the molecular events regulating programmed cell death.
Bardelli
A
A
Institute for Cancer Research (I.R.C.C.), University of Torino School of Medicine, Italy.
Longati
P
P
Albero
D
D
Goruppi
S
S
Schneider
C
C
Ponzetto
C
C
Comoglio
P M
PM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics; D008099:Liver / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism* / Q000494:pharmacology; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D014157:Transcription Factors; D014162:Transfection / Q000235:genetics; D014443:Tyrosine / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C090468:TP53BP2 protein, human; D014157:Transcription Factors; D014443:Tyrosine; D005047:Etoposide; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D019311:Staurosporine