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 gr owth factor (HGF) receptor. This protein was identified as BAG-1, a re cently characterized Bcl-2 functional partner, which prolongs cell sur vival through unknown mechanisms. Overexpression of BAG-1 in liver pro genitor cells enhances protection from apoptosis by HGF. Association o f the receptor with BAG-1 occurs in intact cells, is mediated by the C -terminal region of BAG-1 and is independent from tyrosine phosphoryla tion of the receptor. Formation of the complex is increased rapidly fo llowing induction of apoptosis. BAG-1 also enhances platelet-derived g rowth 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 a re required for protection from apoptosis. The finding of a link betwe en growth factor receptors and the anti-apoptotic machinery fills a ga p in the understanding of the molecular events regulating programmed c ell death.