Abstract

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.