RESUMO
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.
Assuntos
Apoptose/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Proteínas Reguladoras de Apoptose , Western Blotting , Proteínas de Transporte/genética , Células Cultivadas , Clonagem Molecular , Proteínas de Ligação a DNA , Etoposídeo/farmacologia , Regulação da Expressão Gênica/genética , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Camundongos , Mutação/genética , Fosforilação , Proteínas Proto-Oncogênicas c-met , Receptores Proteína Tirosina Quinases/farmacologia , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Estaurosporina/farmacologia , Fatores de Transcrição , Transfecção/genética , Tirosina/metabolismoAssuntos
Cromoblastomicose/diagnóstico , Transplante de Rim , Fungos Mitospóricos/isolamento & purificação , Carcinoma de Células Escamosas/diagnóstico , Cromoblastomicose/etiologia , Doença Crônica , Diagnóstico Diferencial , Europa (Continente) , Humanos , Masculino , Pessoa de Meia-Idade , Pele/microbiologia , Neoplasias Cutâneas/diagnósticoRESUMO
Hepatocyte Growth Factor (HGF) is a pleiotropic factor, capable of evoking complex biological responses such as mitogenesis, motogenesis and morphogenesis in a variety of epithelial and endothelial cells. Nonetheless, the meaning of the acronym is consistent with the key role of the factor in liver regeneration, in vivo and in liver development during embryogenesis. The receptor for HGF is the tyrosine kinase encoded by the c-MET proto-oncogene. Upon ligand binding, the receptor kinase is activated by tyrosine autophosphorylation and recruits cytoplasmic transducers involved in HGF-triggered signal transduction. We investigated the role of HGF as a survival factor in protecting cells from apoptosis and we show that HGF is able to counteract staurosporin-induced apoptosis of epithelial cells.
