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Zarnegar/Elsevier
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Growth factor receptors can promote life, and now Reza Zarnegar and colleagues (University of Pittsburgh, Pittsburgh, PA) show they can also prevent death, via physical interactions with death receptors.
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! U5 ?$ {) U# d, hHepatocyte growth factor (HGF) binds to and activates the receptor tyrosine kinase Met, which promotes cell survival by activating antiapoptotic programs such as the PI-3 kinase signaling cascade. The opposite result is triggered when Fas ligand (FasL) binds to the death receptor Fas, triggering its homotrimerization and the formation of a docking site for death-inducing factors, such as caspase-8. Aggregation of Fas independent of FasL is believed to be sufficient to initiate apoptosis, but under growth conditions is somehow prevented.Zarnegar has now shown that Met directly associates with the majority of Fas, preventing self aggregation. Additionally, Met binding masks the FasL binding site on Fas, thereby preventing ligand-induced homotrimerization. Only high concentrations of FasL will displace Met, allowing Fas to trigger the activation of caspases and the progression of cell death. In vivo, Met overexpression makes transgenic mice resistant to hepatic apoptosis induced by Fas.6 P% L0 J) w* H* T, O
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Fas binding does not inhibit HGF binding of Met, so that HGF/Met signaling can still occur. But high concentrations of HGF can dissociate Met from Fas, sensitizing cells to death ligands. These results explain previous, seemingly paradoxical, reports that HGF could both prevent and induce cell death in culture.
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The extracellular domain of Met alone is necessary to bind to and inhibit Fas. Thus, says Zarnegar, "Met acts as a double-edged sword against apotosis from the outside and inside of the cell," via its Fas-binding and antiapoptotic signaling activities, respectively. In cancerous cells, high levels of Met may down-regulate apoptosis by both methods, so cells are resistant to both extrinsic (death receptor) and intrinsic (DNA damage) apoptotic signals.
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) A- q: H3 @7 N# H1 rWang, X., et al. 2002. Mol. Cell. 9:411–421.(Met binds to Fas (left) to reduce Fas-in) |
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发表于 2009-3-6 00:19
发表于 2026-7-28 00:42
