Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in a PI3k-Akt-dependent manner.
The FasL-Fas couple is a general death mediator whose activated signals lead to caspase-8 activation and apoptosis in adult hepatocytes. Suppression of caspase-8 activation and cell death is a protective mechanism modulated by the FLICE-Like Inhibitory Protein (FLIP). Although hepatocyte growth factor (HGF) and its receptor Met are known to mediate cell survival in developing livers, the molecular mechanisms involved in this process are poorly understood. We show here that Met activation by HGF impairs Fas-triggered apoptosis of primary embryonic hepatocytes and cell survival correlates with inhibition of caspase-8 and caspase-3 activities. Furthermore, we found that HGF treatment prevents degradation of FLIPL triggered by Fas activation. In contrast to this, Met activation does not modulate FLIPL levels and its stability in untreated cells, thus showing the specificity of this regulatory mechanism for embryonic hepatocyte survival. Knocking down FLIP expression abolishes the ability of Met to inhibit Fas-triggered hepatocyte death, demonstrating the functional requirement of FLIP in HGF anti-apoptotic signals. By combining genetic and pharmacological approaches, we also demonstrate that the PI3K-Akt pathway is required in embryonic hepatocytes to prevent Fas-triggered FLIP degradation and death. Thus, Met acting on PI3K and Akt ensures high levels of FLIPL, and disruption of this pathway contributes to hepatic apoptosis and possibly to Fas-related liver diseases.
Moumen
Anice
A
Developmental Biology Institute of Marseille-Luminy (IBDML) UMR 6216, CNRS-Univ. de la Mediterranée, Marseille, France.
Ieraci
Alessandro
A
Patané
Salvatore
S
Solé
Carme
C
Comella
Joan X
JX
Dono
Rosanna
R
Maina
Flavio
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D002867:Chromones; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D019014:fas Receptor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one