title: PINCH-1 promotes Bcl-2-dependent survival signalling and inhibits JNK-mediated apoptosis in the primitive endoderm.
abstract: The focal adhesion (FA) protein PINCH-1 is required for the survival of primitive endoderm (PrE) cells. How PINCH-1 regulates this fundamental process is not known. Here, we use embryoid bodies (EBs) and isolated EB-derived PrE cells to investigate the mechanisms by which PINCH-1 promotes PrE survival. We report that loss of PINCH-1 in PrE cells leads to a sustained activity of JNK and the pro-apoptotic factor Bax. Mechanistically, the sustained JNK activation was due to diminished levels of the JNK inhibitory factor Ras suppressor protein-1 (RSU-1), whose stability was severely reduced upon loss of PINCH-1. Chemical inhibition of JNK attenuated apoptosis of PrE cells but failed to reduce Bax activity. The increased Bax activity was associated with reduced integrin signalling and diminished Bcl-2 levels, which were shown to inhibit Bax. Altogether our findings show that PINCH-1 is a pro-survival factor that prevents apoptosis of PrE cells by modulating two independent signalling pathways; PINCH-1 inhibits JNK-mediated apoptosis by stabilising the PINCH-1 binding protein RSU-1 and promotes Bcl-2-dependent pro-survival signalling downstream of integrins.
authors.affiliation: Max Planck Institute of Biochemistry, Department for Molecular Medicine, 82152 Martinsried, Germany. Eloi.Montanez@med.uni-muenchen.de
authors.forename: Eloi
authors.initials: E
authors.lastname: Montanez
authors.forename: Esra
authors.initials: E
authors.lastname: Karaköse
authors.forename: Denise
authors.initials: D
authors.lastname: Tischner
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D004707:Endoderm / Q000166:cytology* / Q000378:metabolism; D004789:Enzyme Activation; D017353:Gene Deletion; D016023:Integrins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D055550:Protein Stability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016023:Integrins; D060588:LIM Domain Proteins; C490232:Lims1 protein, mouse; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C484099:Rsu1 protein, mouse; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases