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PINCH-1 promotes Bcl-2-dependent survival signalling and inhibits JNK-mediated apoptosis in the primitive endoderm

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons78416

Montanez,  Eloi
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78184

Karaköse,  Esra
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons77945

Fässler,  Reinhard
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Montanez, E., Karaköse, E., Tischner, D., Villunger, A., & Fässler, R. (2012). PINCH-1 promotes Bcl-2-dependent survival signalling and inhibits JNK-mediated apoptosis in the primitive endoderm. JOURNAL OF CELL SCIENCE, 125(21), 5233-5240. doi:10.1242/jcs.112029.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-7CC7-5
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 proapoptotic 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.