Sef interacts with TAK1 and mediates JNK activation and apoptosis |
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Authors: | Yang Xuehui Kovalenko Dmitry Nadeau Robert J Harkins Lauren K Mitchell Jane Zubanova Olga Chen Pei-Yu Friesel Robert |
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Institution: | Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA. |
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Abstract: | Sef was recently identified as a negative regulator of fibroblast growth factor (FGF) signaling in a genetic screen of zebrafish and subsequently in mouse and humans. By inhibiting FGFR1 tyrosine phosphorylation and/or Ras downstream events, Sef inhibits FGF-mediated ERK activation and cell proliferation as well as PC12 cell differentiation. Here we show that Sef and a deletion mutant of Sef lacking the extracellular domain (SefIC) physically interact with TAK1 (transforming growth factor-beta-associated kinase) and activate JNK through a TAK1-MKK4-JNK pathway. Sef and SefIC overexpression also resulted in apoptotic cell death, while dominant negative forms of MKK4 and TAK1 blocked Sef-mediated JNK activation and attendant 293T cell apoptosis. These investigations reveal a novel activating function of Sef that is distinct from its inhibitory effect on FGF receptor signaling and ERK activation. |
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