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XB-ART-3233
J Biol Chem 2004 Sep 10;27937:38099-102. doi: 10.1074/jbc.C400318200.
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Sef interacts with TAK1 and mediates JNK activation and apoptosis.

Yang X , Kovalenko D , Nadeau RJ , Harkins LK , Mitchell J , Zubanova O , Chen PY , Friesel R .


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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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Species referenced: Xenopus
Genes referenced: fgfr1 map3k7 mapk1 mapk8 nr2c2 tfcp2