J Biol Chem. September 10, 2004; 279 (37):
Yang X , Kovalenko D , Nadeau RJ , Harkins LK , Mitchell J , Zubanova O , Chen PY , Friesel R .
AbstractSef 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.
Pubmed Id: 15277532Article link: J Biol Chem.