Sef interacts with TAK1 and mediates JNK activation and apoptosis.
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.
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA.
Xuehui
X
Yang
Dmitry
D
Kovalenko
Robert J
RJ
Nadeau
Lauren K
LK
Harkins
Jane
J
Mitchell
Olga
O
Zubanova
Pei-Yu
PY
Chen
Robert
R
Friesel
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005434:Flow Cytometry; D017353:Gene Deletion; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D016716:PC12 Cells; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D051381:Rats; D018123:Receptors, Interleukin / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014981:Xenopus; D000099151:MAP Kinase Kinase Kinase 7
D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D018123:Receptors, Interleukin; D000099151:MAP Kinase Kinase Kinase 7; C477526:IL17RD protein, human