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.
Yang
Xuehui
X
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA.
Kovalenko
Dmitry
D
Nadeau
Robert J
RJ
Harkins
Lauren K
LK
Mitchell
Jane
J
Zubanova
Olga
O
Chen
Pei-Yu
PY
Friesel
Robert
R
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