Phosphorylation of FADD/ MORT1 at serine 194 and association with a 70-kDa cell cycle-regulated protein kinase.
The adapter molecule Fas-associated death domain protein (FADD)/mediator of receptor-induced toxicity-1 (MORT1) is essential for signal transduction of the apoptosis-inducing receptor CD95 (APO-1/Fas) as it connects the activated receptor with the effector caspase-8. FADD also plays a role in embryonic development and the cell cycle reentry of T cells. FADD is phosphorylated at serine residues. We now show that phosphorylation exclusively occurs at serine 194. The phosphorylation of FADD was found to correlate with the cell cycle. In cells arrested at the G2/M boundary with nocodazole, FADD was quantitatively phosphorylated, whereas only nonphosphorylated FADD was found in cells arrested in G1/S with hydroxyurea. In this context, we have identified a 70-kDa cell cycle-regulated kinase that specifically binds to the C-terminal half of FADD. Because CD95-mediated apoptosis is independent of the cell cycle, phosphorylation of FADD may regulate its apoptosis-independent functions.
Scaffidi
C
C
Tumor Immunology Program, Applied Tumorvirology, German Cancer Research Center, Heidelberg, Germany.
Volkland
J
J
Blomberg
I
I
Hoffmann
I
I
Krammer
P H
PH
Peter
M E
ME
D048868:Adaptor Proteins, Signal Transducing; D002051:Burkitt Lymphoma; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000276:immunology; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D053200:Fas-Associated Death Domain Protein; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000378:metabolism; D006801:Humans; D008970:Molecular Weight; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D012694:Serine; D018844:Cyclin-Dependent Kinases