title: Regulation of protein kinase C inactivation by Fas-associated protein with death domain.
abstract: Protein kinase C (PKC) plays important roles in diverse cellular processes. PKC has been implicated in regulating Fas-associated protein with death domain (FADD), an important adaptor protein involved in regulating death receptor-mediated apoptosis. FADD also plays an important role in non-apoptosis processes. The functional interaction of PKC and FADD in non-apoptotic processes has not been examined. In this study, we show that FADD is involved in maintaining the phosphorylation of the turn motif and hydrophobic motif in the activated conventional PKC (cPKC). A phosphoryl-mimicking mutation (S191D) in FADD (FADD-D) abolished the function of FADD in the facilitation of the turn motif and hydrophobic motif dephosphorylation of cPKC, suggesting that phosphorylation of Ser-191 negatively regulates FADD. We show that FADD interacts with PP2A, which is a major phosphatase involved in dephosphorylation of activated cPKC and FADD deficiency abolished PP2A mediated dephosphorylation of cPKC. We show that FADD deficiency leads to increased stability and activity of cPKC, which, in turn, promotes cytoskeleton reorganization, cell motility, and chemotaxis. Collectively, these results reveal a novel function of FADD in a non-apoptotic process by modulating cPKC dephosphorylation, stability, and signaling termination.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, Nanjing University, Nanjing 210093, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Pan
authors.initials: P
authors.lastname: Du
authors.forename: Bingya
authors.initials: B
authors.lastname: Yang
authors.forename: Hongqin
authors.initials: H
authors.lastname: Zhuang
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.forename: Chun
authors.initials: C
authors.lastname: Yao
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Wu
authors.initials: W
authors.lastname: Yin
authors.forename: Jiahuang
authors.initials: J
authors.lastname: Li
authors.forename: Weijuan
authors.initials: W
authors.lastname: Zheng
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Zichun
authors.initials: Z
authors.lastname: Hua
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D004795:Enzyme Stability; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D015398:Signal Transduction
chemical_list: D053200:Fas-Associated Death Domain Protein; D007527:Isoenzymes; D011493:Protein Kinase C; D054648:Protein Phosphatase 2