蛋白激酶C(PKC)是G蛋白偶聯(lián)受體系統(tǒng)中的效應(yīng)物, 能激活細(xì)胞質(zhì)中的靶酶參與生化反應(yīng)的調(diào)控, 同時也能作用于細(xì)胞核中的轉(zhuǎn)錄因子, 參與基因表達的調(diào)控, 與細(xì)胞的生長和分化息息相關(guān),。FADD又名Mort1,它是一種死亡域蛋白,與Fas胞漿區(qū)呈特異性結(jié)合,故名Fas相關(guān)死亡域蛋白(Fas-associated with death domain protein),，F(xiàn)ADD是一種胞漿蛋白,死亡受體配體或激動抗體與細(xì)胞表面死亡受體結(jié)合后,募集FADD,構(gòu)成信號復(fù)合體,轉(zhuǎn)導(dǎo)凋亡信號,。
研究發(fā)現(xiàn)，F(xiàn)ADD除了參與調(diào)節(jié)PKC的功能,，也參與了多種非凋亡有關(guān)的細(xì)胞內(nèi)進程,。但是在非凋亡進程中，PKC與FADD的相互作用機制目前還不明確,。
一般來說,，新合成的PKC一般需要經(jīng)歷活化莖環(huán)(Activation-loop,A-loop)、轉(zhuǎn)角模體(Turn motif,TM)以及疏水模體(hydrophobic motif,HM)的程序性磷酸化過程才能成熟,獲得進一步活化的功能,。在這項研究里,，南京大學(xué)華子春教授課題組發(fā)現(xiàn)，F(xiàn)ADD參與調(diào)節(jié)了蛋白激酶C的失活,。相關(guān)研究成果于5月11日發(fā)表在The Journal of Biological Chemistry上,。
在研究過程中，一種FADD的磷?；M的突變(S191D),，促進了TM及HM的脫磷酸化，這表明S191的磷酸化作用負(fù)調(diào)節(jié)了FADD,。
PP2A是一種與cPKC脫磷酸化有關(guān)的主要的磷酸酶,。研究發(fā)現(xiàn)，F(xiàn)ADD能與PP2A相互作用,，而且FADD的缺陷破壞了PP2A介導(dǎo)的cPKC的脫磷酸化作用,。
進一步研究表明,，F(xiàn)ADD缺陷導(dǎo)致了cPKC穩(wěn)定性及活性增強,，反過來促進了細(xì)胞骨架重構(gòu),、運動及趨化性。
總的來說,，這些結(jié)果表明了FADD一種新的功能：在非凋亡過程中,，F(xiàn)ADD能夠調(diào)節(jié)cPKC的去磷酸化、穩(wěn)定性及信號終止,。（生物谷Deepblue編譯）
doi: 10.1074/jbc.M112.342170
PMC:
PMID:
Regulation of PKC Inactivation by FADD
Wei Cheng, Lu Wang, Rong Zhang, Pan Du, Bingya Yang, Hongqin Zhuang, Bo Tang, Chun Yao, Mei Yu, Yuxuan Wang, Jing Zhang, Wu Yin, Jiahuang Li, Weijuan Zheng, Min Lu and Zichun Hua.
TProtein kinase C (PKC) plays important roles in diverse cellular processes. PKC has been implicated in regulating 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 turn motif (TM) and hydrophobic motif (HM) 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 TM and HM dephosphorylation of cPKC, suggesting that phosphorylation of S191 negatively regulates FADD.We show that FADD interacts with PP2A, a major phosphatase involved in dephosphorylation of activated cPKC and FADD deficiency abolished PP2A mediated dephosphorylation of cPKC. We show that FADD deficiency leads 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.
