蛋白激酶C(PKC)是G蛋白偶联受体系统中的效应物, 能激活细胞质中的靶酶参与生化反应的调控, 同时也能作用于细胞核中的转录因子, 参与基因表达的调控, 与细胞的生长和分化息息相关。FADD又名Mort1,它是一种死亡域蛋白,与Fas胞浆区呈特异性结合,故名Fas相关死亡域蛋白(Fas-associated with death domain protein),FADD是一种胞浆蛋白,死亡受体配体或激动抗体与细胞表面死亡受体结合后,募集FADD,构成信号复合体,转导凋亡信号。
研究发现,FADD除了参与调节PKC的功能,也参与了多种非凋亡有关的细胞内进程。但是在非凋亡进程中,PKC与FADD的相互作用机制目前还不明确。
一般来说,新合成的PKC一般需要经历活化茎环(Activation-loop,A-loop)、转角模体(Turn motif,TM)以及疏水模体(hydrophobic motif,HM)的程序性磷酸化过程才能成熟,获得进一步活化的功能。在这项研究里,南京大学华子春教授课题组发现,FADD参与调节了蛋白激酶C的失活。相关研究成果于5月11日发表在The Journal of Biological Chemistry上。
在研究过程中,一种FADD的磷酰基模拟的突变(S191D),促进了TM及HM的脱磷酸化,这表明S191的磷酸化作用负调节了FADD。
PP2A是一种与cPKC脱磷酸化有关的主要的磷酸酶。研究发现,FADD能与PP2A相互作用,而且FADD的缺陷破坏了PP2A介导的cPKC的脱磷酸化作用。
进一步研究表明,FADD缺陷导致了cPKC稳定性及活性增强,反过来促进了细胞骨架重构、运动及趋化性。
总的来说,这些结果表明了FADD一种新的功能:在非凋亡过程中,FADD能够调节cPKC的去磷酸化、稳定性及信号终止。(生物谷Deepblue编译)
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.