Binding of protein kinase B to the plakin family member periplakin
Binding of protein kinase B to the plakin family member periplakin
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DOI：
10.1242/jcs.00069
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发表时间：
2002-10-15
影响因子：
4
通讯作者：
Burgering, BMT
中科院分区：
文献类型：
--
作者：
van den Heuvel, APJ;de Vries-Smits, AMM;Burgering, BMT
丝氨酸/苏氨酸激酶B(PKB/c-Akt)位于磷脂酸肌醇3-激酶(PI3K)的下游，在细胞周期调控、细胞存活和转录调控等多种生长因子诱导的细胞反应中起着重要的中介作用。PI3K激活产生3‘-磷酸化磷脂酰肌醇脂质(PtdIns3P)，而PKB激活需要依赖PtdIns3P的膜转位和上游激酶的磷酸化。然而，PKB的激活和功能也受到与其他蛋白质相互作用的调节。在这里，我们显示了PKB与细胞连接蛋白Plakin家族的成员Perplakin的结合。PKB和周斑蛋白之间的相互作用被映射到PKB的Pleckstrin Homology(PH)结构域的一部分，该区域可能不参与脂质结合，并且与周斑蛋白的结合确实不影响PKB的激活。因此，我们研究了PERPLAKIN可能作为PKB的支架或定位信号的可能性。在细胞中，内源性周斑蛋白定位于不同的细胞室，包括质膜、中间丝结构、细胞核和线粒体。围绕PKB结合区的周斑蛋白C末端部分的过度表达，导致主要的中间丝定位和很少的核染色。这也导致了核PKB信号的抑制，这表明抑制PKB依赖的叉头转录因子调节。这些结果提示，在PKB介导的信号转导中，周斑蛋白可能作为一种定位信号发挥作用。
The serine/threonine kinase protein kinase B (PKB/c-Akt) acts downstream of the lipid kinase phosphoinositide 3-kinase (PI3K) and functions as an essential mediator in many growth-factor-induced cellular responses such as cell cycle regulation, cell survival and transcriptional regulation. PI3K activation generates 3'-phosphorylated phosphatidylinositol lipids (PtdIns3P) and PKB activation requires PtdIns3P-dependent membrane translocation and phosphorylation by upstream kinases. However PKB activation and function is also regulated by interaction with other proteins. Here we show binding of PKB to periplakin, a member of the plakin family of cytolinker proteins. Interaction between PKB and periplakin was mapped to part of the pleckstrin homology (PH) domain of PKB, which is probably not involved in lipid binding, and indeed binding to periplakin did not affect PKB activation. We therefore investigated the possibility that periplakin may act as a scaffold or localization signal for PKB. In cells endogenous periplakin localizes to different cellular compartments, including plasma membrane, intermediate filament structures, the nucleus and mitochondria. Overexpression of the C-terminal part of periplakin, encompassing the PKB binding region, results in predominant intermediate filament localization and little nuclear staining. This also resulted in inhibition of nuclear PKB signalling as indicated by inhibition of PKB-dependent Forkhead transcription factor regulation. These results suggest a possible role for periplakin as a localization signal in PKB-mediated signalling.