Marshall Jeremy D S, Mellor Paul, Ruan Xuan, Whitecross Dielle E, Moore Stanley A, Anderson Deborah H
Cancer Research Group, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5, Canada.
Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5, Canada.
Oncotarget. 2018 Dec 11;9(97):36975-36992. doi: 10.18632/oncotarget.26432.
The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in regulating cell growth and cell survival and is frequently deregulated in cancer cells. p85α regulates the p110α lipid kinase, and also stabilizes and stimulates PTEN, the lipid phosphatase that downregulates this pathway. In this report, we determined that the p85α BH domain binds several phosphorylated phosphoinositide lipids, an interaction that could help localize p85α to membranes rich in these lipids. We also identified key residues responsible for mediating PTEN - p85α complex formation. Based on these experimental results, a docking model for the PTEN - p85α BH domain complex was developed that is consistent with the known binding interactions for both PTEN and p85α. This model involves extensive side-chain and peptide backbone contacts between both the PASE and C2 domains of PTEN with the p85α BH domains. The p85α BH domain residues shown to be important for PTEN binding were p85α residues E212, Q221, K225, R228 and H234. We also verified experimentally the importance of PTEN-E91 in mediating the interaction with the p85α BH domain. These results shed new light on the mechanism of PTEN regulation by p85α.
磷脂酰肌醇3激酶（PI3K）信号通路在调节细胞生长和细胞存活中起关键作用，且在癌细胞中常常失调。p85α调节p110α脂质激酶，还能稳定并刺激PTEN（下调该信号通路的脂质磷酸酶）。在本报告中，我们确定p85α的BH结构域能结合多种磷酸化的磷酸肌醇脂质，这种相互作用可能有助于将p85α定位到富含这些脂质的膜上。我们还鉴定出了介导PTEN与p85α复合物形成的关键残基。基于这些实验结果，构建了PTEN - p85α BH结构域复合物的对接模型，该模型与PTEN和p85α已知的结合相互作用一致。此模型涉及PTEN的PASE和C2结构域与p85α BH结构域之间广泛的侧链和肽主链接触。已证明对PTEN结合重要的p85α BH结构域残基为p85α的E212、Q221、K225、R228和H234残基。我们还通过实验验证了PTEN的E91在介导与p85α BH结构域相互作用中的重要性。这些结果为p85α对PTEN的调控机制提供了新的线索。
