biostudies-literatureUnknown9(97)Marshall JDSThe phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in regulating cell growth and cell survival and is frequently deregulated in cancer cells. p85? regulates the p110? lipid kinase, and also stabilizes and stimulates PTEN, the lipid phosphatase that downregulates this pathway. In this report, we determined that the p85? BH domain binds several phosphorylated phosphoinositide lipids, an interaction that could help localize p85? to membranes rich in these lipids. We also identified key residues responsible for mediating PTEN - p85? complex formation. Based on these experimental results, a docking model for the PTEN - p85? BH domain complex was developed that is consistent with the known binding interactions for both PTEN and p85?. This model involves extensive side-chain and peptide backbone contacts between both the PASE and C2 domains of PTEN with the p85? BH domains. The p85? BH domain residues shown to be important for PTEN binding were p85? residues E212, Q221, K225, R228 and H234. We also verified experimentally the importance of PTEN-E91 in mediating the interaction with the p85? BH domain. These results shed new light on the mechanism of PTEN regulation by p85?.Oncotarget36975-36992https://www.ebi.ac.uk/biostudies/studies/S-EPMC6319338biostudies-literatureInsight into the PTEN - p85? interaction and lipid binding properties of the p85? BH domain.PMC6319338Anderson DHRuan XMoore SAMellor PMarshall JDSWhitecross DEfalseInsight into the PTEN - p85? interaction and lipid binding properties of the p85? BH domain.The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in regulating cell growth and cell survival and is frequently deregulated in cancer cells. p85? regulates the p110? lipid kinase, and also stabilizes and stimulates PTEN, the lipid phosphatase that downregulates this pathway. In this report, we determined that the p85? BH domain binds several phosphorylated phosphoinositide lipids, an interaction that could help localize p85? to membranes rich in these lipids. We also identified key residues responsible for mediating PTEN - p85? complex formation. Based on these experimental results, a docking model for the PTEN - p85? BH domain complex was developed that is consistent with the known binding interactions for both PTEN and p85?. This model involves extensive side-chain and peptide backbone contacts between both the PASE and C2 domains of PTEN with the p85? BH domains. The p85? BH domain residues shown to be important for PTEN binding were p85? residues E212, Q221, K225, R228 and H234. We also verified experimentally the importance of PTEN-E91 in mediating the interaction with the p85? BH domain. These results shed new light on the mechanism of PTEN regulation by p85?.2018-01-01T00:00:00Z2018 Dec2021-02-20T02:27:34Z2019-03-26T22:37:34ZS-EPMC63193383065192910.18632/oncotarget.26432