Research Papers:

Insight into the PTEN – p85α interaction and lipid binding properties of the p85α BH domain

Jeremy D.S. Marshall _, Paul Mellor, Xuan Ruan, Dielle E. Whitecross, Stanley A. Moore and Deborah H. Anderson

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Oncotarget. 2018; 9:36975-36992. https://doi.org/10.18632/oncotarget.26432

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Jeremy D.S. Marshall1,2, Paul Mellor1, Xuan Ruan1, Dielle E. Whitecross1, Stanley A. Moore2 and Deborah H. Anderson1,2,3

1Cancer Research Group, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5, Canada

2Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5, Canada

3Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, S7N 5E5, Canada

Correspondence to:

Deborah H. Anderson, email: [email protected]

Keywords: PTEN; p85α; regulatory mechanism; lipid binding; structure

Received: August 09, 2018     Accepted: November 26, 2018     Published: December 11, 2018


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.

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