Insight into the PTEN - P85α Interaction and Lipid Binding Properties of the P85α BH Domain

Overview

Journal Oncotarget

Specialty Oncology

Date 2019 Jan 18

PMID 30651929

Citations 2

Authors

Jeremy D S Marshall

Paul Mellor

Xuan Ruan

Dielle E Whitecross

Stanley A Moore

Deborah H Anderson

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

The orchestrated signaling by PI3Kα and PTEN at the membrane interface.

Kotzampasi D, Premeti K, Papafotika A, Syropoulou V, Christoforidis S, Cournia Z Comput Struct Biotechnol J. 2022; 20:5607-5621.

PMID: 36284707 PMC: 9578963. DOI: 10.1016/j.csbj.2022.10.007.

Impact of p85α Alterations in Cancer.

Marshall J, Whitecross D, Mellor P, Anderson D Biomolecules. 2019; 9(1).

PMID: 30650664 PMC: 6359268. DOI: 10.3390/biom9010029.

References

Baraldi E, Djinovic Carugo K, Hyvonen M, Surdo P, Riley A, Potter B . Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate. Structure. 1999; 7(4):449-60. DOI: 10.1016/s0969-2126(99)80057-4. View

Harpur A, Layton M, Das P, Bottomley M, Panayotou G, Driscoll P . Intermolecular interactions of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. J Biol Chem. 1999; 274(18):12323-32. DOI: 10.1074/jbc.274.18.12323. View

Lee J, Yang H, Georgescu M, Di Cristofano A, Maehama T, Shi Y . Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell. 1999; 99(3):323-34. DOI: 10.1016/s0092-8674(00)81663-3. View

King T, Fang Y, Mahon E, Anderson D . Using a phage display library to identify basic residues in A-Raf required to mediate binding to the Src homology 2 domains of the p85 subunit of phosphatidylinositol 3'-kinase. J Biol Chem. 2000; 275(46):36450-6. DOI: 10.1074/jbc.M004720200. View

Georgescu M, Kirsch K, Kaloudis P, Yang H, Pavletich N, Hanafusa H . Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor. Cancer Res. 2001; 60(24):7033-8. View

Dong J, Li C, Sipe T, Frierson Jr H . Mutations of PTEN/MMAC1 in primary prostate cancers from Chinese patients. Clin Cancer Res. 2001; 7(2):304-8. View

Cuevas B, Lu Y, Mao M, Zhang J, Lapushin R, Siminovitch K . Tyrosine phosphorylation of p85 relieves its inhibitory activity on phosphatidylinositol 3-kinase. J Biol Chem. 2001; 276(29):27455-61. DOI: 10.1074/jbc.M100556200. View

Cantley L . The phosphoinositide 3-kinase pathway. Science. 2002; 296(5573):1655-7. DOI: 10.1126/science.296.5573.1655. View

Campbell R, Liu F, Ross A . Allosteric activation of PTEN phosphatase by phosphatidylinositol 4,5-bisphosphate. J Biol Chem. 2003; 278(36):33617-20. DOI: 10.1074/jbc.C300296200. View

10.

McGlade C, Ellis C, Reedijk M, Anderson D, Mbamalu G, Reith A . SH2 domains of the p85 alpha subunit of phosphatidylinositol 3-kinase regulate binding to growth factor receptors. Mol Cell Biol. 1992; 12(3):991-7. PMC: 369531. DOI: 10.1128/mcb.12.3.991-997.1992. View

11.

Comeau S, Gatchell D, Vajda S, Camacho C . ClusPro: an automated docking and discrimination method for the prediction of protein complexes. Bioinformatics. 2003; 20(1):45-50. DOI: 10.1093/bioinformatics/btg371. View

12.

Comeau S, Gatchell D, Vajda S, Camacho C . ClusPro: a fully automated algorithm for protein-protein docking. Nucleic Acids Res. 2004; 32(Web Server issue):W96-9. PMC: 441492. DOI: 10.1093/nar/gkh354. View

13.

Chamberlain M, Berry T, Pastor M, Anderson D . The p85alpha subunit of phosphatidylinositol 3'-kinase binds to and stimulates the GTPase activity of Rab proteins. J Biol Chem. 2004; 279(47):48607-14. DOI: 10.1074/jbc.M409769200. View

14.

Luo J, Sobkiw C, Logsdon N, Watt J, Signoretti S, OConnell F . Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice by the p85 regulatory subunits of phosphoinositide 3-kinase. Proc Natl Acad Sci U S A. 2005; 102(29):10238-43. PMC: 1174923. DOI: 10.1073/pnas.0504378102. View

15.

Engelman J, Luo J, Cantley L . The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006; 7(8):606-19. DOI: 10.1038/nrg1879. View

16.

Taniguchi C, Tran T, Kondo T, Luo J, Ueki K, Cantley L . Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN. Proc Natl Acad Sci U S A. 2006; 103(32):12093-7. PMC: 1524929. DOI: 10.1073/pnas.0604628103. View

17.

Trotman L, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H . Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell. 2007; 128(1):141-56. PMC: 1855245. DOI: 10.1016/j.cell.2006.11.040. View

18.

Miled N, Yan Y, Hon W, Perisic O, Zvelebil M, Inbar Y . Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science. 2007; 317(5835):239-42. DOI: 10.1126/science.1135394. View

19.

Huang C, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu V, Kinzler K . The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science. 2007; 318(5857):1744-8. DOI: 10.1126/science.1150799. View

20.

Chalhoub N, Baker S . PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol. 2008; 4:127-50. PMC: 2710138. DOI: 10.1146/annurev.pathol.4.110807.092311. View