Activation of the PI3K Pathway in Cancer Through Inhibition of PTEN by Exchange Factor P-REX2a

Overview

Journal Science

Specialty Science

Date 2009 Sep 5

PMID 19729658

Citations 128

Authors

Barry Fine

Cindy Hodakoski

Susan Koujak

Tao Su

Lao H Saal

Matthew Maurer

Benjamin Hopkins

Megan Keniry

Maria Luisa Sulis

Sarah Mense

Hanina Hibshoosh

Ramon Parsons

Affiliations

Soon will be listed here.

Abstract

PTEN (phosphatase and tensin homolog on chromosome 10) is a tumor suppressor whose cellular regulation remains incompletely understood. We identified phosphatidylinositol 3,4,5-trisphosphate RAC exchanger 2a (P-REX2a) as a PTEN-interacting protein. P-REX2a mRNA was more abundant in human cancer cells and significantly increased in tumors with wild-type PTEN that expressed an activated mutant of PIK3CA encoding the p110 subunit of phosphoinositide 3-kinase subunit alpha (PI3Kalpha). P-REX2a inhibited PTEN lipid phosphatase activity and stimulated the PI3K pathway only in the presence of PTEN. P-REX2a stimulated cell growth and cooperated with a PIK3CA mutant to promote growth factor-independent proliferation and transformation. Depletion of P-REX2a reduced amounts of phosphorylated AKT and growth in human cell lines with intact PTEN. Thus, P-REX2a is a component of the PI3K pathway that can antagonize PTEN in cancer cells.

Citing Articles

High glucose couples DJ-1 with PTEN to activate PDGFRβ for renal proximal tubular cell injury.

Das F, Ghosh-Choudhury N, Kasinath B, Sharma K, Ghosh Choudhury G PLoS One. 2025; 20(1):e0311828.

PMID: 39761275 PMC: 11703087. DOI: 10.1371/journal.pone.0311828.

Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma.

Ford C, Koludrovic D, Centeno P, Foth M, Tsonou E, Vlahov N Cancer Res. 2024; 85(4):808-824.

PMID: 39636745 PMC: 11831108. DOI: 10.1158/0008-5472.CAN-23-2814.

Melanoma genomics - will we go beyond BRAF in clinics?.

Mirek J, Bal W, Olbryt M J Cancer Res Clin Oncol. 2024; 150(9):433.

PMID: 39340537 PMC: 11438618. DOI: 10.1007/s00432-024-05957-2.

Understanding P-Rex regulation: structural breakthroughs and emerging perspectives.

Jones G, Ellisdon A Biochem Soc Trans. 2024; 52(4):1849-1860.

PMID: 39023851 PMC: 11668296. DOI: 10.1042/BST20231546.

Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma.

Zhou Y, Mo S, Cui H, Sun R, Zhang W, Zhuang X Natl Sci Rev. 2024; 11(5):nwae150.

PMID: 38803565 PMC: 11129594. DOI: 10.1093/nsr/nwae150.

References

Maehama T, Dixon J . The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998; 273(22):13375-8. DOI: 10.1074/jbc.273.22.13375. View

Fejzo M, Godfrey T, Chen C, Waldman F, Gray J . Molecular cytogenetic analysis of consistent abnormalities at 8q12-q22 in breast cancer. Genes Chromosomes Cancer. 1998; 22(2):105-13. DOI: 10.1002/(sici)1098-2264(199806)22:2<105::aid-gcc4>3.0.co;2-0. View

Donald S, Hill K, Lecureuil C, Barnouin R, Krugmann S, Coadwell W . P-Rex2, a new guanine-nucleotide exchange factor for Rac. FEBS Lett. 2004; 572(1-3):172-6. DOI: 10.1016/j.febslet.2004.06.096. View

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

Sun J, Liu W, Adams T, Sun J, Li X, Turner A . DNA copy number alterations in prostate cancers: a combined analysis of published CGH studies. Prostate. 2007; 67(7):692-700. DOI: 10.1002/pros.20543. View

Baker S . PTEN enters the nuclear age. Cell. 2007; 128(1):25-8. DOI: 10.1016/j.cell.2006.12.023. View

Vogelstein B, Fearon E, Hamilton S, Kern S, Preisinger A, Leppert M . Genetic alterations during colorectal-tumor development. N Engl J Med. 1988; 319(9):525-32. DOI: 10.1056/NEJM198809013190901. View

Rosenfeldt H, Vazquez-Prado J, Gutkind J . P-REX2, a novel PI-3-kinase sensitive Rac exchange factor. FEBS Lett. 2004; 572(1-3):167-71. DOI: 10.1016/j.febslet.2004.06.097. View

Debnath J, Brugge J . Modelling glandular epithelial cancers in three-dimensional cultures. Nat Rev Cancer. 2005; 5(9):675-88. DOI: 10.1038/nrc1695. View

10.

Courtois-Cox S, Williams S, Reczek E, Johnson B, McGillicuddy L, Johannessen C . A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 2006; 10(6):459-72. PMC: 2692661. DOI: 10.1016/j.ccr.2006.10.003. View

11.

Eng C . PTEN: one gene, many syndromes. Hum Mutat. 2003; 22(3):183-98. DOI: 10.1002/humu.10257. View

12.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S . PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275(5308):1943-7. DOI: 10.1126/science.275.5308.1943. View

13.

McConnachie G, Pass I, Walker S, Downes C . Interfacial kinetic analysis of the tumour suppressor phosphatase, PTEN: evidence for activation by anionic phospholipids. Biochem J. 2003; 371(Pt 3):947-55. PMC: 1223325. DOI: 10.1042/BJ20021848. View

14.

Hill K, Krugmann S, Andrews S, Coadwell W, Finan P, Welch H . Regulation of P-Rex1 by phosphatidylinositol (3,4,5)-trisphosphate and Gbetagamma subunits. J Biol Chem. 2004; 280(6):4166-73. DOI: 10.1074/jbc.M411262200. View

15.

Isakoff S, Engelman J, Irie H, Luo J, Brachmann S, Pearline R . Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005; 65(23):10992-1000. DOI: 10.1158/0008-5472.CAN-05-2612. View

16.

Leslie N, Downes C . PTEN function: how normal cells control it and tumour cells lose it. Biochem J. 2004; 382(Pt 1):1-11. PMC: 1133909. DOI: 10.1042/BJ20040825. View

17.

Qin J, Xie Y, Wang B, Hoshino M, Wolff D, Zhao J . Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis. Oncogene. 2009; 28(16):1853-63. PMC: 2672965. DOI: 10.1038/onc.2009.30. View

18.

Yu Z, Fotouhi-Ardakani N, Wu L, Maoui M, Wang S, Banville D . PTEN associates with the vault particles in HeLa cells. J Biol Chem. 2002; 277(43):40247-52. DOI: 10.1074/jbc.M207608200. View

19.

Sjoblom T, Jones S, Wood L, Parsons D, Lin J, Barber T . The consensus coding sequences of human breast and colorectal cancers. Science. 2006; 314(5797):268-74. DOI: 10.1126/science.1133427. View

20.

Adler A, Lin M, Horlings H, Nuyten D, van de Vijver M, Chang H . Genetic regulators of large-scale transcriptional signatures in cancer. Nat Genet. 2006; 38(4):421-30. PMC: 1435790. DOI: 10.1038/ng1752. View