Research ArticleCancer

PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion

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Science Signaling  31 Mar 2015:
Vol. 8, Issue 370, pp. ra32
DOI: 10.1126/scisignal.2005840

Turning the tables on an inhibitor

Loss-of-function mutations are commonly detected in the tumor suppressor PTEN in various cancers. The lipid phosphatase activity of PTEN inhibits cell proliferation. In cancer, enhanced cell proliferation and migration often go hand in hand. Indeed, PTEN is inhibited by PREX2, a protein that promotes cell migration. Mense et al. found that the inhibition was reciprocal: Independently from its lipid phosphatase activity, PTEN suppressed the activity of PREX2. Forms of PREX2 with cancer-associated mutations were not inhibited by PTEN, inhibited the lipid phosphatase activity of PTEN, and promoted cancer cell invasion. Analysis of human tumors revealed a correlation between PREX2 mutation and high PTEN expression, suggesting that tumors select for PREX2 mutants with attenuated PTEN inhibition.


The tumor suppressor PTEN restrains cell migration and invasion by a mechanism that is independent of inhibition of the PI3K pathway and decreased activation of the kinase AKT. PREX2, a widely distributed GEF that activates the GTPase RAC1, binds to and inhibits PTEN. We used mouse embryonic fibroblasts and breast cancer cell lines to show that PTEN suppresses cell migration and invasion by blocking PREX2 activity. In addition to metabolizing the phosphoinositide PIP3, PTEN inhibited PREX2-induced invasion by a mechanism that required the tail domain of PTEN, but not its lipid phosphatase activity. Fluorescent nucleotide exchange assays revealed that PTEN inhibited the GEF activity of PREX2 toward RAC1. PREX2 is a frequently mutated GEF in cancer, and examination of human tumor data showed that PREX2 mutation was associated with high PTEN expression. Therefore, we tested whether cancer-derived somatic PREX2 mutants, which accelerate tumor formation of immortalized melanocytes, were inhibited by PTEN. The three stably expressed, somatic PREX2 cancer mutants that we tested were resistant to PTEN-mediated inhibition of invasion but retained the ability to inhibit the lipid phosphatase activity of PTEN. In vitro analysis showed that PTEN did not block the GEF activity of two PREX2 cancer mutants and had a reduced binding affinity for the third. Thus, PTEN antagonized migration and invasion by restraining PREX2 GEF activity, and PREX2 mutants are likely selected in cancer to escape PTEN-mediated inhibition of invasion.

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