Engineering ePTEN, an enhanced PTEN with increased tumor suppressor activities

Hoai Nghia Nguyen, Jr Ming Yang, Yashar Afkari, Ben Ho Park, Hiromi Sesaki, Peter N. Devreotes, Miho Iijima

Research output: Contribution to journalArticle

Abstract

The signaling lipid phosphatidylinositol (3,4,5)-trisphosphate (PIP3) is a key regulator of cell proliferation, survival, and migration and the enzyme that dephosphorylates it, phosphatase and tensin homolog (PTEN), is an important tumor suppressor. As excess PIP3 signaling is a hallmark of many cancers, its suppression through activation of PTEN is a potential cancer intervention. Using a heterologous expression system in which human PTEN-GFP is expressed in Dictyostelium cells, we identified mutations in the membrane-binding regulatory interface that increase the recruitment of PTEN to the plasma membrane due to enhanced association with PI(4,5)P2. We engineered these into an enhanced PTEN (ePTEN) with approximately eightfold increased ability to suppress PIP3 signaling. Upon expression in human cells, ePTEN decreases PIP3 levels in the plasma membrane; phosphorylation of AKT, a major downstream event in PIP3 signaling; and cell proliferation and migration. Thus, the activation of PTEN can readjust PIP3 signaling and may serve as a feasible target for anticancer therapies.

Original languageEnglish (US)
Pages (from-to)E2684-E2693
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number26
DOIs
StatePublished - Jul 1 2014

Keywords

  • Chemotaxis
  • Membrane localization
  • PI3 kinase signaling
  • Protein engineering
  • Protein interaction

ASJC Scopus subject areas

  • General

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