PTEN functions by recruitment to cytoplasmic vesicles

Adam Naguib, Gyula Bencze, Hyejin Cho, Wu Zheng, Ante Tocilj, Elad Elkayam, Christopher R. Faehnle, Nadia Jaber, Christopher P. Pratt, Muhan Chen, Wei Xing Zong, Michael S. Marks, Leemor Joshua-Tor, Darryl J. Pappin, Lloyd C. Trotman

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

PTEN is proposed to function at the plasma membrane, where receptor tyrosine kinases are activated. However, the majority of PTEN is located throughout the cytoplasm. Here, we show that cytoplasmic PTEN is distributed along microtubules, tethered tovesicles via phosphatidylinositol 3-phosphate (PI(3)P), the signature lipid of endosomes. We demonstrate that the non-catalytic C2 domain of PTEN specifically binds PI(3)P through the CBR3 loop. Mutations render this loop incapable of PI(3)P binding and abrogate PTEN-mediated inhibition of PI 3-kinase/AKT signaling. This loss of function is rescued by fusion of the loop mutant PTEN to FYVE, the canonical PI(3)P binding domain, demonstrating the functional importance of targeting PTEN to endosomal membranes. Beyond revealing an upstream activation mechanism of PTEN, our data introduce the concept of PI 3-kinase signal activation on the vast plasma membrane that is contrasted by PTEN-mediated signal termination on the small, discrete surfaces of internalized vesicles.

Original languageEnglish (US)
Pages (from-to)255-268
Number of pages14
JournalMolecular cell
Volume58
Issue number2
DOIs
StatePublished - Apr 16 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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