PTEN Functions by Recruitment to Cytoplasmic Vesicles

Naguib, Adam, Bencze, Gyula, Cho, Hyejin, Zheng, Wu, Tocilj, Ante, Elkayam, Elad, Faehnle, Christopher R, Jaber, Nadia, Pratt, Christopher P, Chen, Muhan, Zong, Wei-Xing, Marks, Michael S, Joshua-Tor, Leemor, Pappin, Darryl J, Trotman, Lloyd C (2015) PTEN Functions by Recruitment to Cytoplasmic Vesicles. Molecular Cell, 58 (2). pp. 255-268. ISSN 1097-2765

URL: http://www.ncbi.nlm.nih.gov/pubmed/25866245
DOI: 10.1016/j.molcel.2015.03.011

Abstract

Summary 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 to vesicles 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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
CSHL Authors:
Communities: CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
CSHL Cancer Center Program > Signal Transduction
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service
CSHL Cancer Center Shared Resources > Bioinformatics Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Mass Spectrometry Service
CSHL Cancer Center Shared Resources > Microscopy Service
CSHL Cancer Center Shared Resources > Proteomics Service
CSHL labs > Joshua-Tor lab
CSHL labs > Pappin lab
CSHL labs > Trotman lab
CSHL Cancer Center Shared Resources > DNA Sequencing Service
Depositing User: Matt Covey
Date Deposited: 16 Apr 2015 20:01
Last Modified: 04 Nov 2015 20:29
PMCID: PMC4423730
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31335

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