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Mol Cell. 2015 Apr 16;58(2):255-68. doi: 10.1016/j.molcel.2015.03.011. Epub 2015 Apr 9.

PTEN functions by recruitment to cytoplasmic vesicles.

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; W. M. Keck Structural Biology Laboratory, Cold Spring Harbor, NY 11724, USA.
3
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; W. M. Keck Structural Biology Laboratory, Cold Spring Harbor, NY 11724, USA; Howard Hughes Medical Institute, Cold Spring Harbor, NY 11724, USA.
4
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
5
Department of Pathology & Laboratory of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology & Laboratory of Medicine and Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: trotman@cshl.edu.

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 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.

PMID:
25866245
PMCID:
PMC4423730
DOI:
10.1016/j.molcel.2015.03.011
[Indexed for MEDLINE]
Free PMC Article
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