title: PTEN functions by recruitment to cytoplasmic vesicles.
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.
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Adam
authors: A
authors: Naguib
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Gyula
authors: G
authors: Bencze
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Hyejin
authors: H
authors: Cho
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Wu
authors: W
authors: Zheng
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; W. M. Keck Structural Biology Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Ante
authors: A
authors: Tocilj
authors: 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.
authors: Elad
authors: E
authors: Elkayam
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; W. M. Keck Structural Biology Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Christopher R
authors: CR
authors: Faehnle
authors: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
authors: Nadia
authors: N
authors: Jaber
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Christopher P
authors: CP
authors: Pratt
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Muhan
authors: M
authors: Chen
authors: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
authors: Wei-Xing
authors: WX
authors: Zong
authors: 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.
authors: Michael S
authors: MS
authors: Marks
authors: 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.
authors: Leemor
authors: L
authors: Joshua-Tor
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Darryl J
authors: DJ
authors: Pappin
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: trotman@cshl.edu.
authors: Lloyd C
authors: LC
authors: Trotman
mesh_terms: D000818:Animals; D001665:Binding Sites; D051379:Mice; D008870:Microtubules / Q000201:enzymology; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D051059:PTEN Phosphohydrolase / Q000737:chemistry* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D017433:Protein Structure, Secondary; D015398:Signal Transduction; D022161:Transport Vesicles / Q000378:metabolism*
chemical_list: D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse