A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN

Meghdad Rahdar, Takanari Inoue, Tobias Meyer, Jin Zhang, Francisca Vazquez, Peter N Devreotes

Research output: Contribution to journalArticle

Abstract

The PI 3-phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10), one of the most important tumor suppressors, must associate with the plasma membrane to maintain appropriate steady-state levels of phosphatidylinositol 3,4,5-triphosphate. Yet the mechanism of membrane binding has received little attention and the key determinants that regulate localization, a phosphatidylinositol 4,5-bisphosphate (PIP2) binding motif and a cluster of phosphorylated C-terminal residues, were not included in the crystal structure. We report that membrane binding requires PIP2 and show that phosphorylation regulates an intramolecular interaction. A truncated version of the enzyme, PTEN1-351, bound strongly to the membrane, an effect that was reversed by co-expression of the remainder of the molecule, PTEN352-403. The separate fragments associated in vitro, an interaction dependent on phosphorylation of the C-terminal cluster, a portion of the PIP2 binding motif, integrity of the phosphatase domain, and the CBR3 loop. Our investigation provides direct evidence for a model in which PTEN switches between open and closed states and phosphorylation favors the closed conformation, thereby regulating localization and function. Small molecules targeting these interactions could potentially serve as therapeutic agents in antagonizing Ras or PI3K-driven tumors. The study also stresses the importance of determining the structure of the native enzyme.

Original languageEnglish (US)
Pages (from-to)480-485
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number2
DOIs
StatePublished - Jan 13 2009

Fingerprint

Phosphorylation
Phosphoric Monoester Hydrolases
Membranes
PTEN Phosphohydrolase
Neoplasms
Chromosomes, Human, Pair 10
Enzymes
Phosphatidylinositols
Phosphatidylinositol 3-Kinases
Cell Membrane
Therapeutics
phosphatidylinositol 3,4,5-triphosphate
In Vitro Techniques
Tensins

Keywords

  • IRAP
  • Phosphatase
  • PI3K
  • PIP2
  • PIP3

ASJC Scopus subject areas

  • General

Cite this

@article{ed6f6fa12f6746669188220de87b8d2f,
title = "A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN",
abstract = "The PI 3-phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10), one of the most important tumor suppressors, must associate with the plasma membrane to maintain appropriate steady-state levels of phosphatidylinositol 3,4,5-triphosphate. Yet the mechanism of membrane binding has received little attention and the key determinants that regulate localization, a phosphatidylinositol 4,5-bisphosphate (PIP2) binding motif and a cluster of phosphorylated C-terminal residues, were not included in the crystal structure. We report that membrane binding requires PIP2 and show that phosphorylation regulates an intramolecular interaction. A truncated version of the enzyme, PTEN1-351, bound strongly to the membrane, an effect that was reversed by co-expression of the remainder of the molecule, PTEN352-403. The separate fragments associated in vitro, an interaction dependent on phosphorylation of the C-terminal cluster, a portion of the PIP2 binding motif, integrity of the phosphatase domain, and the CBR3 loop. Our investigation provides direct evidence for a model in which PTEN switches between open and closed states and phosphorylation favors the closed conformation, thereby regulating localization and function. Small molecules targeting these interactions could potentially serve as therapeutic agents in antagonizing Ras or PI3K-driven tumors. The study also stresses the importance of determining the structure of the native enzyme.",
keywords = "IRAP, Phosphatase, PI3K, PIP2, PIP3",
author = "Meghdad Rahdar and Takanari Inoue and Tobias Meyer and Jin Zhang and Francisca Vazquez and Devreotes, {Peter N}",
year = "2009",
month = "1",
day = "13",
doi = "10.1073/pnas.0811212106",
language = "English (US)",
volume = "106",
pages = "480--485",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "2",

}

TY - JOUR

T1 - A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN

AU - Rahdar, Meghdad

AU - Inoue, Takanari

AU - Meyer, Tobias

AU - Zhang, Jin

AU - Vazquez, Francisca

AU - Devreotes, Peter N

PY - 2009/1/13

Y1 - 2009/1/13

N2 - The PI 3-phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10), one of the most important tumor suppressors, must associate with the plasma membrane to maintain appropriate steady-state levels of phosphatidylinositol 3,4,5-triphosphate. Yet the mechanism of membrane binding has received little attention and the key determinants that regulate localization, a phosphatidylinositol 4,5-bisphosphate (PIP2) binding motif and a cluster of phosphorylated C-terminal residues, were not included in the crystal structure. We report that membrane binding requires PIP2 and show that phosphorylation regulates an intramolecular interaction. A truncated version of the enzyme, PTEN1-351, bound strongly to the membrane, an effect that was reversed by co-expression of the remainder of the molecule, PTEN352-403. The separate fragments associated in vitro, an interaction dependent on phosphorylation of the C-terminal cluster, a portion of the PIP2 binding motif, integrity of the phosphatase domain, and the CBR3 loop. Our investigation provides direct evidence for a model in which PTEN switches between open and closed states and phosphorylation favors the closed conformation, thereby regulating localization and function. Small molecules targeting these interactions could potentially serve as therapeutic agents in antagonizing Ras or PI3K-driven tumors. The study also stresses the importance of determining the structure of the native enzyme.

AB - The PI 3-phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10), one of the most important tumor suppressors, must associate with the plasma membrane to maintain appropriate steady-state levels of phosphatidylinositol 3,4,5-triphosphate. Yet the mechanism of membrane binding has received little attention and the key determinants that regulate localization, a phosphatidylinositol 4,5-bisphosphate (PIP2) binding motif and a cluster of phosphorylated C-terminal residues, were not included in the crystal structure. We report that membrane binding requires PIP2 and show that phosphorylation regulates an intramolecular interaction. A truncated version of the enzyme, PTEN1-351, bound strongly to the membrane, an effect that was reversed by co-expression of the remainder of the molecule, PTEN352-403. The separate fragments associated in vitro, an interaction dependent on phosphorylation of the C-terminal cluster, a portion of the PIP2 binding motif, integrity of the phosphatase domain, and the CBR3 loop. Our investigation provides direct evidence for a model in which PTEN switches between open and closed states and phosphorylation favors the closed conformation, thereby regulating localization and function. Small molecules targeting these interactions could potentially serve as therapeutic agents in antagonizing Ras or PI3K-driven tumors. The study also stresses the importance of determining the structure of the native enzyme.

KW - IRAP

KW - Phosphatase

KW - PI3K

KW - PIP2

KW - PIP3

UR - http://www.scopus.com/inward/record.url?scp=58849102128&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58849102128&partnerID=8YFLogxK

U2 - 10.1073/pnas.0811212106

DO - 10.1073/pnas.0811212106

M3 - Article

C2 - 19114656

AN - SCOPUS:58849102128

VL - 106

SP - 480

EP - 485

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 2

ER -