Tumor suppressor PTEN mediates sensing of chemoattractant gradients

Cell. 2002 May 31;109(5):599-610. doi: 10.1016/s0092-8674(02)00745-6.

Abstract

Shallow gradients of chemoattractants, sensed by G protein-linked signaling pathways, elicit localized binding of PH domains specific for PI(3,4,5)P3 at sites on the membrane where rearrangements of the cytoskeleton and pseudopod extension occur. Disruption of the PI 3-phosphatase, PTEN, in Dictyostelium discoideum dramatically prolonged and broadened the PH domain relocation and actin polymerization responses, causing the cells lacking PTEN to follow a circuitous route toward the attractant. Exogenously expressed PTEN-GFP localized to the surface membrane at the rear of the cell. Membrane localization required a putative PI(4,5)P2 binding motif and was required for chemotaxis. These results suggest that specific phosphoinositides direct actin polymerization to the cell's leading edge and regulation of PTEN through a feedback loop plays a critical role in gradient sensing and directional migration.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Animals
  • Cell Membrane / metabolism*
  • Cell Polarity / physiology
  • Chemotaxis / physiology*
  • Cytosol / metabolism
  • Dictyostelium / cytology
  • Dictyostelium / enzymology*
  • Dictyostelium / genetics
  • Down-Regulation / physiology
  • Green Fluorescent Proteins
  • Indicators and Reagents / metabolism
  • Luminescent Proteins / metabolism
  • Mutation / genetics
  • Nucleotides, Cyclic / genetics
  • Nucleotides, Cyclic / metabolism
  • PTEN Phosphohydrolase
  • Phosphatidylinositol Phosphates / metabolism*
  • Phosphatidylinositols / metabolism
  • Phosphoric Monoester Hydrolases / deficiency*
  • Phosphoric Monoester Hydrolases / genetics
  • Polymers / metabolism
  • Protein Structure, Tertiary / physiology
  • Pseudopodia / metabolism*
  • Pseudopodia / ultrastructure
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics

Substances

  • Indicators and Reagents
  • Luminescent Proteins
  • Nucleotides, Cyclic
  • Phosphatidylinositol Phosphates
  • Phosphatidylinositols
  • Polymers
  • Tumor Suppressor Proteins
  • phosphatidylinositol 3,4,5-triphosphate
  • Green Fluorescent Proteins
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase