Tumor suppressor PTEN mediates sensing of chemoattractant gradients.
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.
Iijima
Miho
M
Department of Cell Biology, Johns Hopkins University, School of Medicine, 21205, Baltimore, MD, USA
Devreotes
Peter
P
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D016764:Cell Polarity / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D004023:Dictyostelium / Q000166:cytology / Q000201:enzymology* / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology; D049452:Green Fluorescent Proteins; D007202:Indicators and Reagents / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009712:Nucleotides, Cyclic / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics; D011108:Polymers / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D011554:Pseudopodia / Q000378:metabolism* / Q000648:ultrastructure; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics
D007202:Indicators and Reagents; D008164:Luminescent Proteins; D009712:Nucleotides, Cyclic; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D011108:Polymers; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D049452:Green Fluorescent Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase