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PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signaling.

The EMBO journal | Feb 22, 2006

PTEN, a tumor suppressor frequently inactivated in many human cancers, directly antagonizes the activity of phosphatidylinositol-3-OH kinase (PI3K) by dephosphorylating phosphoinositides. We show here that PTEN interacts directly with the NHERF1 and NHERF2 (Na+/H+ exchanger regulatory factor) homologous adaptor proteins through the PDZ motif of PTEN and the PDZ1 domain of NHERF1 or both PDZ domains of NHERF2. NHERFs were shown to interact directly with platelet-derived growth factor receptor (PDGFR), and we demonstrate the assembly of a ternary complex between PTEN, NHERFs and PDGFR. The activation of the PI3K pathway after PDGFR stimulation was prolonged in NHERF1(-/-) mouse embryonic fibroblasts as compared to wild-type cells, consistent with defective PTEN recruitment to PDGFR in the absence of NHERF1. Depletion of NHERF2 by small interfering RNA similarly increased PI3K signaling. Phenotypically, the loss of NHERF1 enhanced the PDGF-induced cytoskeletal rearrangements and chemotactic migration of the cells. These data indicate that, in normal cells, NHERF proteins recruit PTEN to PDGFR to restrict the activation of the PI3K.

Pubmed ID: 16456542 RIS Download

Mesh terms: Animals | Cell Line, Tumor | Chemotaxis | Cytoskeleton | Enzyme Activation | Fibroblasts | Humans | Mice | PTEN Phosphohydrolase | Phosphatidylinositol 3-Kinases | Phosphoproteins | Platelet-Derived Growth Factor | Receptors, Platelet-Derived Growth Factor | Sodium-Hydrogen Antiporter

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA107201
  • Agency: NCI NIH HHS, Id: P30 CA016672
  • Agency: NCI NIH HHS, Id: CA16672
  • Agency: NCI NIH HHS, Id: CA09299-26
  • Agency: NCI NIH HHS, Id: T32 CA009299
  • Agency: NCI NIH HHS, Id: CA107201

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