View the Current Issue

Article

  • The EMBO Journal (2006) 25, 910 - 920
  • doi:10.1038/sj.emboj.7600979

Published online: 2 February 2006

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

Yoko Takahashi1, Fabiana C Morales1, Erica L Kreimann1 and Maria-Magdalena Georgescu1,2

  1. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Maria-Magdalena Georgescu, The University of Texas MD Anderson Cancer Center, Basic Science Research Building, Room S5.8336A, 6767 Bertner Avenue, Houston, TX 77030, USA. Tel.: +1 713 834 6201; Fax: +1 713 834 6230; E-mail: mgeorges@mdanderson.org

Received 17 May 2005; Accepted 9 January 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.

  • Keywords:

    • cancer,
    • EBP50,
    • NHERF,
    • PDGFR,
    • PTEN