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PMID: 16456542 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The EMBO journal ·Vol. 25 ·No. 4 ·2006-02-22 ·Pages 910-20

Takahashi Y, Morales FC, Kreimann EL, Georgescu MM

Abstract

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.

MeSH Terms
Animals Cell Line, Tumor Chemotaxis/drug effects,physiology Cytoskeleton/metabolism Enzyme Activation/drug effects,physiology Fibroblasts/enzymology Humans Mice PTEN Phosphohydrolase/deficiency,metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphoproteins/metabolism Platelet-Derived Growth Factor/metabolism,pharmacology Receptors, Platelet-Derived Growth Factor/metabolism Sodium-Hydrogen Exchangers
Chemicals
Phosphoproteins Platelet-Derived Growth Factor Sodium-Hydrogen Exchangers sodium-hydrogen exchanger regulatory factor Phosphatidylinositol 3-Kinases Receptors, Platelet-Derived Growth Factor PTEN Phosphohydrolase PTEN protein, human Pten protein, mouse
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Takahashi Yoko
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Morales Fabiana C
Kreimann Erica L
Georgescu Maria-Magdalena
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7600979
Published
2006-02-22
Epub
2006-00-02
Pages
910-20
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1383560
Subset
IM
Grants
NCI NIH HHS · R01 CA107201 · United States
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · CA16672 · United States
NCI NIH HHS · CA09299-26 · United States
NCI NIH HHS · T32 CA009299 · United States
NCI NIH HHS · CA107201 · United States
External Links
PubMed source DOI: 10.1038/sj.emboj.7600979 PMC Full Text View journal details
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