PTEN Tumor Suppressor Associates with NHERF Proteins to Attenuate PDGF Receptor Signaling

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2006 Feb 4

PMID 16456542

Citations 108

Authors

Yoko Takahashi

Fabiana C Morales

Erica L Kreimann

Maria-Magdalena Georgescu

Affiliations

Soon will be listed here.

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.

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References

Shenolikar S, Minkoff C, Steplock D, Evangelista C, Liu M, Weinman E . N-terminal PDZ domain is required for NHERF dimerization. FEBS Lett. 2001; 489(2-3):233-6. DOI: 10.1016/s0014-5793(01)02109-3. View

Andres-Pons A, Valiente M, Torres J, Gil A, Rogla I, Ripoll F . Functional definition of relevant epitopes on the tumor suppressor PTEN protein. Cancer Lett. 2005; 223(2):303-12. DOI: 10.1016/j.canlet.2004.09.047. View

Lau A, Hall R . Oligomerization of NHERF-1 and NHERF-2 PDZ domains: differential regulation by association with receptor carboxyl-termini and by phosphorylation. Biochemistry. 2001; 40(29):8572-80. DOI: 10.1021/bi0103516. View

Vazquez F, Grossman S, Takahashi Y, Rokas M, Nakamura N, Sellers W . Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem. 2001; 276(52):48627-30. DOI: 10.1074/jbc.C100556200. View

Waite K, Eng C . Protean PTEN: form and function. Am J Hum Genet. 2002; 70(4):829-44. PMC: 379112. DOI: 10.1086/340026. View

Ingraffea J, Reczek D, Bretscher A . Distinct cell type-specific expression of scaffolding proteins EBP50 and E3KARP: EBP50 is generally expressed with ezrin in specific epithelia, whereas E3KARP is not. Eur J Cell Biol. 2002; 81(2):61-8. DOI: 10.1078/0171-9335-00218. View

Das S, Dixon J, Cho W . Membrane-binding and activation mechanism of PTEN. Proc Natl Acad Sci U S A. 2003; 100(13):7491-6. PMC: 164614. DOI: 10.1073/pnas.0932835100. View

Demoulin J, Seo J, Ekman S, Grapengiesser E, Hellman U, Ronnstrand L . Ligand-induced recruitment of Na+/H+-exchanger regulatory factor to the PDGF (platelet-derived growth factor) receptor regulates actin cytoskeleton reorganization by PDGF. Biochem J. 2003; 376(Pt 2):505-10. PMC: 1223789. DOI: 10.1042/BJ20030385. View

Sumitomo M, Iwase A, Zheng R, Navarro D, Kaminetzky D, Shen R . Synergy in tumor suppression by direct interaction of neutral endopeptidase with PTEN. Cancer Cell. 2004; 5(1):67-78. DOI: 10.1016/s1535-6108(03)00331-3. View

10.

Mahimainathan L, Ghosh Choudhury G . Inactivation of platelet-derived growth factor receptor by the tumor suppressor PTEN provides a novel mechanism of action of the phosphatase. J Biol Chem. 2004; 279(15):15258-68. DOI: 10.1074/jbc.M314328200. View

11.

Kang Y, Jeon E, Lee H, Oh Y, Suh P, Jung J . NHERF2 increases platelet-derived growth factor-induced proliferation through PI-3-kinase/Akt-, ERK-, and Src family kinase-dependent pathway. Cell Signal. 2004; 16(7):791-800. DOI: 10.1016/j.cellsig.2003.12.003. View

12.

Li C, Roy K, Dandridge K, Naren A . Molecular assembly of cystic fibrosis transmembrane conductance regulator in plasma membrane. J Biol Chem. 2004; 279(23):24673-84. DOI: 10.1074/jbc.M400688200. View

13.

Wymann M, Arcaro A . Platelet-derived growth factor-induced phosphatidylinositol 3-kinase activation mediates actin rearrangements in fibroblasts. Biochem J. 1994; 298 Pt 3:517-20. PMC: 1137889. DOI: 10.1042/bj2980517. View

14.

Hollenberg S, Sternglanz R, Cheng P, Weintraub H . Identification of a new family of tissue-specific basic helix-loop-helix proteins with a two-hybrid system. Mol Cell Biol. 1995; 15(7):3813-22. PMC: 230620. DOI: 10.1128/MCB.15.7.3813. View

15.

Doyle D, Lee A, Lewis J, Kim E, Sheng M, Mackinnon R . Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ. Cell. 1996; 85(7):1067-76. DOI: 10.1016/s0092-8674(00)81307-0. View

16.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S . PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275(5308):1943-7. DOI: 10.1126/science.275.5308.1943. View

17.

Steck P, Pershouse M, Jasser S, Yung W, Lin H, Ligon A . Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997; 15(4):356-62. DOI: 10.1038/ng0497-356. View

18.

Lee J, Yang H, Georgescu M, Di Cristofano A, Maehama T, Shi Y . Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell. 1999; 99(3):323-34. DOI: 10.1016/s0092-8674(00)81663-3. View

19.

Leslie N, Gray A, Pass I, Orchiston E, Downes C . Analysis of the cellular functions of PTEN using catalytic domain and C-terminal mutations: differential effects of C-terminal deletion on signalling pathways downstream of phosphoinositide 3-kinase. Biochem J. 2000; 346 Pt 3:827-33. PMC: 1220919. View

20.

Wu X, Hepner K, Do D, Kaye M, Yuan X, Wood J . Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2. Proc Natl Acad Sci U S A. 2000; 97(8):4233-8. PMC: 18208. DOI: 10.1073/pnas.97.8.4233. View