1. ¹Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. ²Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3. ³Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence: Dr M-M Georgescu, The University of Texas, MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX 77030, USA. E-mail: mgeorges@mdanderson.org

Received 20 October 2006; Revised 15 January 2007; Accepted 15 January 2007; Published online 26 February 2007.

Abstract

Anchorage-independent growth is a hallmark of tumor growth and results from enhanced proliferation and altered cell–cell and cell-matrix interactions. By using gene-deficient mouse embryonic fibroblasts (MEFs), we showed for the first time that NHERF1/EBP50 (Na/H exchanger regulator factor 1/ezrin-radixin-moesin binding phosphoprotein 50), an adapter protein with membrane localization under physiological conditions, inhibits cell motility and is required to suppress anchorage-independent growth. Both NHERF1 PDZ domains are necessary for the tumor suppressor effect. NHERF1 associates directly through the PDZ2 domain with -catenin and is required for -catenin localization at the cell–cell junctions in MEFs. Mechanistically, the absence of NHERF1 selectively decreased the interaction of -catenin with E-cadherin, but not with N-cadherin. The ensuing disorganization of E-cadherin-mediated adherens junctions as well as the observed moderate increase in -catenin transcriptional activity contributed most likely to the anchorage-independent growth of NHERF1-deficient MEFs. In vivo, NHERF1 is specifically localized at the apical brush-border membrane in intestinal epithelial cells and is required to maintain a fraction of the cortical -catenin at this level. Thus, NHERF1 emerges as a cofactor essential for the integrity of epithelial tissues by maintaining the proper localization and complex assembly of -catenin.