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Vol. 18, Issue 5, 1768-1780, May 2007

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The NHERF1 PDZ2 Domain Regulates PKA–RhoA–p38-mediated NHE1 Activation and Invasion in Breast Tumor Cells

Rosa A. Cardone^*, Antonia Bellizzi^*,, Giovanni Busco^*, Edward J. Weinman^,, Maria E. Dell'Aquila^||, Valeria Casavola^*, Amalia Azzariti, Anita Mangia, Angelo Paradiso^,¶, and Stephan J. Reshkin^*,¶

Departments of *General and Environmental Physiology and ^||Animal Production, University of Bari, 70126 Bari, Italy; Clinical Experimental Oncology Laboratory, National Cancer Institute Giovanni Paolo II, 70126 Bari, Italy; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; and Medical Service, Department of Veterans Affairs Medical Center, Baltimore, MD 21201

Submitted July 21, 2006; Revised February 6, 2007; Accepted February 21, 2007
Monitoring Editor: John Cleveland

Understanding the signal transduction systems governing invasion is fundamental for the design of therapeutic strategies against metastasis. Na⁺/H⁺ exchanger regulatory factor (NHERF1) is a postsynaptic density 95/disc-large/zona occludens (PDZ) domain-containing protein that recruits membrane receptors/transporters and cytoplasmic signaling proteins into functional complexes. NHERF1 expression is altered in breast cancer, but its effective role in mammary carcinogenesis remains undefined. We report here that NHERF1 overexpression in human breast tumor biopsies is associated with metastatic progression, poor prognosis, and hypoxia-inducible factor-1 expression. In cultured tumor cells, hypoxia and serum deprivation increase NHERF1 expression, promote the formation of leading-edge pseudopodia, and redistribute NHERF1 to these pseudopodia. This pseudopodial localization of NHERF1 was verified in breast biopsies and in three-dimensional Matrigel culture. Furthermore, serum deprivation and hypoxia stimulate the Na⁺/H⁺ exchanger, invasion, and activate a protein kinase A (PKA)-gated RhoA/p38 invasion signal module. Significantly, NHERF1 overexpression was sufficient to induce these morphological and functional changes, and it potentiated their induction by serum deprivation. Functional experiments with truncated and binding groove-mutated PDZ domain constructs demonstrated that NHERF1 regulates these processes through its PDZ2 domain. We conclude that NHERF1 overexpression enhances the invasive phenotype in breast cancer cells, both alone and in synergy with exposure to the tumor microenvironment, via the coordination of PKA-gated RhoA/p38 signaling.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

^¶ These authors contributed equally to this work.

Address correspondence to: S. J. Reshkin (reshkin{at}biologia.uniba.it)

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