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Vol. 15, Issue 12, 5470-5480, December 2004

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The Na⁺/H⁺ Exchanger Regulatory Factor Stabilizes Epidermal Growth Factor Receptors at the Cell Surface

Cheri S. Lazar ^*, Catherine M. Cresson , Douglas A. Lauffenburger , and Gordon N. Gill ^* 

^* Departments of Medicine and Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0650; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139

Submitted March 19, 2004; Revised September 13, 2004; Accepted September 14, 2004
Monitoring Editor: Juan S. Bonifacino

Ligand binding to cell surface receptors initiates both signal transduction and endocytosis. Although signaling may continue within the endocytic compartment, down-regulation is the major mechanism that controls the concentration of cell surface receptors, their ability to receive environmental signals, and the ultimate strength of biological signaling. Internalization, recycling, and trafficking of receptor tyrosine kinases (RTKs) within the endosome compartment are each regulated to control the overall process of down-regulation. We have identified the Na⁺/H⁺ exchanger regulatory factor (NHERF) as an important molecular component that stabilizes epidermal growth factor receptors (EGFRs) at the cell surface to restrict receptor down-regulation. The NH₂-terminal PDZ domain (PDZ 1) of NHERF specifically binds to an internal peptide motif located within the COOH-terminal regulatory domain of EGFR. Expression of NHERF slows the rate of EGF-induced receptor degradation. A point mutation that abolishes the PDZ 1 recognition sequence of EGFR enhances the rate of ligand-induced endocytosis and down-regulation of EGFR. Similarly, expression of a dominant negative mutant of NHERF enhances EGF-induced receptor down-regulation. In contrast to -adrenergic receptors where NHERF enhances recycling of internalized receptors, NHERF stabilizes EGFR at the cell surface and slows the rate of endocytosis without affecting recycling. Although the mechanisms differ, for both RTKs and G protein-coupled receptors, the overall effect of NHERF is to enhance the fraction of receptors present at the cell surface.

Abbreviations used: CFTR, cycstic fibrosis transmembrane conductance regulator; EGFR, epidermal growth factor receptor; ERM, Ezrin, Radizin, Moesin binding domain; GPCR, G protein-coupled receptor; NHERF, Na⁺/H⁺ exchanger regulatory factor; PDZ, domain initially identified in PSD 95, discs large and Z0-1 proteins; RTK, receptor tyrosine kinase.

Corresponding author. E-mail address: ggill{at}ucsd.edu.

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