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Vol. 19, Issue 4, 1637-1645, April 2008

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Na/H Exchange Regulatory Factor 1, a Novel AKT-associating Protein, Regulates Extracellular Signal-regulated Kinase Signaling through a B-Raf–Mediated Pathway

Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261

Submitted November 6, 2007; Revised December 26, 2007; Accepted February 5, 2008
Monitoring Editor: Gerard Evan

Na/H exchange regulatory factor 1 (NHERF1) is a scaffolding protein that regulates signaling and trafficking of several G protein-coupled receptors (GPCRs), including the parathyroid hormone receptor (PTH1R). GPCRs activate extracellular signal-regulated kinase (ERK)1/2 through different mechanisms. Here, we characterized NHERF1 regulation of PTH1R-stimulated ERK1/2. Parathyroid hormone (PTH) stimulated ERK1/2 phosphorylation by a protein kinase A (PKA)-dependent, but protein kinase C-, cyclic adenosine 5'-monophosphate-, and Rap1-independent pathway in Chinese hamster ovary cells stably transfected with the PTH1R and engineered to express NHERF1 under the control of tetracycline. NHERF1 blocked PTH-induced ERK1/2 phosphorylation downstream of PKA. This suggested that NHERF1 inhibitory effects on ERK1/2 occur at a postreceptor locus. Forskolin activated ERK1/2, and this effect was blocked by NHERF1. NHERF1 interacted with AKT and inhibited ERK1/2 activation by decreasing the stimulatory effect of 14-3-3 binding to B-Raf, while increasing the inhibitory influence of AKT negative regulation on ERK1/2 activation. This novel regulatory mechanism provides a new model by which cytoplasmic adapter proteins modulate ERK1/2 activation through a receptor-independent mechanism involving B-Raf.

Address correspondence to: Peter A. Friedman (paf10{at}pitt.edu)

Abbreviations used: CHO, Chinese hamster ovary; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; GPCR, G protein-coupled receptor; HA, hemagglutinin; MAPK, mitogen-activated protein kinases; NHERF1, Na/H exchange regulatory factor 1; PDGF, platelet-derived growth factor; PTH, parathyroid hormone; PTH1R, type 1 parathyroid hormone and parathyroid hormone-related peptide receptor; Tet, tetracycline; TO, tandem tetracycline operator sequences; TR, tetracycline repressor; PKA, protein kinase A.