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MBC in Press, published online ahead of print February 13, 2008
Mol. Biol. Cell 10.1091/mbc.E07-11-1114

A more recent version of this article appeared on April 1, 2008
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Submitted on November 6, 2007
Revised on December 26, 2007
Accepted on February 5, 2008

NHERF1, a Novel AKT-associating Protein, Regulates ERK Signaling through a B-Raf Mediated Pathway

Bin Wang, Yanmei Yang, and Peter A. Friedman

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

Monitoring Editor: Gerard Evan

NHERF1 is a scaffolding protein that regulates signaling and trafficking of several G protein-coupled receptors, including the parathyroid hormone receptor (PTH1R). GPCRs activate ERK1/2 through different mechanisms. Here, we characterized NHERF1 regulation of PTH1R-stimulated ERK1/2. PTH stimulated ERK1/2 phosphorylation by a PKA-dependent, but PKC-, EPAC-, and Rap1-independent pathway in CHO 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 post-receptor 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)






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