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J. Biol. Chem., Vol. 280, Issue 12, 11281-11288, March 25, 2005

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Parathyroid Hormone Receptor Trafficking Contributes to the Activation of Extracellular Signal-regulated Kinases but Is Not Required for Regulation of cAMP Signaling^*

Colin A. Syme, Peter A. Friedman, and Alessandro Bisello¶

From the Division of Endocrinology and Metabolism, Department of Medicine and the Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Agonist-mediated activation of the type 1 parathyroid hormone receptor (PTH1R) results in several signaling events and receptor endocytosis. It is well documented that arrestins contribute to desensitization of both G_s- and G_q-mediated signaling and mediate PTH1R internalization. However, whether PTH1R trafficking directly contributes to signaling remains unclear. To address this question, we investigated the role of PTH1R trafficking in cAMP signaling and activation of extracellular signal-regulated kinases ERK1/2 in HEK-293 cells. Dominant negative forms of dynamin (K44A-dynamin) and -arrestin1 (-arrestin1-(319–418)) abrogated PTH1R internalization but had no effect on cAMP signaling; neither acute cAMP production by PTH nor desensitization and resensitization of cAMP signaling were affected. Therefore, PTH1R trafficking is not necessary for regulation of cAMP signaling. PTH-(1–34) induced rapid and robust activation of ERK1/2. A PTHrP-based analog ([p-benzoylphenylalanine¹, Ile⁵,Arg^11,13,Tyr³⁶]PTHrP-(1–36)NH₂), which selectively activates the G_s/cAMP pathway without inducing PTH1R endocytosis, failed to stimulate ERK1/2 activity. Inhibition of PTH1R endocytosis by K44A-dynamin dampened ERK1/2 activation in response to PTH-(1–34) by 69%. Incubation with the epidermal growth factor receptor inhibitor AG1478 reduced ERK1/2 phosphorylation further. In addition, ERK1/2 phosphorylation occurred following internalization of a PTH1R mutant induced by PTH-(7–34) in the absence of G protein signaling. Collectively, these data indicate that PTH1R trafficking and G_q (but not G_s) signaling independently contribute to ERK1/2 activation, predominantly via transactivation of the epidermal growth factor receptor.

Received for publication, November 29, 2004

^* This work was supported by National Institutes of Health Grants DK-62078 (to A. B.) and DK-54171 (to P. A. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, E1140 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261. Tel.: 412-648-7347; Fax: 412-648-3290; E-mail: biselloa{at}msx.dept-med.pitt.edu.

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