HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Am J Physiol Renal Physiol 292: F1028-F1034, 2007. First published November 14, 2006; doi:10.1152/ajprenal.00288.2006
0363-6127/07 $8.00

This Article Free upon publication Full Text Full Text (PDF) All Versions of this Article: 292/3/F1028    most recent 00288.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Sneddon, W. B. Articles by Friedman, P. A. Search for Related Content PubMed PubMed Citation Articles by Sneddon, W. B. Articles by Friedman, P. A.

Extracellular signal-regulated kinase activation by parathyroid hormone in distal tubule cells

¹Department of Pharmacology and ²Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Submitted 26 July 2006 ; accepted in final form 9 November 2006

The PTH receptor (PTH1R) activates multiple signaling pathways, including extracellular signal-regulated kinases 1 and 2 (ERK1/2). The role of epidermal growth factor receptor (EGFR) transactivation in ERK1/2 activation by PTH in distal kidney cells, a primary site of PTH action, was characterized. ERK1/2 phosphorylation was stimulated by PTH and blocked by the EGFR inhibitor, AG1478. Upon PTH stimulation, metalloprotease cleavage of membrane-bound heparin-binding fragment (HB-EGF) induced EGFR transactivation of ERK. Conditioned media from PTH-treated distal kidney cells activated ERK in HEK-293 cells. AG1478 added to HEK-293 cells ablated transactivation by conditioned media. HB-EGF directly activated ERK1/2 in HEK-293 cells. Pretreatment of distal kidney cells with the metalloprotease inhibitor GM-6001 abolished transactivation of ERK1/2 by PTH. The role of the PTH1R COOH terminus in PTX-sensitive ERK1/2 activation was characterized in HEK-293 cells transfected with wild-type PTH1R, with a PTH1R mutated at its COOH terminus, or with PTH1R truncated at position 480. PTH stimulated ERK by wild-type, mutated and truncated PTH1Rs 21-, 27- and 57-fold, respectively. Thus, the PTH1R COOH terminus exerts an inhibitory effect on ERK activation. EBP50, a scaffolding protein that binds to the PDZ recognition domain of the PTH1R, impaired PTH but not isoproterenol or calcitonin-induced ERK activation. Pertussis toxin inhibited PTH-stimulated ERK1/2 by mutated and truncated PTH1Rs and abolished ERK1/2 activation by wild-type PTH1R. We conclude that ERK phosphorylation in distal kidney cells by PTH requires PTH1R activation of G_i, which leads to stimulation of metalloprotease-mediated cleavage of HB-EGF and transactivation of the EGFR and is regulated by EBP50.

PTH receptor signaling; receptor internalization; epidermal growth factor transactivation; matrix metalloproteinase; EBP50/NHERF1

This article has been cited by other articles:

				S. J. Khundmiri, M. Ameen, N. A. Delamere, and E. D. Lederer PTH-mediated regulation of Na+-K+-ATPase requires Src kinase-dependent ERK phosphorylation Am J Physiol Renal Physiol, August 1, 2008; 295(2): F426 - F437. [Abstract] [Full Text] [PDF]

				S.-K. Cha, T. Wu, and C.-L. Huang Protein kinase C inhibits caveolae-mediated endocytosis of TRPV5 Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1212 - F1221. [Abstract] [Full Text] [PDF]

				B. Wang, Y. Yang, and P. A. Friedman Na/H Exchange Regulatory Factor 1, a Novel AKT-associating Protein, Regulates Extracellular Signal-regulated Kinase Signaling through a B-Raf-Mediated Pathway Mol. Biol. Cell, April 1, 2008; 19(4): 1637 - 1645. [Abstract] [Full Text] [PDF]