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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 22, 2006; DOI: 10.1124/jpet.106.104000

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Received for publication March 6, 2006.
Revised May 18, 2006.
Accepted for publication May 18, 2006.

COLLAGENASES 2 and 3 MEDIATE EPIDERMAL GROWTH FACTOR RECEPTOR TRANSACTIVATION by BRADYKININ B2 RECEPTOR in KIDNEY CELLS

Yurii V. Mukhin 1, Monika Gooz 1, John R. Raymond 1, Maria N. Garnovskaya 2*

1 Medical University of South Carolina; Ralph H. Johnson VA Medical Center 2 Ralph H. Johnson VA Medical Center; Medical University of South Carolina

* Address correspondence to: E-mail: garnovsk{at}musc.edu

Abstract

We have previously shown that stimulation of extracellular signal-regulated protein kinase (ERK) by bradykinin (BK) in inner medullary collecting duct (mIMCD-3) cells is mediated by epidermal growth factor receptor (EGFR) transactivation. The mechanism of EGFR transactivation appeared to be novel as it does not require phospholipase C, Ca2+, calmodulin, protein kinase C, G{alpha}i subunits, or EGFR-B2 receptor hetero-dimerization. In this study we demonstrated the involvement of matrix metalloproteinases (MMPs) in B2 receptor-induced EGFR transactivation using their broad-spectrum inhibitors batimastat and GM-6001. Selective inhibitors for collagenases 2 and 3 (MMP-8 and MMP-13) blocked BK-induced EGFR phosphorylation and ERK activation, whereas inhibitors for MMP-1, 2, 3, 7 or 9 were without effect. Transfection of mIMCD-3 cells with MMP-8 siRNA resulted in ~ 50% decrease of BK-induced ERK activation. A neutralizing antibody against MMP-13 as well as transfection with MMP-13 siRNA produced similar effect. Inhibition of both collagenases resulted in ~ 65% decrease of BK-induced ERK activation, supporting roles for both enzymes. Stimulation of mIMCD-3 cells with 10 nM BK increased the activity of collagenases in concentrated culture media within 10 minutes. Moreover, recombinant MMP-13 and MMP-8, when applied to mIMCD-3 cells for 10 minutes without BK, stimulated tyrosine phosphorylation of EGFR, and caused ~ 250% increase over basal ERK phosphorylation comparable with BK-induced ERK activation. Collagenases-induced ERK activation was inhibited by AG-1478, and thus dependent on EGFR tyrosine kinase activity. These studies demonstrate a novel role for collagenases 2 and 3 in signaling of the Gq-coupled BK B2 receptor in mIMCD-3 cells.


Key words: bradykinin, epidermal growth factor receptor, extracellular signal-regulated protein kinase, inner medullary collecting duct cells, matrix metalloproteinases, signal transduction




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