Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway

Anush Oganesian, Vladimir Yarov-Yarovoy, William C. Parks, Debra A. Schwinn

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

We previously identified a naturally occurringhumanSNP, G247R, in the third intracellular loop of the α 1a-adrenergic receptor (α 1a-247R) and demonstrated that constitutive expression of α 1a-247R results in twofold increased cell proliferation compared with WT. In the present study we elucidate molecular mechanisms and signal transduction pathwaysresponsible for increased cell proliferation unique to α 1a-247R, but not α 1a-WT, α 1b, or α 1dAR subtypes. We show that elevated levels of matrix metalloproteinase-7 (MMP7) and a disintegrin and metalloproteinase-12 (ADAM12) in α 1a-247R-expressing cells are responsible for EGF receptor (EGFR) transactivation, downstreamERK activation, and increased cell proliferation; this pathway is confirmed using MMP, EGFR, and ERK inhibitors. We demonstrate that EGFR transactivation and downstream ERK activation depends on increased shedding of heparin-binding EGF. Finally, we demonstrate that knockdown of MMP7 or β-arrestin1 by shRNAs results in attenuation of proliferation of cells expressing α 1a-247R. Importantly, accelerated cell proliferation triggered by the α 1a-247R is serum- and agonist-independent, providing unique evidence for constitutive active coupling to the β-arrestin1/MMP/EGFR transactivation pathway by any G protein-coupled receptor. These findings raise the possibility of a previously unexplored mechanismfor sympathetically mediated human hypertension triggered by a naturally occurring human genetic variant.

Original languageEnglish (US)
Pages (from-to)19796-19801
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number49
DOIs
StatePublished - Dec 6 2011

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