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

Content Provider	PubMed Central
Author	Oganesian, Anush Vladimir, Yarov-yarovoy Parks, William C. Schwinn, Debra A.
Abstract	We previously identified a naturally occurring human SNP, G247R, in the third intracellular loop of the α1a-adrenergic receptor (α1a-247R) and demonstrated that constitutive expression of α1a-247R results in twofold increased cell proliferation compared with WT. In the present study we elucidate molecular mechanisms and signal transduction pathways responsible for increased cell proliferation unique to α1a-247R, but not α1a-WT, α1b, or α1dAR subtypes. We show that elevated levels of matrix metalloproteinase-7 (MMP7) and a disintegrin and metalloproteinase-12 (ADAM12) in α1a-247R–expressing cells are responsible for EGF receptor (EGFR) transactivation, downstream ERK 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 α1a-247R. Importantly, accelerated cell proliferation triggered by the α1a-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 mechanism for sympathetically mediated human hypertension triggered by a naturally occurring human genetic variant.
Related Links	http://dx.doi.org/10.1073/pnas.1116271108
Ending Page	19801
Page Count	6
Starting Page	19796
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	49
Volume Number	108
Language	English
Publisher	National Academy of Sciences
Publisher Date	2011-12-06
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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