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

17 Citations (Scopus)

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

Fingerprint

Epidermal Growth Factor Receptor
Adrenergic Receptors
Transcriptional Activation
Cell Proliferation
Matrix Metalloproteinase 7
Matrix Metalloproteinases
Disintegrins
Medical Genetics
Metalloproteases
G-Protein-Coupled Receptors
Epidermal Growth Factor
Heparin
Signal Transduction
Hypertension
Serum

ASJC Scopus subject areas

  • General

Cite this

Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway. / Oganesian, Anush; Yarov-Yarovoy, Vladimir; Parks, William C.; Schwinn, Debra A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 49, 06.12.2011, p. 19796-19801.

Research output: Contribution to journalArticle

@article{0b089e5155064dd985b2151d89d29a1b,
title = "Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway",
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.",
author = "Anush Oganesian and Vladimir Yarov-Yarovoy and Parks, {William C.} and Schwinn, {Debra A.}",
year = "2011",
month = "12",
day = "6",
doi = "10.1073/pnas.1116271108",
language = "English (US)",
volume = "108",
pages = "19796--19801",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "49",

}

TY - JOUR

T1 - Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway

AU - Oganesian, Anush

AU - Yarov-Yarovoy, Vladimir

AU - Parks, William C.

AU - Schwinn, Debra A.

PY - 2011/12/6

Y1 - 2011/12/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=83755183109&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83755183109&partnerID=8YFLogxK

U2 - 10.1073/pnas.1116271108

DO - 10.1073/pnas.1116271108

M3 - Article

C2 - 22089237

AN - SCOPUS:83755183109

VL - 108

SP - 19796

EP - 19801

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 49

ER -