TY - JOUR
T1 - Genetic evidence that b-arrestins are dispensable for the initiation of b2-adrenergic receptor signaling to ERK
AU - O'Hayre, Morgan
AU - Eichel, Kelsie
AU - Avino, Silvia
AU - Zhao, Xuefeng
AU - Steffen, Dana J.
AU - Feng, Xiaodong
AU - Kawakami, Kouki
AU - Aoki, Junken
AU - Messer, Karen
AU - Sunahara, Roger
AU - Inoue, Asuka
AU - Von Zastrow, Mark
AU - Gutkind, J. Silvio
N1 - Funding Information:
This study was partially supported by the National Institute of Dental and Craniofacial Research intramural program at the NIH (J.S.G. and M.O.). A.I. received funding from Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (JPMJPR1331) and the PRIME, Japan Agency for Medical Research and Development, and J.A. received funding from Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology. J.S.G. received funding from University of California, San Diego (UCSD) Moores Cancer Center and Department of Pharmacology. M.v.Z. received funding from the National Institute on Drug Abuse (DA012864 and DA06511). K.E. is a recipient of an NSF Graduate Research Fellowship. DJ.S. was supported in part by the UCSD Graduate Training Program in Cellular and Molecular Pharmacology through an institutional training grant from the National Institute of General Medical Sciences (T32 GM007752).
Publisher Copyright:
Copyright © 2017 The Authors, some rights reserved.
PY - 2017/6/20
Y1 - 2017/6/20
N2 - The b2-adrenergic receptor (b2AR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that b-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of b-arrestin 1 (b-arr1) and b-arr2 in b2AR internalization, trafficking, and signaling to ERK. We found that only b-arr2 was essential for b2AR internalization. Unexpectedly, b-arr1 and b-arr2 and receptor internalization were dispensable for ERK activation. Instead, b2AR signaled through Gas and Gbg subunits through a pathway that involved the tyrosine kinase SRC, the adaptor protein SHC, the guanine nucleotide exchange factor SOS, the small GTPase RAS, and the kinases RAF and MEK, which led to ERK activation. These findings provide a molecular framework for b2AR signaling through b-arrestin-independent pathways in key physiological functions and under pathological conditions.
AB - The b2-adrenergic receptor (b2AR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that b-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of b-arrestin 1 (b-arr1) and b-arr2 in b2AR internalization, trafficking, and signaling to ERK. We found that only b-arr2 was essential for b2AR internalization. Unexpectedly, b-arr1 and b-arr2 and receptor internalization were dispensable for ERK activation. Instead, b2AR signaled through Gas and Gbg subunits through a pathway that involved the tyrosine kinase SRC, the adaptor protein SHC, the guanine nucleotide exchange factor SOS, the small GTPase RAS, and the kinases RAF and MEK, which led to ERK activation. These findings provide a molecular framework for b2AR signaling through b-arrestin-independent pathways in key physiological functions and under pathological conditions.
UR - http://www.scopus.com/inward/record.url?scp=85021129764&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021129764&partnerID=8YFLogxK
U2 - 10.1126/scisignal.aal3395
DO - 10.1126/scisignal.aal3395
M3 - Article
C2 - 28634209
AN - SCOPUS:85021129764
VL - 10
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
SN - 1937-9145
IS - 484
M1 - eaal3395
ER -