O'Hayre Morgan, Eichel Kelsie, Avino Silvia, Zhao Xuefeng, Steffen Dana J, Feng Xiaodong, Kawakami Kouki, Aoki Junken, Messer Karen, Sunahara Roger, Inoue Asuka, von Zastrow Mark, Gutkind J Silvio
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20852, USA.
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA.
Sci Signal. 2017 Jun 20;10(484):eaal3395. doi: 10.1126/scisignal.aal3395.
The β-adrenergic receptor (βAR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that β-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 β-arrestin 1 (β-arr1) and β-arr2 in βAR internalization, trafficking, and signaling to ERK. We found that only β-arr2 was essential for βAR internalization. Unexpectedly, β-arr1 and β-arr2 and receptor internalization were dispensable for ERK activation. Instead, βAR signaled through Gα and Gβγ 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 βAR signaling through β-arrestin-independent pathways in key physiological functions and under pathological conditions.
β-肾上腺素能受体（βAR）为阐明G蛋白偶联受体（GPCR）如何控制细胞内信号传导提供了一个范例，其中包括发现与配体激活的GPCR结合的β-抑制蛋白对GPCR功能至关重要。我们使用基因组编辑、条件性基因缺失和小干扰RNA（siRNA）来确定β-抑制蛋白1（β-arr1）和β-抑制蛋白2（β-arr2）在βAR内化、转运以及向细胞外调节蛋白激酶（ERK）信号传导中的作用。我们发现只有β-arr2对βAR内化至关重要。出乎意料的是，β-arr1和β-arr2以及受体内化对于ERK激活是可有可无的。相反，βAR通过涉及酪氨酸激酶SRC、衔接蛋白SHC、鸟嘌呤核苷酸交换因子SOS、小GTP酶RAS以及激酶RAF和丝裂原活化蛋白激酶激酶（MEK）的途径，通过Gα和Gβγ亚基发出信号，从而导致ERK激活。这些发现为βAR在关键生理功能和病理条件下通过不依赖β-抑制蛋白的途径进行信号传导提供了一个分子框架。
