Constitutive signal bias mediated by the human GHRHR splice variant 1

doi:10.1073/pnas.2106606118

	Constitutive signal bias mediated by the human GHRHR splice variant 1
	Cong, Zhaotong 1,2; Zhou, Fulai 3; Zhang, Chao 4,5; Zou, Xinyu 6; Zhang, Huibing 7; Wang, Yuzhe 5,8; Zhou, Qingtong 1; Cai, Xiaoqing 3,8; Liu, Qiaofeng 2; Li, Jie 1
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2021-10-05
卷号	118 期号:40 页码:10
关键词	class B1 GPCR receptor bias cancer cell proliferation
ISSN号	0027-8424
DOI	10.1073/pnas.2106606118
通讯作者	Xu, H. Eric(eric.xu@simm.ac.cn) ; Cheng, Xi(xicheng@simm.ac.cn) ; Yang, Dehua(dhyang@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn)
英文摘要	Alternative splicing of G protein-coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone-releasing hormone receptor (GHRHR) is capable of transducing biased signal. Differing only at the receptor N terminus, GHRHR predominantly activates Gs while SV1 selectively couples to beta-arrestins. Based on the cryogenic electron microscopy structures of SV1 in the apo state or GHRH-bound state in complex with the Gs protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, Gs versus beta-arrestins. As suggested by mutagenesis and functional studies, it appears that GHRH-elicited signal bias toward beta-arrestin recruitment is constitutively mediated by SV1. The level of SV1 expression in prostate cancer cells is also positively correlated with ERK1/2 phosphorylation but negatively correlated with cAMP response. Our findings imply that constitutive signal bias may be a mechanism that ensures cancer cell proliferation.
资助项目	National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Science to Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science to Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Key Basic Research Program of China[2018YFA0507000] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Ministry of Science and Technology of China Major Project[XDB08020303] ; Novo Nordisk-Chinese Academy of Sciences (CAS) Research Fund[NNCAS-2017-1-CC] ; Youth Innovation Promotion Association of CAS[2018319] ; CAS Enrollment ; Sanofi-Aventis-Shanghai Institutes for Biological Sciences Scholarship Program
WOS关键词	HORMONE-RELEASING-HORMONE ; CANCER-CELLS ; INHIBIT GROWTH ; RECEPTOR ; ANTAGONISTS ; EXPRESSION ; ACTIVATION ; SPLICE-VARIANT-1 ; PROLIFERATION ; ENVIRONMENT
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATL ACAD SCIENCES
WOS记录号	WOS:000705930300019
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298448]
专题	中国科学院上海药物研究所
通讯作者	Xu, H. Eric; Cheng, Xi; Yang, Dehua; Wang, Ming-Wei
作者单位	1.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China 2.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.Huazhong Univ Sci & Technol, Sch Artificial Intelligence & Automat, Wuhan 430074, Peoples R China 7.Zhejiang Univ, Dept Biophys, Sch Med, Hangzhou 310058, Peoples R China 8.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 9.Fudan Univ, Eye & ENT Hosp, Shanghai 200031, Peoples R China 10.Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Cong, Zhaotong,Zhou, Fulai,Zhang, Chao,et al. Constitutive signal bias mediated by the human GHRHR splice variant 1[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2021,118(40):10.
APA	Cong, Zhaotong.,Zhou, Fulai.,Zhang, Chao.,Zou, Xinyu.,Zhang, Huibing.,...&Wang, Ming-Wei.(2021).Constitutive signal bias mediated by the human GHRHR splice variant 1.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,118(40),10.
MLA	Cong, Zhaotong,et al."Constitutive signal bias mediated by the human GHRHR splice variant 1".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 118.40(2021):10.