Activation of insulin-like growth factor-1 receptor (IGF-1R) promotes growth of colorectal cancer through triggering the MEX3A-mediated degradation of RIG-Ⅰ  

作　　者：Qiaobo Xie Yanyan Chu Wenmin Yuan Yanan Li Keqin Li Xinfeng Wu Xiaohui Liu Rui Xu Shuxiang Cui Xianjun Qu 

机构地区：[1]Department of Pharmacology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China [2]Ocean University of China,School of Medicine and Pharmacy,Qingdao 266075,China [3]Marine Biomedical Research Institute of Qingdao,Qingdao 266075,China [4]Department of Toxicology and Sanitary Chemistry,Beijing Key Laboratory of Environmental Toxicology,School of Public Health,Capital Medical University,Beijing 100069,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第7期2963-2975,共13页药学学报（英文版）

基　　金：supported by Beijing Natural Science Foundation(7222253,China);National Natural Science Foundation of China(81973350/82173841);supported by Beijing Natural Science Foundation(7212149,China)。

摘　　要：Insulin-like growth factor-1 receptor(IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers.However,targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings.Here,we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I.The active β-arrestin-2 scaffolds this disobliging signaling to talk with MEX3A.In response to ligands,IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250,opening the middle loop(Leu130-Cys141) to the RING domain of MEX3A through the conformational changes of βarr2.The models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I.The assay of the mutants βarr2Y64Aand βarr2Y250Afurther confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of MEX3A.The truncated-βarr2 and the peptide ATQAIRIF,which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes,thus blocking the IGF-1R-triggered RIG-I degradation.Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway.Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I.In summary,we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.

关 键 词：IGF-1R RIG-Iβ-Arrestin-2(βarr2) K48-linked ubiquitination MEX3A Anti-PD-L1 

分 类 号：R735.34[医药卫生—肿瘤]