Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca_(ER)^(2+)perturbation in hepatocellular carcinoma  

作　　者：Yanan Li Keqin Li Ting Pan Qiaobo Xie Yuyao Cheng Xinfeng Wu Rui Xu Xiaohui Liu Li Liu Jiangming Gao Wenmin Yuan Xianjun Qu Shuxiang Cui 

机构地区：[1]Department of Toxicology and Sanitary Chemistry,Beijing Key Laboratory of Environmental Toxicology,School of Public Health,Capital Medical University,Beijing 100069,China [2]Department of Pharmacology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China [3]Department of Pharmacology,Marine Biomedical Research Institute of Qingdao,Qingdao 266071,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第9期3744-3755,共12页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(81973350,China);supported by the National Natural Science Foundation of China(81872884 and 82173841,China);Beijing Natural Science Foundation(7222253,China)。

摘　　要：The well-known insulin-like growth factor 1(IGF1)/IGF-1 receptor(IGF-1R)signaling pathway is overexpressed in many tumors,and is thus an attractive target for cancer treatment.However,results have often been disappointing due to crosstalk with other signals.Here,we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma(HCC)cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2(SERCA2)activity.In response to ligand binding,IGF-1Rβis translocated into the ER byβ-arrestin2(β-arr2).Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ.SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβlevels.ER IGF-1Rβphosphorylates SERCA2 on Tyr^(990)to enhance its activity.Mutation of SERCA2-Tyr^(990)disrupted the interaction of ER IGF-1Rβwith SERCA2,and therefore ER IGF-1Rβfailed to promote SERCA2 activity.The enhancement of SERCA2 activity triggered Ca_(ER)^(2+)perturbation,leading to an increase in autophagy.Thapsigargin blocked the interaction between SERCA2and ER IGF-1Rβand therefore SERCA2 activity,resulting in inhibition of HCC growth.In conclusion,the translocation of IGF-1R into the ER triggers Ca_(ER)^(2+)perturbation by enhancing SERCA2 activity through phosphorylating Tyr^(990)in HCC.

关 键 词：IGF-1R HCC Endoplasmic reticulum(ER) SERCA2 Ca_(ER)^(2+)perturbation βarrestin-2(β-arr2) SERCA2^(Y990) THAPSIGARGIN 

分 类 号：R735.7[医药卫生—肿瘤]