著名的胰岛素样生长因子1（IGF1）/IGF-1受体（IGF-1R）信号通路在许多肿瘤中过度表达，因此成为肿瘤治疗的有吸引力的靶点。然而，由于与其他信号的交互作用，结果往往令人失望。在这里，我们报告了IGF-1R信号通过IGF-1R转位到内质网增强肌球蛋白—内质网钙ATP酶2（SERCA2）活性来促进肝细胞癌（HCC）细胞的生长。在配体结合的情况下，IGF-1Rβ通过β-阻滞素2（β-arr2）转位到内质网。质谱分析确定SERCA2是内质网IGF-1Rβ的靶标。SERCA2的活性严重依赖于内质网IGF-1Rβ的增加。内质网IGF-1Rβ在Tyr990位点磷酸化SERCA2以增强其活性。SERCA2-Tyr990的突变破坏了内质网IGF-1Rβ与SERCA2的相互作用，从而内质网IGF-1Rβ无法促进SERCA2的活性。SERCA2活性的增强引发了Ca2+ER的扰动，导致自噬的增加。硫酸锂阻断了SERCA2与内质网IGF-1Rβ之间的相互作用，从而抑制了SERCA2的活性，导致HCC的生长受到抑制。总之，IGF-1R转位到内质网通过磷酸化HCC中的Tyr990，增强SERCA2活性，从而引发Ca2+ER的扰动。©2023中国药学会和中国医学科学院药物研究所。Elsevier B.V. 负责制作和主办。

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-1Rβ is translocated into the ER by β-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-1Rβ levels. ER IGF-1Rβ phosphorylates SERCA2 on Tyr990 to enhance its activity. Mutation of SERCA2-Tyr990 disrupted the interaction of ER IGF-1Rβ with SERCA2, and therefore ER IGF-1Rβ failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca2+ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rβ and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca2+ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr990 in HCC.© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.