Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2DER perturbation in hepatocellular carcinoma

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-1Rb is translocated into the ER by b-arrestin2 (b-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rb. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rb levels. ER IGF-1Rb phosphorylates SERCA2 on Tyr990 to enhance its activity. Mutation of SERCA2-Tyr990 disrupted the interaction of ER IGF-1Rb with SERCA2, and therefore ER IGF-1Rb failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca2 thorn ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rb and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca2 thorn 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. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).