Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER 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-1R β is translocated into the ER by β -arrestin2 (β -arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1R β. SERCA2 activity is heavily dependent on the increase in ER IGF-1R β levels. ER IGF-1R β phosphorylates SERCA2 on Tyr⁹⁹⁰ to enhance its activity. Mutation of SERCA2-Tyr⁹⁹⁰ disrupted the interaction of ER IGF-1R β with SERCA2, and therefore ER IGF-1R β 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-1R β 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. IGF-1R β was translocated into the ER, leading to the phosphorylation of SERCA2 on Tyr⁹⁹⁰. SERCA2 enhancement triggered Ca²⁺ ER perturbation, resulting in the increase of autophagy in HCC cells. [Display omitted] [ABSTRACT FROM AUTHOR]