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 signali...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383523001946 |
| _version_ | 1797690189101924352 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yanan Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T01:55:58Z |
| format | Article |
| id | doaj.art-36f6f2e940474e3e873761c3a5e4b1a0 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-03-12T01:55:58Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-36f6f2e940474e3e873761c3a5e4b1a02023-09-08T04:33:18ZengElsevierActa Pharmaceutica Sinica B2211-38352023-09-0113937443755Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinomaYanan Li0Keqin Li1Ting Pan2Qiaobo Xie3Yuyao Cheng4Xinfeng Wu5Rui Xu6Xiaohui Liu7Li Liu8Jiangming Gao9Wenmin Yuan10Xianjun Qu11Shuxiang Cui12Department of Toxicology and Sanitary Chemistry, Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing 100069, ChinaDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Toxicology and Sanitary Chemistry, Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing 100069, ChinaDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Toxicology and Sanitary Chemistry, Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing 100069, ChinaDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Pharmacology, Marine Biomedical Research Institute of Qingdao, Qingdao 266071, ChinaDepartment of Pharmacology, Marine Biomedical Research Institute of Qingdao, Qingdao 266071, ChinaDepartment of Pharmacology, Marine Biomedical Research Institute of Qingdao, Qingdao 266071, ChinaDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; Corresponding authors. Tel./fax: +86 10 83911516.Department of Toxicology and Sanitary Chemistry, Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing 100069, China; Corresponding authors. Tel./fax: +86 10 83911516.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.http://www.sciencedirect.com/science/article/pii/S2211383523001946IGF-1RHCCEndoplasmic reticulum (ER)SERCA2Ca2+ER perturbationβarrestin-2 (β-arr2) |
| spellingShingle | 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 Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma Acta Pharmaceutica Sinica B IGF-1R HCC Endoplasmic reticulum (ER) SERCA2 Ca2+ER perturbation βarrestin-2 (β-arr2) |
| title | Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma |
| title_full | Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma |
| title_fullStr | Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma |
| title_full_unstemmed | Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma |
| title_short | Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma |
| title_sort | translocation of igf 1r in endoplasmic reticulum enhances serca2 activity to trigger ca2 er perturbation in hepatocellular carcinoma |
| topic | IGF-1R HCC Endoplasmic reticulum (ER) SERCA2 Ca2+ER perturbation βarrestin-2 (β-arr2) |
| url | http://www.sciencedirect.com/science/article/pii/S2211383523001946 |
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