RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation
Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the parafollicular C-cells, which produces the hormone calcitonin. RET is a transmembrane receptor protein-tyrosine kinase, which is highly expressed in MTC. Our previous studies reported that cyclin-dependent kinase 5 (CDK5)...
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MDPI AG
2021-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/6/860 |
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| author | Chia-Herng Yue Muhammet Oner Chih-Yuan Chiu Mei-Chih Chen Chieh-Lin Teng Hsin-Yi Wang Jer-Tsong Hsieh Chih-Ho Lai Ho Lin |
| author_facet | Chia-Herng Yue Muhammet Oner Chih-Yuan Chiu Mei-Chih Chen Chieh-Lin Teng Hsin-Yi Wang Jer-Tsong Hsieh Chih-Ho Lai Ho Lin |
| author_sort | Chia-Herng Yue |
| collection | DOAJ |
| description | Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the parafollicular C-cells, which produces the hormone calcitonin. RET is a transmembrane receptor protein-tyrosine kinase, which is highly expressed in MTC. Our previous studies reported that cyclin-dependent kinase 5 (CDK5) plays a crucial role in cancer progression, including MTC. However, the role of CDK5 in GDNF-induced RET signaling in medullary thyroid cancer proliferation remains unknown. Here, we investigated RET activation and its biochemically interaction with CDK5 in GDNF-induced medullary thyroid cancer proliferation. Our results demonstrated that GDNF stimulated RET phosphorylation and thus subsequently resulted in CDK5 activation by its phosphorylation. Activated CDK5 further caused STAT3 activation by its specific phosphorylation at Ser727. Moreover, we also found that GDNF treatment enhanced ERK1/2 and EGR1 activity, which is involved in p35 activation. Interestingly, we identified for the first time that CDK5 physically interacted with RET protein in MTC. Overall, our results provide a new mechanism for medullary thyroid cancer cell proliferation, suggesting that targeting CDK5 may be a promising therapeutic candidate for human medullary thyroid cancer in the near future. |
| first_indexed | 2024-03-10T10:32:57Z |
| format | Article |
| id | doaj.art-265d2386b14841d896ec8b6213603e21 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T10:32:57Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-265d2386b14841d896ec8b6213603e212023-11-21T23:27:44ZengMDPI AGBiomolecules2218-273X2021-06-0111686010.3390/biom11060860RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 ActivationChia-Herng Yue0Muhammet Oner1Chih-Yuan Chiu2Mei-Chih Chen3Chieh-Lin Teng4Hsin-Yi Wang5Jer-Tsong Hsieh6Chih-Ho Lai7Ho Lin8Department of Surgery, Tung’s Taichung Metro Harbor Hospital, Taichung 435403, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung 402204, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung 402204, TaiwanTranslational Cell Therapy Center, Department of Medical Research, China Medical University Hospital, Taichung 404332, TaiwanDivision of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung 40201, TaiwanDepartment of Nuclear Medicine, Taichung Veterans General Hospital, Taichung 40705, TaiwanDepartment of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung 402204, TaiwanMedullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the parafollicular C-cells, which produces the hormone calcitonin. RET is a transmembrane receptor protein-tyrosine kinase, which is highly expressed in MTC. Our previous studies reported that cyclin-dependent kinase 5 (CDK5) plays a crucial role in cancer progression, including MTC. However, the role of CDK5 in GDNF-induced RET signaling in medullary thyroid cancer proliferation remains unknown. Here, we investigated RET activation and its biochemically interaction with CDK5 in GDNF-induced medullary thyroid cancer proliferation. Our results demonstrated that GDNF stimulated RET phosphorylation and thus subsequently resulted in CDK5 activation by its phosphorylation. Activated CDK5 further caused STAT3 activation by its specific phosphorylation at Ser727. Moreover, we also found that GDNF treatment enhanced ERK1/2 and EGR1 activity, which is involved in p35 activation. Interestingly, we identified for the first time that CDK5 physically interacted with RET protein in MTC. Overall, our results provide a new mechanism for medullary thyroid cancer cell proliferation, suggesting that targeting CDK5 may be a promising therapeutic candidate for human medullary thyroid cancer in the near future.https://www.mdpi.com/2218-273X/11/6/860human medullary thyroid carcinomaCDK5/p35RETSTAT3ERK1/2EGR1 |
| spellingShingle | Chia-Herng Yue Muhammet Oner Chih-Yuan Chiu Mei-Chih Chen Chieh-Lin Teng Hsin-Yi Wang Jer-Tsong Hsieh Chih-Ho Lai Ho Lin RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation Biomolecules human medullary thyroid carcinoma CDK5/p35 RET STAT3 ERK1/2 EGR1 |
| title | RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation |
| title_full | RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation |
| title_fullStr | RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation |
| title_full_unstemmed | RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation |
| title_short | RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation |
| title_sort | ret regulates human medullary thyroid cancer cell proliferation through cdk5 and stat3 activation |
| topic | human medullary thyroid carcinoma CDK5/p35 RET STAT3 ERK1/2 EGR1 |
| url | https://www.mdpi.com/2218-273X/11/6/860 |
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