PKG II secreted via the classical endoplasmic reticulum–Golgi apparatus secretory pathway blocks the activation of EGFR through phosporalting its threonine 406 and has an anti-tumor effect
Background: Protein kinase G type II (PKG II) is a serine/threonine-protein kinase that was originally isolated from the small intestinal mucosa with primary functions in the secretion of small intestinal mucosal cells, secretion of renin and aldosterone, and chondrocyte activities. Recent studies h...
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| Format: | Article |
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IMR Press
2022-02-01
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| Series: | Frontiers in Bioscience-Landmark |
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| Online Access: | https://www.imrpress.com/journal/FBL/27/2/10.31083/j.fbl2702053 |
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| author | Yan Wu Min Wu Zibin Wang Ji Pang Miaolin Zhu Ting Lan Xiaoyuan Yao Hai Qian Xinyue Lin Lu Jiang Yan Tao Yujie Zhang Yongchang Chen |
| author_facet | Yan Wu Min Wu Zibin Wang Ji Pang Miaolin Zhu Ting Lan Xiaoyuan Yao Hai Qian Xinyue Lin Lu Jiang Yan Tao Yujie Zhang Yongchang Chen |
| author_sort | Yan Wu |
| collection | DOAJ |
| description | Background: Protein kinase G type II (PKG II) is a serine/threonine-protein kinase that was originally isolated from the small intestinal mucosa with primary functions in the secretion of small intestinal mucosal cells, secretion of renin and aldosterone, and chondrocyte activities. Recent studies have shown that PKG II exerts anti-tumor effects, while a previous study by our group confirmed that PKG II inhibited the proliferation and migration of cancer cells. Interestingly, PKG II, which was typically bound to the intracellular side of the membrane, was detected in the serum and cell culture medium as a diagnostic biomarker of tumor growth. Thus, the aim of the present study was to elucidate the function and the targets of PKG II, and the mechanism underlying the secretion of this kinase. Methods: Construction of peptides and plasmids, RNA interference, Immunoelectron microscopy, Co-immunoprecipitation, N-glycosylation assay and Isolation of the Golgi apparatus were applied to investigate the secretory mechanism, and the targets and function of PKG II. Results: PKG II was secreted by enterochromaffin (EC) cells, which were components of the endocrine system in the gastrointestinal tract. Myristoylation of glycine 2 and the N-terminal sequence, especially the amino acids 3–30, acted as a signal peptide to induce the secretion of PKG II via the conventional protein secretory pathway. Moreover, recombinant PKG II inhibited the epidermal growth factor (EGF)-induced activation of the EGF receptor via phosphorylating the T406 of the extracellular domain and blocked EGF-triggered proliferation of various cancer cells. Conclusions: These results revealed a correlation between the endocrine system and the secretion of protein kinase, suggesting a novel protein secretory pathway. The resuls also indicated that secreted PKG II was a potential diagnostic biomarker and an inhibitor of tumor. |
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| issn | 2768-6701 |
| language | English |
| last_indexed | 2024-12-18T10:39:02Z |
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| spelling | doaj.art-879749b1ab9e4433b6a8e0e39c7787f42022-12-21T21:10:41ZengIMR PressFrontiers in Bioscience-Landmark2768-67012022-02-0127205310.31083/j.fbl2702053S2768-6701(22)00391-4PKG II secreted via the classical endoplasmic reticulum–Golgi apparatus secretory pathway blocks the activation of EGFR through phosporalting its threonine 406 and has an anti-tumor effectYan Wu0Min Wu1Zibin Wang2Ji Pang3Miaolin Zhu4Ting Lan5Xiaoyuan Yao6Hai Qian7Xinyue Lin8Lu Jiang9Yan Tao10Yujie Zhang11Yongchang Chen12Department of Physiology, School of Medicine, Jiangsu University, 212013 Zhenjiang, Jiangsu, ChinaDepartment of Physiology, School of Medicine, Jiangsu University, 212013 Zhenjiang, Jiangsu, ChinaAnalytical and Testing Center, Nanjing Medical University, 211166 Nanjing, Jiangsu, ChinaDepartment of Physiology, School of Medicine, Jiangsu University, 212013 Zhenjiang, Jiangsu, ChinaDepartment of Physiology, School of Medicine, Jiangsu University, 212013 Zhenjiang, Jiangsu, ChinaDepartment of Physiology, School of Medicine, Jiangsu University, 212013 Zhenjiang, Jiangsu, ChinaDepartment of Physiology, School of Medicine, Jiangsu University, 212013 Zhenjiang, Jiangsu, ChinaDepartment of Physiology, School of Medicine, Jiangsu University, 212013 Zhenjiang, Jiangsu, ChinaDepartment of Physiology, School of Medicine, Jiangsu University, 212013 Zhenjiang, Jiangsu, ChinaDepartment of Physiology, School of Medicine, Jiangsu University, 212013 Zhenjiang, Jiangsu, ChinaDepartment of Physiology, School of Medicine, Jiangsu University, 212013 Zhenjiang, Jiangsu, ChinaDepartment of Physiology, Nanjing Medical University, 211166 Nanjing, Jiangsu, ChinaDepartment of Physiology, School of Medicine, Jiangsu University, 212013 Zhenjiang, Jiangsu, ChinaBackground: Protein kinase G type II (PKG II) is a serine/threonine-protein kinase that was originally isolated from the small intestinal mucosa with primary functions in the secretion of small intestinal mucosal cells, secretion of renin and aldosterone, and chondrocyte activities. Recent studies have shown that PKG II exerts anti-tumor effects, while a previous study by our group confirmed that PKG II inhibited the proliferation and migration of cancer cells. Interestingly, PKG II, which was typically bound to the intracellular side of the membrane, was detected in the serum and cell culture medium as a diagnostic biomarker of tumor growth. Thus, the aim of the present study was to elucidate the function and the targets of PKG II, and the mechanism underlying the secretion of this kinase. Methods: Construction of peptides and plasmids, RNA interference, Immunoelectron microscopy, Co-immunoprecipitation, N-glycosylation assay and Isolation of the Golgi apparatus were applied to investigate the secretory mechanism, and the targets and function of PKG II. Results: PKG II was secreted by enterochromaffin (EC) cells, which were components of the endocrine system in the gastrointestinal tract. Myristoylation of glycine 2 and the N-terminal sequence, especially the amino acids 3–30, acted as a signal peptide to induce the secretion of PKG II via the conventional protein secretory pathway. Moreover, recombinant PKG II inhibited the epidermal growth factor (EGF)-induced activation of the EGF receptor via phosphorylating the T406 of the extracellular domain and blocked EGF-triggered proliferation of various cancer cells. Conclusions: These results revealed a correlation between the endocrine system and the secretion of protein kinase, suggesting a novel protein secretory pathway. The resuls also indicated that secreted PKG II was a potential diagnostic biomarker and an inhibitor of tumor.https://www.imrpress.com/journal/FBL/27/2/10.31083/j.fbl2702053enterochromaffin cellsprotein kinase g type iiprotein secretionepidermal growth factor receptorthreonine 406 |
| spellingShingle | Yan Wu Min Wu Zibin Wang Ji Pang Miaolin Zhu Ting Lan Xiaoyuan Yao Hai Qian Xinyue Lin Lu Jiang Yan Tao Yujie Zhang Yongchang Chen PKG II secreted via the classical endoplasmic reticulum–Golgi apparatus secretory pathway blocks the activation of EGFR through phosporalting its threonine 406 and has an anti-tumor effect Frontiers in Bioscience-Landmark enterochromaffin cells protein kinase g type ii protein secretion epidermal growth factor receptor threonine 406 |
| title | PKG II secreted via the classical endoplasmic reticulum–Golgi apparatus secretory pathway blocks the activation of EGFR through phosporalting its threonine 406 and has an anti-tumor effect |
| title_full | PKG II secreted via the classical endoplasmic reticulum–Golgi apparatus secretory pathway blocks the activation of EGFR through phosporalting its threonine 406 and has an anti-tumor effect |
| title_fullStr | PKG II secreted via the classical endoplasmic reticulum–Golgi apparatus secretory pathway blocks the activation of EGFR through phosporalting its threonine 406 and has an anti-tumor effect |
| title_full_unstemmed | PKG II secreted via the classical endoplasmic reticulum–Golgi apparatus secretory pathway blocks the activation of EGFR through phosporalting its threonine 406 and has an anti-tumor effect |
| title_short | PKG II secreted via the classical endoplasmic reticulum–Golgi apparatus secretory pathway blocks the activation of EGFR through phosporalting its threonine 406 and has an anti-tumor effect |
| title_sort | pkg ii secreted via the classical endoplasmic reticulum golgi apparatus secretory pathway blocks the activation of egfr through phosporalting its threonine 406 and has an anti tumor effect |
| topic | enterochromaffin cells protein kinase g type ii protein secretion epidermal growth factor receptor threonine 406 |
| url | https://www.imrpress.com/journal/FBL/27/2/10.31083/j.fbl2702053 |
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