Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis

Abstract Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics ar...

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Autores principales:	Yan Yu, Xiao-Dan Peng, Xiao-Jun Qian, Kai-Ming Zhang, Xiang Huang, Yu-Hong Chen, Yun-Tian Li, Gong-Kan Feng, Hai-Liang Zhang, Xue-Lian Xu, Shun Li, Xuan Li, Jia Mai, Zhi-Ling Li, Yun Huang, Dong Yang, Li-Huan Zhou, Zhuo-Yan Zhong, Jun-Dong Li, Rong Deng, Xiao-Feng Zhu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Medicine R Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/6601f6c66f7649e89ed624b91b63f812
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spelling	oai:doaj.org-article:6601f6c66f7649e89ed624b91b63f8122021-12-05T12:07:20ZFis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis10.1038/s41392-021-00790-22059-3635https://doaj.org/article/6601f6c66f7649e89ed624b91b63f8122021-12-01T00:00:00Zhttps://doi.org/10.1038/s41392-021-00790-2https://doaj.org/toc/2059-3635Abstract Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.Yan YuXiao-Dan PengXiao-Jun QianKai-Ming ZhangXiang HuangYu-Hong ChenYun-Tian LiGong-Kan FengHai-Liang ZhangXue-Lian XuShun LiXuan LiJia MaiZhi-Ling LiYun HuangDong YangLi-Huan ZhouZhuo-Yan ZhongJun-Dong LiRong DengXiao-Feng ZhuNature Publishing GrouparticleMedicineRBiology (General)QH301-705.5ENSignal Transduction and Targeted Therapy, Vol 6, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Biology (General) QH301-705.5
spellingShingle	Medicine R Biology (General) QH301-705.5 Yan Yu Xiao-Dan Peng Xiao-Jun Qian Kai-Ming Zhang Xiang Huang Yu-Hong Chen Yun-Tian Li Gong-Kan Feng Hai-Liang Zhang Xue-Lian Xu Shun Li Xuan Li Jia Mai Zhi-Ling Li Yun Huang Dong Yang Li-Huan Zhou Zhuo-Yan Zhong Jun-Dong Li Rong Deng Xiao-Feng Zhu Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis
description	Abstract Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.
format	article
author	Yan Yu Xiao-Dan Peng Xiao-Jun Qian Kai-Ming Zhang Xiang Huang Yu-Hong Chen Yun-Tian Li Gong-Kan Feng Hai-Liang Zhang Xue-Lian Xu Shun Li Xuan Li Jia Mai Zhi-Ling Li Yun Huang Dong Yang Li-Huan Zhou Zhuo-Yan Zhong Jun-Dong Li Rong Deng Xiao-Feng Zhu
author_facet	Yan Yu Xiao-Dan Peng Xiao-Jun Qian Kai-Ming Zhang Xiang Huang Yu-Hong Chen Yun-Tian Li Gong-Kan Feng Hai-Liang Zhang Xue-Lian Xu Shun Li Xuan Li Jia Mai Zhi-Ling Li Yun Huang Dong Yang Li-Huan Zhou Zhuo-Yan Zhong Jun-Dong Li Rong Deng Xiao-Feng Zhu
author_sort	Yan Yu
title	Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis
title_short	Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis
title_full	Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis
title_fullStr	Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis
title_full_unstemmed	Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis
title_sort	fis1 phosphorylation by met promotes mitochondrial fission and hepatocellular carcinoma metastasis
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/6601f6c66f7649e89ed624b91b63f812
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Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis

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