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 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.

• Authors: 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
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 6 Issue 1 Pg. 401 (12 01 2021) ISSN: 2059-3635 [Electronic] England
• PMID: 34848680 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• FIS1 protein, human
• Membrane Proteins
• Mitochondrial Proteins
• MET protein, human
• Proto-Oncogene Proteins c-met

Topics

• Carcinoma, Hepatocellular (genetics, metabolism)
• HeLa Cells
• Humans
• Liver Neoplasms (genetics, metabolism)
• Membrane Proteins (genetics, metabolism)
• Mitochondria, Liver (genetics, metabolism)
• Mitochondrial Dynamics
• Mitochondrial Proteins (genetics, metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-met (genetics, metabolism)