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.
Highlights
Liver cancer is the second leading cause of cancer death worldwide because of the high rate of metastasis.[1]
Due to adverse side reactions and limited therapeutic effects, many clinical trials of selected Met inhibitors were hindered at Stage II or III,[11,12] There still remains a need for a clearer understanding of the hepatocyte growth factor (HGF)/Met pathway to accelerate Met-targeting strategy development
We examined the interaction of Met with other proteins involved in mitochondrial dynamics
Summary
Liver cancer is the second leading cause of cancer death worldwide because of the high rate of metastasis.[1]. Subcellular fractionation SIM-based immunofluorescent experiments and observed a studies revealed that HGF treatment stimulated Met localization in significant increase in Drp[1] puncta on mitochondria when the the mitochondrial fraction (Fig. 1j) Overall, these results show that cells were treated with HGF (Fig. 3d). In a subcellular fractionation assay, we found that Met−/− Huh[7] cells re-expressed with KD-Met exhibited reduced mitochondrial expression of Drp[1] compared to cells re-expressed with WT-Met (Supplementary Fig. S3a) These data establish that Met kinase promotes Drp[1] mitochondrial assembly and facilitates mitochondrial fission through Fis[1] protein. Met mediated Fis[1] Y38 phosphorylation facilitates cell metastasis in vitro and in vivo We investigated that whether Fis[1] pY38 promoted cellular lamellipodia or invadopodia formation, which was resulted from mitochondrial fission-based mitochondria redistribution and necessary for cell migration. Our findings defined a central role of Met in activating Fis[1] by tyrosine phosphorylation and promoting mitochondrial fission to facilitate HCC metastasis, suggesting its use in novel strategies to inhibit tumor recurrence and metastasis
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