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 func...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 ton tacts betwee n 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(Fisl pY38).Fisl 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.展开更多
基金This study was supported by the Natural Science Foundation of China(81772624,81972855,81630079,and 81972442)the Science and Technology Project of Guangzhou(201803010007)+4 种基金the Natural Science Foundation of Guangdong Province(2017A030313481,2021 Al 515010092)the National Postdoctoral Program for Innovative Talents(BX2021391)the Fundamental Research Funds for the Central Universities(17ykjc25)the National Key R&D Program of China(2017YFC0908501)the Open Funds of State Key Laboratory of Oncology in South China(KY013714).
文摘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 ton tacts betwee n 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(Fisl pY38).Fisl 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.
