Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis.
Signal Transduct Target Ther
; 6(1): 401, 2021 12 01.
Article
de En
| MEDLINE
| ID: mdl-34848680
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Mitochondries du foie
/
Carcinome hépatocellulaire
/
Protéines proto-oncogènes c-met
/
Protéines mitochondriales
/
Dynamique mitochondriale
/
Tumeurs du foie
/
Protéines membranaires
Type d'étude:
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
Signal Transduct Target Ther
Année:
2021
Type de document:
Article
Pays d'affiliation:
Chine