Mimp, a mitochondrial carrier homologue, inhibits Met-HGF/SF-induced scattering and tumorigenicity by altering Met-HGF/SF signaling pathways.
We have recently shown that Mimp, a mitochondrial carrier protein homologue, is induced by Met-hepatocyte growth factor/scatter factor (HGF/SF) signaling and decreases the mitochondrial membrane potential in DA3 mammary adenocarcinoma cells. We show here that induction of Mimp leads to growth arrest in response to HGF/SF by arresting cells at the S phase of the cell cycle. Induction of Mimp or its transient expression does not lead to apoptosis. Mimp also attenuates HGF/SF-induced cellular scattering in vitro and tumor growth in vivo. The exogenous induction of Mimp at levels similar to its endogenous induction by HGF/SF increases the level of the Met protein and its phosphorylation by HGF/SF but reduces the levels of Shc and prevents the HGF/SF-induced tyrosine phosphorylation of Grb2 and Shc. In contrast, the level of phosphatidylinositol 3-kinase (PI3K) increases following Mimp induction and the level of phosphorylated PI3K in response to HGF/SF is unaffected by the exogenous induction of Mimp. Moreover, exogenous Mimp prevents the HGF/SF-induced transcription of the serum response element-luciferase reporter gene. Our results show that Mimp expression reduces Met-HGF/SF-induced proliferation and scattering by attenuating and altering the downstream signaling of Met. These data show a new link between a tyrosine kinase growth factor receptor and a mitochondrial carrier homologue that regulates cellular growth, motility, and tumorigenicity.
Leibowitz-Amit
Raya
R
Department of Human Microbiology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
Tsarfaty
Galia
G
Abargil
Yamit
Y
Yerushalmi
Gil M
GM
Horev
Judith
J
Tsarfaty
Ilan
I
D001943:Breast Neoplasms; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D007668:Kidney; D026901:Membrane Transport Proteins / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
C066855:HGF protein, human; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C550380:Mtch2 protein, mouse; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met