Met-HGF/SF signal transduction induces mimp, a novel mitochondrial carrier homologue, which leads to mitochondrial depolarization.
Met-hepatocyte growth factor/scatter factor (HGF/SF) signaling plays an important role in epithelial tissue morphogenesis, lumen formation, and tumorigenicity. We have recently demonstrated that HGF/SF also alters the metabolic activity of cells by enhancing both the glycolytic and oxidative phosphorylation pathways of energy production. Using differential display polymerase chain reaction, we cloned a novel gene, designated mimp (Met-Induced Mitochondrial Protein), which is upregulated in NIH-3T3 cells cotransfected with both HGF/SF and Met (HMH cells). Northern and Western blot analyses showed that mimp is induced in several Met-expressing cell lines following treatment with HGF/SF. Mimp encodes a 33-kDa protein that shows sequence homology to the family of mitochondrial carrier proteins (MCPs). Murine Mimp (mMimp) is expressed in a wide variety of tissues, exhibiting an expression pattern similar to Met. Predominant expression is seen in liver, kidney, heart, skeletal muscle, and testis. Using immunostaining for HA-tagged mMimp and a GFP-mMimp chimeric protein as well as subcellular fractionation, we determined that Mimp is primarily localized to the mitochondria. Ectopic expression of mMimp in the Met-responsive adenocarcinoma cell line, DA3, reduced the mitochondrial membrane potential (uncoupling activity). The extent of the mitochondrial depolarization positively correlated with the level of Mimp expression. Our results demonstrate that Mimp is a novel mitochondrial carrier homologue upregulated by Met-HGF/SF signal transduction, which leads to mitochondrial depolarization, and suggest novel links among tyrosine kinase signaling, mitochondrial function, and cellular bioenergetics.
Yerushalmi
Gil M
GM
Department of Human Microbiology, Sackler Faculty of Medicine, Tel-Aviv University, Israel.
Leibowitz-Amit
Raya
R
Shaharabany
Miriam
M
Tsarfaty
Ilan
I
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000276:immunology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020869:Gene Expression Profiling; D015723:Gene Library; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D008564:Membrane Potentials; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014162:Transfection
D002352:Carrier Proteins; D017931:DNA Primers; D018076:DNA, Complementary; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C550380:Mtch2 protein, mouse; D017228:Hepatocyte Growth Factor; D003576:Electron Transport Complex IV; D019859:Proto-Oncogene Proteins c-met