PMID:19875448

Citation	O'Callaghan, KM, Ayllon, V, O'Keeffe, J, Wang, Y, Cox, OT, Loughran, G, Forgac, M and O'Connor, R (2010) Heme-binding protein HRG-1 is induced by insulin-like growth factor I and associates with the vacuolar H+-ATPase to control endosomal pH and receptor trafficking. J. Biol. Chem. 285:381-91
Abstract	Endocytosis and trafficking of receptors and nutrient transporters are dependent on an acidic intra-endosomal pH that is maintained by the vacuolar H(+)-ATPase (V-ATPase) proton pump. V-ATPase activity has also been associated with cancer invasiveness. Here, we report on a new V-ATPase-associated protein, which we identified in insulin-like growth factor I (IGF-I) receptor-transformed cells, and which was separately identified in Caenorhabditis elegans as HRG-1, a member of a family of heme-regulated genes. We found that HRG-1 is present in endosomes but not in lysosomes, and it is trafficked to the plasma membrane upon nutrient withdrawal in mammalian cells. Suppression of HRG-1 with small interfering RNA causes impaired endocytosis of transferrin receptor, decreased cell motility, and decreased viability of HeLa cells. HRG-1 interacts with the c subunit of the V-ATPase and enhances V-ATPase activity in isolated yeast vacuoles. Endosomal acidity and V-ATPase assembly are decreased in cells with suppressed HRG-1, whereas transferrin receptor endocytosis is enhanced in cells that overexpress HRG-1. Cellular uptake of a fluorescent heme analogue is enhanced by HRG-1 in a V-ATPase-dependent manner. Our findings indicate that HRG-1 regulates V-ATPase activity, which is essential for endosomal acidification, heme binding, and receptor trafficking in mammalian cells. Thus, HRG-1 may facilitate tumor growth and cancer progression.
Links	PubMed PMC2805445 Online version:10.1074/jbc.M109.063248
Keywords	Animals; Cell Line; Cell Membrane/drug effects; Cell Membrane/metabolism; Cell Movement/drug effects; Cell Survival/drug effects; Endocytosis/drug effects; Endosomes/drug effects; Endosomes/enzymology; Gene Expression Regulation/drug effects; Hemeproteins/genetics; Hemeproteins/metabolism; Humans; Hydrogen-Ion Concentration/drug effects; Insulin-Like Growth Factor I/pharmacology; Mice; Protein Binding/drug effects; Protein Transport/drug effects; RNA, Messenger/genetics; RNA, Messenger/metabolism; Rats; Receptors, Transferrin/metabolism; Saccharomyces cerevisiae/metabolism; Vacuolar Proton-Translocating ATPases/metabolism
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