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Gene Review

HGS  -  hepatocyte growth factor-regulated...

Homo sapiens

Synonyms: HRS, Hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs, Protein pp110, Vps27, ...
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Disease relevance of HGS


Psychiatry related information on HGS

  • Both drugs produced a statistically significant improvement in the depressive symptoms as early as the 7th day, measured by the HRS [6].
  • Overall, these results suggest that the HRS exhibited a relatively stable factorial structure based on a large sample of outpatients with unipolar depressive disorders [7].

High impact information on HGS

  • Ubiquitin-binding proteins such as epsins, Hrs, and Vps9 are monoubiquitinated, indicating the general nature of ubiquitin regulation in endocytosis and suggesting new models to explain how recognition of monoubiquitin signals may be regulated [8].
  • The UIM proteins epsins and Hrs are excellent candidates for adaptors that link ubiquitinated cargo to the clathrin-based sorting machinery at appropriate regions of the endosomal or plasma membranes [8].
  • The VHS (Vps27p, Hrs and STAM) domains of the GGA proteins are responsible for the highly specific recognition of these acidic-cluster-dileucine signals [9].
  • The same motif is also found in Hrs and recruits the ESCRT I complex to endosomes through direct interaction with one of its components called TSG101 [4].
  • Further challenging data indicate a wider role for Hrs in the regulation of endosome dynamics [4].

Chemical compound and disease context of HGS

  • Ca(2+) also reverses the Hrs-induced inhibition of early endosome fusion in a tetanus toxin-sensitive manner and removes Hrs from early endosomal membranes [10].
  • The available data suggest that alterations in renal prostaglandin metabolism participate in the pathogenesis of at least two prominent renal complications of liver disease: (a) sodium retention and (b) HRS [11].
  • The age of the recipients (49+/-10 vs 56+/-12; P = 0.05), the total bilirubin level on post-operative day 7 (6.0+/-4.3 vs 10.1+/-5.9 mg/dl; P = 0.04), alcoholic liver disease and the requirement for post-transplant dialysis were predictors of resolution of HRS by univariate analysis [12].
  • It has been suggested that serum nitrite/nitrate levels are highest in patients with functional renal failure (i.e., HRS) and that these levels correlate with the magnitude of endotoxemia [13].

Biological context of HGS


Anatomical context of HGS

  • Our results reveal the TSG101 interaction with HRS as a crucial step in endocytic down-regulation of mitogenic signaling and suggest a role for this interaction in linking the functions of early and late endosomes [15].
  • We find that overexpression of Hrs causes a strong recruitment of STAM2 to endosome membranes [17].
  • To explore the mechanism and cellular function of this complex in mammalian cells, we established an Hrs-defective fibroblastoid cell line (hrs(-/-)); embryos with this genotype died in utero [18].
  • Both Hrs and STAM bind ubiquitin and are involved in endosomal sorting of ubiquitinated cargo proteins for trafficking to the lysosome [19].
  • We found that the endosome-associated hepatocyte responsive serum phosphoprotein (Hrs) inhibited the homotypic fusion of early endosomes [20].

Associations of HGS with chemical compounds


Physical interactions of HGS


Co-localisations of HGS


Regulatory relationships of HGS

  • Depletion of endogenous Hrs by RNA interference similarly caused the mislocalization of exogenously expressed STAM2 to the cytoplasm [19].
  • Overexpression of Hrs inhibited the trafficking of EGFR from early endosomes, resulting in an accumulation of EGFR on early endosomes in both ligand-stimulated and unstimulated cells [27].
  • In contrast, depletion of hepatocyte growth factor receptor substrate (Hrs) only modestly inhibits EGF degradation, does not induce tubulation of the early endosome, and causes the generation of enlarged MVBs that retain the ability to fuse with the lysosome [28].

Other interactions of HGS


Analytical, diagnostic and therapeutic context of HGS

  • Immunofluorescence and subcellular fractionation studies show that Hrs and SNX1 colocalize on early endosomes [16].
  • This novel interaction was identified in a yeast two-hybrid screen using full-length Hrs as bait, and confirmed by in vitro binding assays and co-immunoprecipitation experiments [31].
  • We found by Western blot analyses that immunoglobulins G (IgG) from 18 of 19 anti-HRS positive patient sera react with amino acids 2-44 and 286-509 of HRS [32].
  • Immunoelectron microscopy showed that Hrs was localized to the cytoplasmic surface of these structures [26].
  • In addition, we showed by genomic Southern blot analysis that the human Hrs gene was a single-copy gene with a size of about 20kb [33].


  1. The NF2 interactor, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), associates with merlin in the "open" conformation and suppresses cell growth and motility. Gutmann, D.H., Haipek, C.A., Burke, S.P., Sun, C.X., Scoles, D.R., Pulst, S.M. Hum. Mol. Genet. (2001) [Pubmed]
  2. The neurofibromatosis 2 tumor suppressor protein interacts with hepatocyte growth factor-regulated tyrosine kinase substrate. Scoles, D.R., Huynh, D.P., Chen, M.S., Burke, S.P., Gutmann, D.H., Pulst, S.M. Hum. Mol. Genet. (2000) [Pubmed]
  3. The growth-regulatory protein HCRP1/hVps37A is a subunit of mammalian ESCRT-I and mediates receptor down-regulation. Bache, K.G., Slagsvold, T., Cabezas, A., Rosendal, K.R., Raiborg, C., Stenmark, H. Mol. Biol. Cell (2004) [Pubmed]
  4. Hrs function: viruses provide the clue. Clague, M.J., Urbé, S. Trends Cell Biol. (2003) [Pubmed]
  5. HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein. Pornillos, O., Higginson, D.S., Stray, K.M., Fisher, R.D., Garrus, J.E., Payne, M., He, G.P., Wang, H.E., Morham, S.G., Sundquist, W.I. J. Cell Biol. (2003) [Pubmed]
  6. Comparison of Vivalan (viloxazine hydrochloride) with imipramine in the treatment of depression. A double-blind study. Santonastaso, P., Maistrello, I., Battistin, L. Acta psychiatrica Scandinavica. (1979) [Pubmed]
  7. Factorial structure and factor reliability of the Hamilton Rating Scale for Depression. O'Brien, K.P., Glaudin, V. Acta psychiatrica Scandinavica. (1988) [Pubmed]
  8. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Hicke, L., Dunn, R. Annu. Rev. Cell Dev. Biol. (2003) [Pubmed]
  9. Structural basis for acidic-cluster-dileucine sorting-signal recognition by VHS domains. Misra, S., Puertollano, R., Kato, Y., Bonifacino, J.S., Hurley, J.H. Nature (2002) [Pubmed]
  10. Ca2+ and N-ethylmaleimide-sensitive factor differentially regulate disassembly of SNARE complexes on early endosomes. Yan, Q., Sun, W., McNew, J.A., Vida, T.A., Bean, A.J. J. Biol. Chem. (2004) [Pubmed]
  11. Renal eicosanoids as determinants of renal function in liver disease. Epstein, M., Lifschitz, M. Hepatology (1987) [Pubmed]
  12. The course of type 1 hepato-renal syndrome post liver transplantation. Marik, P.E., Wood, K., Starzl, T.E. Nephrol. Dial. Transplant. (2006) [Pubmed]
  13. Endothelin and nitric oxide in hepatorenal syndrome: a balance reset. Epstein, M., Goligorsky, M.S. J. Nephrol. (1997) [Pubmed]
  14. TOM1 genes map to human chromosome 22q13.1 and mouse chromosome 8C1 and encode proteins similar to the endosomal proteins HGS and STAM. Seroussi, E., Kedra, D., Kost-Alimova, M., Sandberg-Nordqvist, A.C., Fransson, I., Jacobs, J.F., Fu, Y., Pan, H.Q., Roe, B.A., Imreh, S., Dumanski, J.P. Genomics (1999) [Pubmed]
  15. TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation. Lu, Q., Hope, L.W., Brasch, M., Reinhard, C., Cohen, S.N. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  16. Hrs interacts with sorting nexin 1 and regulates degradation of epidermal growth factor receptor. Chin, L.S., Raynor, M.C., Wei, X., Chen, H.Q., Li, L. J. Biol. Chem. (2001) [Pubmed]
  17. STAM and Hrs are subunits of a multivalent ubiquitin-binding complex on early endosomes. Bache, K.G., Raiborg, C., Mehlum, A., Stenmark, H. J. Biol. Chem. (2003) [Pubmed]
  18. Hrs, a mammalian master molecule in vesicular transport and protein sorting, suppresses the degradation of ESCRT proteins signal transducing adaptor molecule 1 and 2. Kobayashi, H., Tanaka, N., Asao, H., Miura, S., Kyuuma, M., Semura, K., Ishii, N., Sugamura, K. J. Biol. Chem. (2005) [Pubmed]
  19. Association with Hrs is required for the early endosomal localization, stability, and function of STAM. Mizuno, E., Kawahata, K., Okamoto, A., Kitamura, N., Komada, M. J. Biochem. (2004) [Pubmed]
  20. Hrs regulates early endosome fusion by inhibiting formation of an endosomal SNARE complex. Sun, W., Yan, Q., Vida, T.A., Bean, A.J. J. Cell Biol. (2003) [Pubmed]
  21. PI3P signaling regulates receptor sorting but not transport in the endosomal pathway. Petiot, A., Faure, J., Stenmark, H., Gruenberg, J. J. Cell Biol. (2003) [Pubmed]
  22. A novel gene oriented in a head-to-head configuration with the human histidyl-tRNA synthetase (HRS) gene encodes an mRNA that predicts a polypeptide homologous to HRS. O'Hanlon, T.P., Raben, N., Miller, F.W. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  23. Neurofibromatosis 2 (NF2) tumor suppressor schwannomin and its interacting protein HRS regulate STAT signaling. Scoles, D.R., Nguyen, V.D., Qin, Y., Sun, C.X., Morrison, H., Gutmann, D.H., Pulst, S.M. Hum. Mol. Genet. (2002) [Pubmed]
  24. An essential role for SNX1 in lysosomal sorting of protease-activated receptor-1: evidence for retromer-, Hrs-, and Tsg101-independent functions of sorting nexins. Gullapalli, A., Wolfe, B.L., Griffin, C.T., Magnuson, T., Trejo, J. Mol. Biol. Cell (2006) [Pubmed]
  25. STAM proteins bind ubiquitinated proteins on the early endosome via the VHS domain and ubiquitin-interacting motif. Mizuno, E., Kawahata, K., Kato, M., Kitamura, N., Komada, M. Mol. Biol. Cell (2003) [Pubmed]
  26. Hrs, a tyrosine kinase substrate with a conserved double zinc finger domain, is localized to the cytoplasmic surface of early endosomes. Komada, M., Masaki, R., Yamamoto, A., Kitamura, N. J. Biol. Chem. (1997) [Pubmed]
  27. A role for Hrs in endosomal sorting of ligand-stimulated and unstimulated epidermal growth factor receptor. Morino, C., Kato, M., Yamamoto, A., Mizuno, E., Hayakawa, A., Komada, M., Kitamura, N. Exp. Cell Res. (2004) [Pubmed]
  28. Distinct roles for Tsg101 and Hrs in multivesicular body formation and inward vesiculation. Razi, M., Futter, C.E. Mol. Biol. Cell (2006) [Pubmed]
  29. CART: an Hrs/actinin-4/BERP/myosin V protein complex required for efficient receptor recycling. Yan, Q., Sun, W., Kujala, P., Lotfi, Y., Vida, T.A., Bean, A.J. Mol. Biol. Cell (2005) [Pubmed]
  30. Growth factors induce differential phosphorylation profiles of the Hrs-STAM complex: a common node in signalling networks with signal-specific properties. Row, P.E., Clague, M.J., Urbé, S. Biochem. J. (2005) [Pubmed]
  31. Huntingtin-associated protein 1 interacts with hepatocyte growth factor-regulated tyrosine kinase substrate and functions in endosomal trafficking. Li, Y., Chin, L.S., Levey, A.I., Li, L. J. Biol. Chem. (2002) [Pubmed]
  32. Epitope studies indicate that histidyl-tRNA synthetase is a stimulating antigen in idiopathic myositis. Martin, A., Shulman, M.J., Tsui, F.W. FASEB J. (1995) [Pubmed]
  33. Human Hrs, a tyrosine kinase substrate in growth factor-stimulated cells: cDNA cloning and mapping of the gene to chromosome 17. Lu, L., Komada, M., Kitamura, N. Gene (1998) [Pubmed]
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