Disease relevance of HGS

• We demonstrate that regulated overexpression of HRS in rat schwannoma cells results in similar effects as overexpression of merlin, including growth inhibition, decreased motility and abnormalities in cell spreading [1].
• The neurofibromatosis 2 tumor suppressor protein interacts with hepatocyte growth factor-regulated tyrosine kinase substrate [2].
• Here, we show that a regulator of proliferation, hepatocellular carcinoma related protein 1 (HCRP1), interacts with Tsg101, hVps28, and their upstream regulator Hrs [3].
• Fusion of Hrs with the gag gene of HIV-1 lacking this motif can complement a defect in virus budding [4].
• HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein [5].

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

• TOM1 genes map to human chromosome 22q13.1 and mouse chromosome 8C1 and encode proteins similar to the endosomal proteins HGS and STAM [14].
• TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation [15].
• Schwannomin molecules with a L46R, L360P, L535P or Q538P missense mutation demonstrated reduced affinity for HRS binding [2].
• These results suggest the possibility that merlin and HRS may regulate cell growth in schwannoma cells through interacting pathways [1].
• Overexpression of Hrs or its SNX1-binding domain inhibits ligand-induced degradation of EGFR, but does not affect either constitutive or ligand-induced receptor-mediated endocytosis [16].

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

• Using yeast two-hybrid interaction cloning, we identified the HGF-regulated tyrosine kinase substrate (HRS) as a schwannomin interactor [2].
• Merlin interacts with HRS in the unfolded, or open, conformation [1].
• They also show that PI3P signaling does not regulate the core machinery of endosome biogenesis and transport, but controls the sorting of down-regulated receptor molecules in early endosomes via Hrs [21].
• Moreover, Hrs inhibition of endosome fusion and its endosomal localization are sensitive to bafilomycin, implying a role for luminal Ca(2+) [10].
• The human histidyl-tRNA synthetase (HRS) gene encodes an enzyme that catalyzes the esterification of histidine to its cognate tRNA as an early step in protein biosynthesis [22].

Physical interactions of HGS

• Previously we demonstrated that the hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) strongly interacts with schwannomin [23].
• Here we examined the biological significance of STAM binding to Hrs [19].
• Deletion of a region located N-terminal to the coiled-coil region and conserved among STAM proteins also severely affected Hrs binding and the endosomal localization of STAM2, suggesting that this region is also involved in these activities [19].
• SNX1 is known to interact with components of the mammalian retromer complex and Hrs, an early endosomal membrane-associated protein [24].
• Now, we report that Tsg101 binds the COOH-terminal region of the endosomal protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs; residues 222-777) [5].

Co-localisations of HGS

• STAM proteins colocalize with Hrs on the early endosome [25].
• A zinc finger domain deletion mutant of Hrs was also colocalized with the transferrin receptor, suggesting that the zinc finger domain is not required for its correct localization [26].

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

• Association with Hrs is required for the early endosomal localization, stability, and function of STAM [19].
• A STAM2 mutant that lacks the coiled-coil region and does not bind Hrs, in contrast, mislocalized to the cytoplasm [19].
• Similarly, we find that hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is not directly involved in bulk solute transport, but is required for EGFR sorting [21].
• CART: an Hrs/actinin-4/BERP/myosin V protein complex required for efficient receptor recycling [29].
• Consistent with this, expression of a dominant-negative form of the E3 ubiquitin ligase, c-Cbl, inhibits EGF- and HGF-dependent Hrs phosphorylation [30].

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].

References