Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS)

The protein contains 777 amino acids for an estimated molecular weight of 86192 Da.

 

Involved in intracellular signal transduction mediated by cytokines and growth factors. When associated with STAM, it suppresses DNA signaling upon stimulation by IL-2 and GM-CSF. Could be a direct effector of PI3-kinase in vesicular pathway via early endosomes and may regulate trafficking to early and late endosomes by recruiting clathrin. May concentrate ubiquitinated receptors within clathrin-coated regions. Involved in down-regulation of receptor tyrosine kinase via multivesicular body (MVBs) when complexed with STAM (ESCRT-0 complex). The ESCRT-0 complex binds ubiquitin and acts as sorting machinery that recognizes ubiquitinated receptors and transfers them to further sequential lysosomal sorting/trafficking processes. May contribute to the efficient recruitment of SMADs to the activin receptor complex. Involved in receptor recycling via its association with the CART complex, a multiprotein complex required for efficient transferrin receptor recycling but not for EGFR degradation. (updated: March 4, 2015)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  5. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  6. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Interpro domains
Total structural coverage: 30%
Model score: 0

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VariantDescription
dbSNP:rs753682847
dbSNP:rs34868130
dbSNP:rs56058441

The reference OMIM entry for this protein is 604375

Human growth factor-regulated tyrosine kinase substrate; hgs
Hepatocyte growth factor-regulated tyrosine kinase substrate; hrs
Hgf-regulated tyrosine kinase substrate

CLONING

Asao et al. (1997) cloned a 110-kD phosphotyrosine protein inducible by stimulation with interleukin-2 (IL2; 147680). They isolated a cDNA clone for the pp110 from the MOLT-beta T-cell line. The deduced amino acid sequence of HGS, which the authors symbolized HRS, was found to be 93% homologous to that of mouse Hrs. HGS contains double zinc finger (FYVE) motifs, a putative coiled-coil sequence, and nucleotide-binding sites. Northern blot analysis detected expression of HGS in lymphoid and nonlymphoid tissues. Immunoblotting, however, determined that the phosphorylated species was found after but not before IL2 stimulation. Lu et al. (1998) cloned a full-length HGS cDNA from a human placenta cDNA library by cross-hybridization, using the mouse Hrs cDNA as a probe. They determined that the cDNA encodes a deduced 777-amino acid protein. Northern blot analysis showed that a 3.0-kb transcript of HGS was present in all adult and fetal tissues tested, with highest expression in testis and peripheral blood leukocytes. Komada et al. (1997) showed that Hrs is localized to the cytoplasmic surface of early endosomes.

MAPPING

By fluorescence in situ hybridization, Asao et al. (1997) mapped the HGS gene to chromosome 17q25. Lu et al. (1998) mapped the HGS gene to chromosome 17 by somatic cell hybridization.

GENE FUNCTION

Asao et al. (1997) found that irrespective of IL2 stimulation, HGS coimmunoprecipitated with STAM (601899), a signal-transducing adaptor molecule that is directly associated with and phosphorylated by JAK3 and JAK2 upon stimulation with IL2 and GMCSF (138960), respectively. A mouse Hrs mutant from which the coiled-coil sequence was deleted lost STAM binding activity. Likewise, a mutant of STAM, lacking part of the coiled-coil sequence, had only weak binding to HGS. The IL2 receptor- or GMCSF receptor-bearing cells transfected with wildtype HGS were inhibited in a dose-dependent manner from proliferating in response to cytokine stimulation by up to 76% and 73%, respectively. Mutant HGS without the coiled-coil sequence failed to inhibit proliferation. Using yeast 2-hybrid interaction cloning, Scoles et al. (2000) determined that schwannomin (NF2; 607379) interacts with the HGF-regulated tyrosine kinase substrate. They demonstrated the interaction both in vivo, by immunoprecipitation of endogenous HRS with endogenous schwannomin, and in vitro, with a binding assay using bacterially purified HRS and schwannomin. The regions of interaction included schwannomin residues 256 to 579 and HRS residues from 480 to the end of either of 2 HRS isoforms. Schwannomin molecules with an L46R, L360P, L535P, or Q538P missense mutation demonstrated reduced affinity for HRS binding. Since HRS is associated with early endosomes and may mediate receptor translocation to the lysosome, the authors used indirect immunofluorescence to demonstrate that schwannomin and HRS colocalize at endosomes in STS26T Schwann cells. The authors hypothesized that schwannomin is involved in HRS-mediated cell signaling. Gutmann et al. (2001) demonstrated that regulated overexpression of HRS in rat schwannoma cells yields effects similar to those seen with overexpression of merlin (or schwannomin), including growth inhibition, decreased motility, and abnormalities in cell spreading. The HRS binding domain of merlin was mapped to residues 453-557. Overexpression of C-terminal merlin had no effect on HRS function, suggesting to the authors ... More on the omim web site

Subscribe to this protein entry history

May 12, 2019: Protein entry updated
Automatic update: model status changed

Nov. 17, 2018: Protein entry updated
Automatic update: model status changed

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

Oct. 27, 2017: Protein entry updated
Automatic update: model status changed

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 604375 was added.

Jan. 24, 2016: Protein entry updated
Automatic update: model status changed