HGS

Summary

HGS (hepatocyte growth factor-regulated tyrosine kinase substrate, HGNC:4897) is a protein-coding gene on chromosome 17q25.3, encoding Hepatocyte growth factor-regulated tyrosine kinase substrate (O14964). Involved in intracellular signal transduction mediated by cytokines and growth factors. It is a selective cancer dependency (DepMap: 81.5% of cell lines).

The protein encoded by this gene regulates endosomal sorting and plays a critical role in the recycling and degradation of membrane receptors. The encoded protein sorts monoubiquitinated membrane proteins into the multivesicular body, targeting these proteins for lysosome-dependent degradation.

Source: NCBI Gene 9146 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 152 total
• Cancer dependency (DepMap): dependent in 81.5% of screened cell lines
• MANE Select transcript: NM_004712

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4897
Approved symbol	HGS
Name	hepatocyte growth factor-regulated tyrosine kinase substrate
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	Hrs, ZFYVE8, Vps27
Ensembl gene	ENSG00000185359
Ensembl biotype	protein_coding
OMIM	604375
Entrez	9146

Gene structure

Transcript identifiers

Ensembl transcripts: 106 — 45 protein_coding, 27 nonsense_mediated_decay, 20 protein_coding_CDS_not_defined, 14 retained_intron

ENST00000329138, ENST00000570355, ENST00000570652, ENST00000571237, ENST00000571518, ENST00000571647, ENST00000571885, ENST00000572392, ENST00000573080, ENST00000573320, ENST00000573949, ENST00000575058, ENST00000575078, ENST00000576087, ENST00000576393, ENST00000576498, ENST00000577012, ENST00000676462, ENST00000676478, ENST00000676484, ENST00000676546, ENST00000676665, ENST00000676704, ENST00000676721, ENST00000676727, ENST00000676729, ENST00000676879, ENST00000676898, ENST00000676963, ENST00000677012, ENST00000677044, ENST00000677109, ENST00000677129, ENST00000677132, ENST00000677159, ENST00000677161, ENST00000677188, ENST00000677209, ENST00000677225, ENST00000677232, ENST00000677243, ENST00000677390, ENST00000677402, ENST00000677463, ENST00000677466, ENST00000677472, ENST00000677484, ENST00000677511, ENST00000677639, ENST00000677663, ENST00000677706, ENST00000677725, ENST00000677728, ENST00000677805, ENST00000677818, ENST00000677872, ENST00000677898, ENST00000678055, ENST00000678096, ENST00000678105, ENST00000678115, ENST00000678142, ENST00000678176, ENST00000678196, ENST00000678218, ENST00000678238, ENST00000678271, ENST00000678296, ENST00000678313, ENST00000678385, ENST00000678387, ENST00000678406, ENST00000678428, ENST00000678478, ENST00000678485, ENST00000678541, ENST00000678550, ENST00000678565, ENST00000678607, ENST00000678658, ENST00000678667, ENST00000678680, ENST00000678748, ENST00000678846, ENST00000678866, ENST00000678893, ENST00000678896, ENST00000678907, ENST00000678926, ENST00000678944, ENST00000678979, ENST00000678981, ENST00000679036, ENST00000679146, ENST00000679168, ENST00000679170, ENST00000679191, ENST00000679235, ENST00000679275, ENST00000679336, ENST00000679340, ENST00000876888, ENST00000876889, ENST00000928319, ENST00000928320, ENST00000961234

RefSeq mRNA: 1 — MANE Select: NM_004712 NM_004712

CCDS: CCDS11784

Canonical transcript exons

ENST00000329138 — 22 exons

Exon	Start	End
ENSE00001296545	81701045	81701131
ENSE00001296588	81693503	81693581
ENSE00001299623	81696357	81696529
ENSE00001299855	81695786	81695999
ENSE00001301435	81696607	81696747
ENSE00001303643	81694924	81695067
ENSE00001306492	81691447	81691571
ENSE00001313160	81693654	81693752
ENSE00001314367	81694815	81694853
ENSE00001319441	81701508	81702121
ENSE00001421749	81696824	81696998
ENSE00002644035	81684011	81684103
ENSE00003485521	81700467	81700600
ENSE00003502698	81687003	81687095
ENSE00003521421	81690182	81690234
ENSE00003534062	81700695	81700814
ENSE00003540029	81693870	81693965
ENSE00003550657	81685605	81685689
ENSE00003564848	81695164	81695223
ENSE00003582480	81690674	81690742
ENSE00003606686	81686312	81686387
ENSE00003790507	81688704	81688827

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.1428 / max 325.6449, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163349	49.6917	1825
163348	1.3904	929
163350	0.0607	15

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	99.19	gold quality
lower esophagus mucosa	UBERON:0035834	99.02	gold quality
sural nerve	UBERON:0015488	98.68	gold quality
metanephros cortex	UBERON:0010533	98.64	gold quality
granulocyte	CL:0000094	98.61	gold quality
right testis	UBERON:0004534	98.57	gold quality
left testis	UBERON:0004533	98.54	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.51	gold quality
adenohypophysis	UBERON:0002196	98.37	gold quality
endocervix	UBERON:0000458	98.25	gold quality
skin of abdomen	UBERON:0001416	98.23	gold quality
mucosa of transverse colon	UBERON:0004991	98.22	gold quality
minor salivary gland	UBERON:0001830	98.19	gold quality
right lobe of thyroid gland	UBERON:0001119	98.18	gold quality
skin of leg	UBERON:0001511	98.16	gold quality
cerebellar hemisphere	UBERON:0002245	98.16	gold quality
body of stomach	UBERON:0001161	98.13	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.12	gold quality
ectocervix	UBERON:0012249	98.08	gold quality
upper lobe of left lung	UBERON:0008952	98.07	gold quality
body of uterus	UBERON:0009853	98.07	gold quality
cerebellar cortex	UBERON:0002129	98.01	gold quality
left lobe of thyroid gland	UBERON:0001120	98.00	gold quality
right ovary	UBERON:0002118	98.00	gold quality
right frontal lobe	UBERON:0002810	98.00	gold quality
tibial nerve	UBERON:0001323	97.96	gold quality
left ovary	UBERON:0002119	97.96	gold quality
transverse colon	UBERON:0001157	97.86	gold quality
esophagus mucosa	UBERON:0002469	97.79	gold quality
left adrenal gland cortex	UBERON:0035825	97.69	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-112	no	2.37
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
HGS	Activation

Upstream regulators (CollecTRI, top): GABPA, HGS, YY1

miRNA regulators (miRDB)

18 targeting HGS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-6073	99.60	70.36	793
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-6737-5P	97.75	66.54	1044
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-125A-3P	97.04	66.92	902

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 81.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• The HRS domain required for merlin binding is narrowed to a region (residues 470-497) containing the predicted coiled-coil domain whereas the major domain responsible for HRS growth suppression is distinct (residues 498-550). (PMID:12444101)
• HRS inhibits Stat3 activation in schwannoma cells. (PMID:12444102)
• Overexpression Hgs in T cells yielded a dose-dependent decrease in cotransfected reporter gene expression, indicating an inhibitory function of this molecule. (PMID:12554698)
• Data suggested that association with Hrs is a prerequisite for signal transducing adaptor molecule function. (PMID:15113837)
• Hrs regulates the sorting of ligand-stimulated and unstimulated growth factor receptors on early endosomes, and the FYVE domain, which is required for Hrs to reside in a microdomain of early endosomes. (PMID:15212941)
• the endosome-associated protein hrs is a subunit of a protein complex containing actinin-4, BERP, and myosin V that is necessary for efficient TfR recycling but not for EGFR degradation (PMID:15772161)
• Analysis with phospho-specific antibodies indicates that 3 kinases generate a signal-specific, combinatorial phosphorylation profile of the Hrs-STAM complex, with the potential of diversifying tyrosine kinase receptor signalling through a common element. (PMID:15828871)
• Hrs plays role in a cargo-specific recycling mechanism, which is critical to controlling functional activity of the largest known family of signaling receptors. (PMID:15944737)
• role of HRS in up-regulating MAPK, presumably involving interaction with PELP1. (PMID:16352611)
• PIKfyve is distributed in microdomains that are distinct from those occupied by EEA1 and Hrs (PMID:16448788)
• Hgs is a novel Smad5 interactor and an inhibitor of bone morphogenetic protein (BMP) signaling. (PMID:16516194)
• These results indicate that Tsg101 is required for the formation of stable vacuolar domains within the early endosome that develop into multivesicular body (MVBs) and Hrs is required for the accumulation of internal vesicles within MVBs. (PMID:16707569)
• HGS and GUK1 were significantly over expressed in GH-secreting adenomas, compared with ACTH-secreting adenomas and nonfunctioning tumors, and with PRL-secreting adenomas, respectively. (PMID:16832584)
• Four proteins (TSG101,Hrs,Aip1/Alix, and Vps4B) of the ESCRT (endosomal sorting complex required for transport) machinery were localized in T cells and macrophages by quantitative electron microscopy. (PMID:17014699)
• Specific sequence in the beta2-adrenergic receptor cytoplasmic tail confers Hrs dependence on receptor recycling. (PMID:17138565)
• hSpry2 binds to the endocytic regulatory protein, hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and blocks intracellular signal propagation. (PMID:17320394)
• We conclude that Hrs is a positive regulator of VEGF-R2 and IR signaling and that ectopic expression of Hrs protects both VEGF-R2 and IR from degradation. (PMID:17445799)
• Targeted disruption of Hrs by small interfering RNA effectively attenuated the proliferation, anchorage-independent growth, tumorigenesis, and metastatic potential of HeLa cells in vitro and in vivo. (PMID:17545595)
• propose a novel function of Hrs, as a crucial player in the maturation of autophagosomes (PMID:17624298)
• HRS mediates post-endocytic trafficking of protease-activated receptor 2 and calcitonin receptor-like receptor (PMID:17675298)
• PELP1 and HRS reallocate to autophagosomes in response to resveratrol treatment, which might be important in the process of autophagy in the cancer cells. (PMID:17804729)
• These results indicate that Eps15b is an endosomally localized isoform of Eps15 that is present in the Hrs complex via direct Hrs interaction and important for the sorting function of this complex. (PMID:18362181)
• these results indicate that precise sorting of IL-2Rbeta from early to late endosomes is mediated by Hrs, a known sorting component of the ubiquitin-dependent machinery, in a manner that is independent of UIM-ubiquitin binding (PMID:18445679)
• Data show that Trak1 interacts with hepatocyte-growth-factor-regulated tyrosine kinase substrate (Hrs), an essential component of the endosomal sorting and trafficking machinery. (PMID:18675823)
• Data show that Hrs is essential for lysosomal targeting but not multivesicular body biogenesis and transport to late endosomes, while SNX3 is required for multivesicular body formation, but not for EGF receptor degradation. (PMID:18767904)
• Plasma hepatocyte growth factor is associated with periampullary cancer. (PMID:20812348)
• ESCRT-0 component HRS is required for HIV-1 Vpu-mediated BST-2/tetherin down-regulation. (PMID:21304933)
• Hrs inhibits HIV-1 production by inhibiting citron kinase-mediated exocytosis. (PMID:21748597)
• These results suggested that HCV secretion from host cells requires Hrs-dependent exosomal pathway in which the viral assembly is also involved. (PMID:22138215)
• Hrs tyrosine phosphorylation detected upon EGF-stimulation. (PMID:22800866)
• Hrs is a regulator of endosomal cholesterol trafficking. (PMID:22832105)
• the role for tumoral c-Met expression or sMet/HGF levels as upfront selection criterion or predictive biomarkers deserve further study in this emerging area of therapeutic focus in RCC (PMID:23867513)
• we identified an interaction between EsxH, which is secreted by the Esx-3 TSSS, and human hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs), a component of the endosomal sorting complex required for transport (ESCRT). (PMID:24204276)
• ESCRT-0 protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is targeted to endosomes independently of signal-transducing adaptor molecule (STAM) and the complex formation with STAM promotes its endosomal dissociation. (PMID:25296754)
• Results demonstrate the existence of crosstalk between beta-catenin signaling and HGS in two different types of cancer (hepatoblastoma and colorectal). (PMID:26715116)
• detailed analysis of the subcellular localization and functional significance of Hrs in macropinocytosis-mediated entry of Kaposi’s Sarcoma-Associated Herpesvirus (PMID:26819309)
• Degradation of CLR-RAMP2 was sensitive to overexpression of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), but not to HRS knockdown, whereas CLRDelta9KR-RAMP2 degradation was unaffected. Overexpression, but not knockdown of HRS, promoted hyperubiquitination of CLR under basal conditions. These results propose a role for ubiquitin and HRS in the regulation of AM-induced degradation of CLR-RAMP2. (PMID:28959041)
• Post-traumatic stress disorder (PTSD) is associated with differential methylation, measured in blood, within HGS and NRG1 across three civilian cohorts. (PMID:30456986)
• The ESCRT-0 protein HRS interacts with the HTLV-II antisense protein APH-2 and suppresses viral replication. [APH-2] (PMID:31597781)
• Study provides in vivo evidence that Beclin 1 suppresses tumor proliferation by regulating the endocytic trafficking and degradation of the EGFR and transferrin (TFR1) receptors. Beclin 1 promoted endosomal recruitment of hepatocyte growth factor tyrosine kinase substrate (HRS), which was necessary for sorting surface receptors to intraluminal vesicles for signal silencing and lysosomal degradation. (PMID:31744816)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hgs	ENSDARG00000020960
mus_musculus	Hgs	ENSMUSG00000025793
rattus_norvegicus	Hgs	ENSRNOG00000036696
drosophila_melanogaster	Hrs	FBGN0031450
caenorhabditis_elegans		WBGENE00004101

Paralogs (10): WDFY1 (ENSG00000085449), GGA1 (ENSG00000100083), TOM1 (ENSG00000100284), GGA2 (ENSG00000103365), STAM2 (ENSG00000115145), GGA3 (ENSG00000125447), STAM (ENSG00000136738), WDFY2 (ENSG00000139668), TOM1L1 (ENSG00000141198), TOM1L2 (ENSG00000175662)

Protein

Protein identifiers

Hepatocyte growth factor-regulated tyrosine kinase substrate — O14964 (reviewed: O14964)

Alternative names: Hrs, Protein pp110

All UniProt accessions (65): A0A0S2Z4R4, A0A7I2V2D8, A0A7I2V2K1, A0A7I2V2K2, A0A7I2V2M1, A0A7I2V2M4, A0A7I2V2R9, A0A7I2V2W5, A0A7I2V307, A0A7I2V310, A0A7I2V319, A0A7I2V331, A0A7I2V363, A0A7I2V3A5, A0A7I2V3C3, A0A7I2V3E9, A0A7I2V3F9, A0A7I2V3I8, A0A7I2V3J3, A0A7I2V3L0, A0A7I2V3N6, A0A7I2V3Q7, A0A7I2V3Z1, A0A7I2V468, A0A7I2V4J7, A0A7I2V4M9, A0A7I2V4X6, A0A7I2V4Z5, A0A7I2V558, A0A7I2V569, A0A7I2V5A2, A0A7I2V5A3, A0A7I2V5B7, A0A7I2V5C4, A0A7I2V5D6, A0A7I2V5E5, A0A7I2V5E7, A0A7I2V5L9, A0A7I2V5N3, A0A7I2V5V1, A0A7I2V5W6, A0A7I2V5X2, A0A7I2V605, A0A7I2V611, A0A7I2V616, A0A7I2V628, A0A7I2V637, A0A7I2V674, A0A7I2V6E0, A0A7I2YQD1, A0A7I2YQH7, A0A7I2YQM4, A0A7I2YQM9, A0A7I2YQP0, A0A7I2YQS8, A0A7I2YQU5, A0A7I2YQY0, O14964, I3L165, I3L1E3, I3L1F1, I3L1P5, I3L2H4, I3L326, I3L346

UniProt curated annotations — full annotation on UniProt →

Function. 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 a 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.

Subunit / interactions. Component of the ESCRT-0 complex composed of STAM or STAM2 and HGS. Part of a complex at least composed of HSG, STAM2 (or probably STAM) and EPS15. Interacts with STAM. Interacts with STAM2. Interacts with EPS15; the interaction is direct, calcium-dependent and inhibited by SNAP25. Identified in a complex with STAM and LITAF. Found in a complex with STAM and E3 ligase ITCH and DTX3L. Interacts with E3 ligase DTX3L; the interaction brings together STAM and HSG, promotes their recruitment to early endosomes and decreases STAM and HGS ubiquitination by ITCH. Interacts with NF2; the interaction is direct. Interacts with ubiquitin; the interaction is direct. Interacts with VPS37C. Interacts with SMAD1, SMAD2 and SMAD3. Interacts with TSG101; the interaction mediates the association with the ESCRT-I complex. Interacts with SNAP25; the interaction is direct and decreases with addition of increasing concentrations of free calcium. Interacts with SNX1; the interaction is direct. Component of a 550 kDa membrane complex at least composed of HGS and SNX1 but excluding EGFR. Interacts with TRAK1. Interacts with TRAK2. Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3. Interacts (via UIM domain) with UBQLN1 (via ubiquitin-like domain). Interacts with ARRDC3. Identified in a complex containing at least ARRDC4, AVPR2 and HGS. Interacts with LAPTM4B; promotes HGS ubiquitination.

Subcellular location. Cytoplasm. Early endosome membrane. Endosome. Multivesicular body membrane.

Tissue specificity. Ubiquitous expression in adult and fetal tissues with higher expression in testis and peripheral blood leukocytes.

Post-translational modifications. Phosphorylated on Tyr-334. A minor site of phosphorylation on Tyr-329 is detected. Phosphorylation occurs in response to EGF, IL-2, GM-CSF and HGF. Ubiquitinated. Ubiquitinated by ITCH.

Domain organisation. Has a double-sided UIM that can bind 2 ubiquitin molecules, one on each side of the helix. The FYVE-type zinc finger domain mediates interactions with phosphatidylinositol 3-phosphate in membranes of early endosomes and penetrates bilayers. The FYVE domain insertion into PtdIns(3)P-enriched membranes is substantially increased in acidic conditions.

Miscellaneous. Dubious isoform produced through aberrant splice sites.

Isoforms (2)

UniProt ID	Names	Canonical?
O14964-1	1, HRSi1	yes
O14964-2	2, HRSi2

RefSeq proteins (1): NP_004703* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000306	Znf_FYVE	Domain
IPR002014	VHS_dom	Domain
IPR003903	UIM_dom	Conserved_site
IPR008942	ENTH_VHS	Homologous_superfamily
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017073	HGS/VPS27	Family
IPR017455	Znf_FYVE-rel	Domain
IPR024641	HRS_helical	Domain

Pfam: PF00790, PF01363, PF12210

UniProt features (56 total): helix 16, binding site 8, region of interest 7, modified residue 6, turn 4, sequence variant 3, domain 2, compositionally biased region 2, mutagenesis site 2, strand 2, chain 1, splice variant 1, zinc finger region 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3OBQ	X-RAY DIFFRACTION	1.4
3ZYQ	X-RAY DIFFRACTION	1.48
4AVX	X-RAY DIFFRACTION	1.68
2D3G	X-RAY DIFFRACTION	1.7
3F1I	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14964-F1	67.77	0.33

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (8): 166; 169; 182; 185; 190; 193; 212; 215

Post-translational modifications (6): 207, 216, 308, 329, 334, 551

Mutagenesis-validated functional residues (2):

Position	Phenotype
266	strongly reduced ubiquitin-binding. reduced degradation of ubiquitinated egfr.
268	strongly reduced ubiquitin-binding. reduced degradation of ubiquitinated egfr.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-182971	EGFR downregulation
R-HSA-432720	Lysosome Vesicle Biogenesis
R-HSA-5689880	Ub-specific processing proteases
R-HSA-6807004	Negative regulation of MET activity
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8875360	InlB-mediated entry of Listeria monocytogenes into host cell
R-HSA-9013420	RHOU GTPase cycle
R-HSA-917729	Endosomal Sorting Complex Required For Transport (ESCRT)
R-HSA-9635644	Inhibition of membrane repair
R-HSA-9636383	Prevention of phagosomal-lysosomal fusion
R-HSA-9706019	RHOBTB3 ATPase cycle

MSigDB gene sets: 281 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_PLATELET_DERIVED_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, REACTOME_ENDOSOMAL_SORTING_COMPLEX_REQUIRED_FOR_TRANSPORT_ESCRT, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_LYSOSOMAL_TRANSPORT, GOBP_ENDOSOME_ORGANIZATION, GCM_GSPT1, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_VESICLE_LOCALIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_VESICLE_ORGANIZATION, MORF_UBE2I, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (21): protein targeting to lysosome (GO:0006622), signal transduction (GO:0007165), negative regulation of cell population proliferation (GO:0008285), membrane invagination (GO:0010324), positive regulation of gene expression (GO:0010628), negative regulation of platelet-derived growth factor receptor signaling pathway (GO:0010642), endosomal transport (GO:0016197), macroautophagy (GO:0016236), negative regulation of angiogenesis (GO:0016525), negative regulation of vascular endothelial growth factor receptor signaling pathway (GO:0030948), receptor internalization (GO:0031623), endocytic recycling (GO:0032456), multivesicular body assembly (GO:0036258), regulation of protein catabolic process (GO:0042176), protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043328), regulation of MAP kinase activity (GO:0043405), negative regulation of receptor signaling pathway via JAK-STAT (GO:0046426), protein localization to membrane (GO:0072657), membrane fission (GO:0090148), positive regulation of exosomal secretion (GO:1903543), protein transport (GO:0015031)

GO Molecular Function (8): zinc ion binding (GO:0008270), protein domain specific binding (GO:0019904), phosphatidylinositol binding (GO:0035091), ubiquitin binding (GO:0043130), ubiquitin-like protein ligase binding (GO:0044389), protein binding (GO:0005515), kinase activity (GO:0016301), metal ion binding (GO:0046872)

GO Cellular Component (11): lysosome (GO:0005764), endosome (GO:0005768), early endosome (GO:0005769), cytosol (GO:0005829), early endosome membrane (GO:0031901), multivesicular body membrane (GO:0032585), ESCRT-0 complex (GO:0033565), extracellular exosome (GO:0070062), phagocytic vesicle lumen (GO:0097013), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Membrane Trafficking	2
Signaling by EGFR	1
trans-Golgi Network Vesicle Budding	1
Deubiquitination	1
Signaling by MET	1
Clathrin-mediated endocytosis	1
Listeria monocytogenes entry into host cells	1
RHO GTPase cycle	1
Response of Mtb to phagocytosis	1
Suppression of phagosomal maturation	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
membrane organization	2
negative regulation of signal transduction	2
protein targeting to vacuole	1
lysosomal transport	1
protein localization to lysosome	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
regulation of platelet-derived growth factor receptor signaling pathway	1
platelet-derived growth factor receptor signaling pathway	1
vesicle-mediated transport	1
intracellular transport	1
autophagosome assembly	1
autophagy	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
regulation of vascular endothelial growth factor receptor signaling pathway	1
vascular endothelial growth factor receptor signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
receptor-mediated endocytosis	1
endosomal transport	1
vesicle-mediated transport to the plasma membrane	1
multivesicular body organization	1
organelle assembly	1
regulation of catabolic process	1
protein catabolic process	1
regulation of protein metabolic process	1
intracellular protein transport	1
late endosome to vacuole transport via multivesicular body sorting pathway	1
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1

Protein interactions and networks

STRING

2158 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HGS	TSG101	Q99816	993
HGS	STAM2	O75886	992
HGS	STAM	Q92783	992
HGS	HPSE	Q9Y251	992
HGS	VPS36	Q86VN1	870
HGS	VPS25	Q9BRG1	841
HGS	VPS28	Q9UK41	796
HGS	CHMP6	Q96FZ7	775
HGS	NF2	P35240	758
HGS	CHMP3	Q9Y3E7	757
HGS	A0A140T963	A0A140T963	757
HGS	EPS15	P42566	738
HGS	VTA1	Q9NP79	717
HGS	CHMP2A	O43633	713
HGS	VPS4A	Q9UN37	711

IntAct

1051 interactions, top by confidence:

A	B	Type	Score
HGS	STAM	psi-mi:“MI:0915”(physical association)	0.860
LDOC1	HGS	psi-mi:“MI:0915”(physical association)	0.850
HGS	ODAD1	psi-mi:“MI:0915”(physical association)	0.850
ODAD1	HGS	psi-mi:“MI:0915”(physical association)	0.850
HGS	LDOC1	psi-mi:“MI:0915”(physical association)	0.850
DAZAP2	HGS	psi-mi:“MI:0915”(physical association)	0.780
KRT31	HGS	psi-mi:“MI:0915”(physical association)	0.780
NUP54	HGS	psi-mi:“MI:0915”(physical association)	0.780
LITAF	HGS	psi-mi:“MI:0915”(physical association)	0.780
HGS	DAZAP2	psi-mi:“MI:0915”(physical association)	0.780
HGS	KRT31	psi-mi:“MI:0915”(physical association)	0.780
HGS	LITAF	psi-mi:“MI:0915”(physical association)	0.780
KRT18	HGS	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (805): HGS (Two-hybrid), HGS (Two-hybrid), HGS (Two-hybrid), HGS (Two-hybrid), HGS (Two-hybrid), HGS (Two-hybrid), HGS (Two-hybrid), LITAF (Two-hybrid), DAZAP2 (Two-hybrid), JAKMIP2 (Two-hybrid), ABI2 (Two-hybrid), BCAS2 (Two-hybrid), NDC80 (Two-hybrid), POGZ (Two-hybrid), EXOC7 (Two-hybrid)

ESM2 similar proteins: A1CEK1, A1CEK6, A1DFN5, A1DFP5, A2QW93, A2QWA2, A3LX75, A4QTV1, A4RF61, O14964, O43125, O80910, O88811, P0CR78, P0CR79, P0CS26, P0CS27, Q0CJU8, Q0CJV3, Q0U4Z8, Q0U6X7, Q0V8S0, Q1E878, Q2GS33, Q2GT05, Q4P5J4, Q4P7Q1, Q4WHN8, Q4WHP5, Q5A895, Q5BBK9, Q5BBL4, Q5XHY7, Q6BNP6, Q6BSD6, Q6C2N2, Q6CFT4, Q6CL17, Q6CVA8, Q6FQJ1

Diamond homologs: A0A0D1E015, A0JMD2, A1CEK1, A1DFP5, A2QWA2, A4QTV1, A8QCE4, A8XJZ8, B0G126, B0WAQ0, B3MT31, B3P851, B4G2G5, B4IC49, B4JHI7, B4K982, B4M140, B4NFJ7, B4PRU6, D2H5P6, D3ZVP7, D4A8G9, E1BLZ4, F1MM41, F7EP40, O13821, O14964, O59722, O76902, O95405, O96838, P0CS26, P0CS27, P34756, P40343, Q05B78, Q08CN9, Q0CJV3, Q0P4S0, Q0U4Z8

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
EGFR	“up-regulates activity”	HGS	phosphorylation
SH3RF1	“down-regulates quantity”	HGS	ubiquitination
HGS	“form complex”	“ESCRT-0 complex”	binding
HGS	up-regulates	SMAD2
EGFR	up-regulates	HGS	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Endosomal Sorting Complex Required For Transport (ESCRT)	5	42.8×	2e-05
Formation of the cornified envelope	8	16.3×	1e-05
Keratinization	9	11.7×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
membrane fission	6	39.8×	1e-06
morphogenesis of an epithelium	7	38.8×	1e-07
intermediate filament organization	8	31.1×	6e-08
epithelial cell differentiation	6	17.0×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

152 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	112
Likely benign	10
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

4078 predictions. Top by Δscore:

Variant	Effect	Δscore
17:81685603:A:AG	acceptor_gain	1.0000
17:81685604:G:GG	acceptor_gain	1.0000
17:81685690:GTGA:G	donor_gain	1.0000
17:81686307:TTCAG:T	acceptor_gain	1.0000
17:81686308:TCA:T	acceptor_loss	1.0000
17:81686308:TCAG:T	acceptor_gain	1.0000
17:81686309:CA:C	acceptor_loss	1.0000
17:81686309:CAG:C	acceptor_gain	1.0000
17:81686310:A:AG	acceptor_gain	1.0000
17:81686310:AGA:A	acceptor_gain	1.0000
17:81686311:G:C	acceptor_gain	1.0000
17:81686311:G:GA	acceptor_gain	1.0000
17:81686311:GA:G	acceptor_gain	1.0000
17:81686311:GAGC:G	acceptor_gain	1.0000
17:81686311:GAGCA:G	acceptor_gain	1.0000
17:81686383:TGGAG:T	donor_gain	1.0000
17:81686384:GGAG:G	donor_gain	1.0000
17:81686384:GGAGG:G	donor_gain	1.0000
17:81686385:GAG:G	donor_gain	1.0000
17:81686385:GAGG:G	donor_gain	1.0000
17:81686386:AG:A	donor_gain	1.0000
17:81686387:GG:G	donor_gain	1.0000
17:81686388:G:GG	donor_gain	1.0000
17:81686388:GT:G	donor_loss	1.0000
17:81686990:T:TA	acceptor_gain	1.0000
17:81686991:G:A	acceptor_gain	1.0000
17:81686998:TGCA:T	acceptor_loss	1.0000
17:81686999:GCA:G	acceptor_loss	1.0000
17:81687000:CAG:C	acceptor_loss	1.0000
17:81687001:A:AG	acceptor_gain	1.0000

AlphaMissense

5081 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:81685611:C:A	A15E	1.000
17:81685623:T:C	L19P	1.000
17:81685626:T:C	L20P	1.000
17:81685640:T:A	W25R	1.000
17:81685640:T:C	W25R	1.000
17:81685642:G:C	W25C	1.000
17:81685642:G:T	W25C	1.000
17:81685661:T:C	C32R	1.000
17:81685662:G:A	C32Y	1.000
17:81685663:C:G	C32W	1.000
17:81685664:G:C	D33H	1.000
17:81685665:A:C	D33A	1.000
17:81685665:A:T	D33V	1.000
17:81685674:G:C	R36P	1.000
17:81686323:C:A	A45D	1.000
17:81686360:C:A	N57K	1.000
17:81686360:C:G	N57K	1.000
17:81686364:C:G	H59D	1.000
17:81686379:G:C	A64P	1.000
17:81686380:C:A	A64D	1.000
17:81686383:T:C	L65P	1.000
17:81687004:T:A	V67D	1.000
17:81687012:T:C	S70P	1.000
17:81687021:A:G	K73E	1.000
17:81687022:A:C	K73T	1.000
17:81687023:G:C	K73N	1.000
17:81687023:G:T	K73N	1.000
17:81687024:A:G	N74D	1.000
17:81687026:C:A	N74K	1.000
17:81687026:C:G	N74K	1.000

dbSNP variants (sampled 300 via entrez): RS1000299525 (17:81700930 C>T), RS1000633808 (17:81699617 G>A), RS1000782977 (17:81697574 G>A,C,T), RS1000835485 (17:81697421 C>G,T), RS1000856090 (17:81684375 G>C), RS1000888873 (17:81684579 C>G,T), RS1001048283 (17:81688186 C>T), RS1001227029 (17:81693315 G>A,T), RS1001294735 (17:81691867 C>A), RS1001489963 (17:81692450 G>A), RS1001562300 (17:81695537 C>T), RS1001578566 (17:81701304 C>A), RS1001633581 (17:81696487 C>T), RS1001969115 (17:81695461 T>C), RS1002119525 (17:81684986 G>A)

Disease associations

OMIM: gene MIM:604375 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000685_3	Eye color traits	9.000000e-14
GCST010002_133	Refractive error	2.000000e-50

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0003949	eye color

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Ozone	affects cotreatment, increases oxidation, increases expression, increases abundance, affects expression	3
Cyclosporine	increases expression	3
bisphenol F	affects cotreatment, increases methylation, increases expression	2
bisphenol A	decreases methylation, increases expression	2
sodium arsenite	decreases expression, increases expression	2
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation, increases expression	2
Acrolein	affects cotreatment, increases oxidation, increases expression, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Particulate Matter	increases expression, decreases expression, affects cotreatment, increases abundance	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
beta-lapachone	decreases expression, increases expression	1
cobaltous chloride	increases expression	1
cupric chloride	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	affects expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vehicle Emissions	decreases expression, increases abundance	1
Cadmium	increases expression, increases abundance	1

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1WQ	Abcam A-549 HGS KO	Cancer cell line	Male
CVCL_D2B3	Abcam HCT 116 HGS KO	Cancer cell line	Male
CVCL_F1PS	HyCyte HeLa KO-hHGS	Cancer cell line	Female
CVCL_SR34	HAP1 HGS (-) 1	Cancer cell line	Male
CVCL_SR35	HAP1 HGS (-) 2	Cancer cell line	Male
CVCL_SR36	HAP1 HGS (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.