Q99LI8 (HGS_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Hepatocyte growth factor-regulated tyrosine kinase substrate

Gene names

Name:	Hgs
Synonyms:	Hrs

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	775 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

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 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. Ref.8
Subunit structure	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. 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. Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3. Interacts with TRAK1 and TRAK2 By similarity. Ref.4 Ref.7 Ref.8 Ref.10 Ref.12
Subcellular location	Cytoplasm. Early endosome membrane; Peripheral membrane protein; Cytoplasmic side. Endosome › multivesicular body membrane; Peripheral membrane protein Ref.1 Ref.7 Ref.9 Ref.11.
Tissue specificity	Ubiquitous expression in adult and fetal tissues with higher expression in testis. Ref.1 Ref.5
Domain	Has a double-sided UIM that can bind 2 ubiquitin molecules, one on each side of the helix By similarity. Ref.4 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 PtdIns3P-enriched membranes is substantially increased in acidic conditions By similarity. Ref.4
Post-translational modification	Phosphorylated on Tyr-334. This phosphorylation occurs in response to EGF. A minor site of phosphorylation on Tyr-329 is detected. Protein phosphorylation may also be triggered in response to IL-2, GM-CSF and HGF. Ref.11 Ubiquitinated by ITCH By similarity.
Disruption phenotype	Mice show a defect in ventral folding morphogenesis, exhibiting two bilateral heart tubes and absence of foregut, and died around embryonic day 11. Significantly enlarged endosomes were also detected in cells of the endoderm. Ref.6 Ref.8
Sequence similarities	Contains 1 FYVE-type zinc finger. Contains 1 UIM (ubiquitin-interacting motif) repeat. Contains 1 VHS domain.

Ontologies

Keywords
Biological process	Protein transport Transport
Cellular component	Cytoplasm Endosome Membrane
Domain	Zinc-finger
Ligand	Metal-binding Zinc
PTM	Acetylation Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	endosome to lysosome transport Inferred from electronic annotation. Source: Compara intracellular protein transport Inferred from electronic annotation. Source: InterPro negative regulation of JAK-STAT cascade Inferred from electronic annotation. Source: Compara
Cellular_component	cytoplasm Inferred from direct assay Ref.1. Source: MGI cytosol Inferred from electronic annotation. Source: Compara early endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell multivesicular body membrane Inferred from electronic annotation. Source: UniProtKB-SubCell secretory granule Inferred from electronic annotation. Source: Compara
Molecular_function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 775	775	Hepatocyte growth factor-regulated tyrosine kinase substrate		PRO_0000098709
Regions
	Domain	15 – 143	129	VHS
	Repeat	258 – 277	20	UIM
	Zinc finger	160 – 220	61	FYVE-type
	Region	225 – 541	317	Interaction with SNX1 By similarity
	Region	443 – 541	99	Interaction with SNAP25 and TRAK2 By similarity
	Region	452 – 570	119	Interaction with STAM1
	Region	478 – 775	298	Interaction with NF2 By similarity
	Compositional bias	503 – 558	56	Gln-rich
	Compositional bias	559 – 763	205	Pro-rich
Amino acid modifications
	Modified residue	207	1	N6-acetyllysine By similarity
	Modified residue	216	1	Phosphotyrosine Ref.13 Ref.15
	Modified residue	308	1	Phosphotyrosine Ref.14
	Modified residue	329	1	Phosphotyrosine Ref.11
	Modified residue	334	1	Phosphotyrosine Ref.11
Experimental info
	Mutagenesis	183	1	R → A: 100-fold loss of affinity for PIP3 and accumulation in the cytosol. Ref.9
	Mutagenesis	215	1	C → S: Accumulation in proteinaceous aggregates devoid of membranes and no interaction with PI3P. Ref.9
	Mutagenesis	269	1	L → A: Loss of protein phosphorylation at Y-329 and Y-334; when associated with A-270. Ref.11
	Mutagenesis	270	1	S → A: Loss of protein phosphorylation at Y-329 and Y-334; when associated with A-269. Ref.10 Ref.11
	Mutagenesis	270	1	S → E: No interaction with ubiquitin. Ref.10 Ref.11
	Mutagenesis	329	1	Y → F: No change in the phosphorylation level. Loss of protein phosphorylation; when associated with F-334. Ref.11
	Mutagenesis	334	1	Y → F: No change in the phosphorylation level. Loss of protein phosphorylation; when associated with F-329. Ref.11
	Sequence conflict	23	1	T → S in AAH03239. Ref.3
	Sequence conflict	584	1	P → S in BAC32676. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q99LI8 [UniParc]. Last modified July 19, 2005. Version 2. Checksum: 0E68BF5AB514865B	FASTA	775	86,015
	10 20 30 40 50 60 MGRGSGTFER LLDKATSQLL LETDWESILQ ICDLIRQGDT QAKYAVNSIK KKVNDKNPHV 70 80 90 100 110 120 ALYALEVMES VVKNCGQTVH DEVANKQTME ELKELLKRQV EVNVRNKILY LIQAWAHAFR 130 140 150 160 170 180 NEPKYKVVQD TYQIMKVEGH VFPEFKESDA MFAAERAPDW VDAEECHRCR VQFGVVTRKH 190 200 210 220 230 240 HCRACGQIFC GKCSSKYSTI PKFGIEKEVR VCEPCYEQLN KKAEGKASST TELPPEYLTS 250 260 270 280 290 300 PLSQQSQLPP KRDETALQEE EELQLALALS QSEAEEKERM RQKTTYTAHP KAEPTPLASS 310 320 330 340 350 360 APPAGSLYSS PVNSSAPLAE DIDPELARYL NRNYWEKKQE EARKSPTPSA PVPLTEPAAQ 370 380 390 400 410 420 PGEGHTAPNS MAEAPLPETD SQPITPCSGP FSEYQNGESE ESHEQFLKAL QNAVSTFVNR 430 440 450 460 470 480 MKSNHMRGRS ITNDSAVLSL FQSINTMHPQ LLELLNQLDE RRLYYEGLQD KLAQIRDARG 490 500 510 520 530 540 ALSALREEHR EKLRRAAEEA ERQRQIQLAQ KLEIMRQKKQ EYLEVQRQLA IQRLQEQEKE 550 560 570 580 590 600 RQMRLEQQKQ TVQMRAQMPA FPLPYAQLQA MPTAGGVLYQ PSGPTSFPAT FSPAGSVEGS 610 620 630 640 650 660 PMHGVYMSQP APATGPYPSM PGTTADPSMV SAYMYPTGAP GAQAAPQAQA GPTTSPAYSS 670 680 690 700 710 720 YQPTPTPGYQ SVASQAPQSL PAISQPPQTS NIGYMGSQPM SMGYQPYNMQ NLMTALPGQD 730 740 750 760 770 ASLPAQQPYI PGQQPLYQQM APSTGPPQQQ PPVAQPAPTQ GPPAQGSEAQ LISFD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Growth factor-induced tyrosine phosphorylation of Hrs, a novel 115-kilodalton protein with a structurally-conserved putative zinc finger domain." Komada M., Kitamura N. Mol. Cell. Biol. 15:6213-6221(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J. Tissue: Corpora quadrigemina.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: FVB/N. Tissue: Mammary tumor.
[4]	"Hrs is associated with STAM, a signal-transducing adaptor molecule. Its suppressive effect on cytokine-induced cell growth." Asao H., Sasaki Y., Arita T., Tanaka N., Endo K., Kasai H., Takeshita T., Endo Y., Fujita T., Sugamura K. J. Biol. Chem. 272:32785-32791(1997) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH STAM1, DOMAIN.
[5]	"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 213:125-132(1998) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY.
[6]	"Hrs, a FYVE finger protein localized to early endosomes, is implicated in vesicular traffic and required for ventral folding morphogenesis." Komada M., Soriano P. Genes Dev. 13:1475-1485(1999) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[7]	"A hrs binding protein having a Src homology 3 domain is involved in intracellular degradation of growth factors and their receptors." Takata H., Kato M., Denda K., Kitamura N. Genes Cells 5:57-69(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH STAM2, SUBCELLULAR LOCATION.
[8]	"Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA." Miura S., Takeshita T., Asao H., Kimura Y., Murata K., Sasaki Y., Hanai J., Beppu H., Tsukazaki T., Wrana J.L., Miyazono K., Sugamura K. Mol. Cell. Biol. 20:9346-9355(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SMAD1; SMAD2 AND SMAD3, DISRUPTION PHENOTYPE, FUNCTION.
[9]	"FYVE and coiled-coil domains determine the specific localisation of Hrs to early endosomes." Raiborg C., Bremnes B., Mehlum A., Gillooly D.J., D'Arrigo A., Stang E., Stenmark H. J. Cell Sci. 114:2255-2263(2001) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF ARG-183 AND CYS-215, SUBCELLULAR LOCATION.
[10]	"Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes." Raiborg C., Bache K.G., Gillooly D.J., Madshus I.H., Stang E., Stenmark H. Nat. Cell Biol. 4:394-398(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH UBIQUITIN, MUTAGENESIS OF SER-270.
[11]	"The UIM domain of Hrs couples receptor sorting to vesicle formation." Urbe S., Sachse M., Row P.E., Preisinger C., Barr F.A., Strous G., Klumperman J., Clague M.J. J. Cell Sci. 116:4169-4179(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT TYR-329 AND TYR-334, MASS SPECTROMETRY, MUTAGENESIS OF LEU-269; SER-270; TYR-329 AND TYR-334, SUBCELLULAR LOCATION.
[12]	"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. 100:7626-7631(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TSG101.
[13]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-216, MASS SPECTROMETRY.
[14]	"Quantitative time-resolved phosphoproteomic analysis of mast cell signaling." Cao L., Yu K., Banh C., Nguyen V., Ritz A., Raphael B.J., Kawakami Y., Kawakami T., Salomon A.R. J. Immunol. 179:5864-5876(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-308, MASS SPECTROMETRY. Tissue: Mast cell.
[15]	"Large-scale identification and evolution indexing of tyrosine phosphorylation sites from murine brain." Ballif B.A., Carey G.R., Sunyaev S.R., Gygi S.P. J. Proteome Res. 7:311-318(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-216, MASS SPECTROMETRY. Tissue: Brain.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	D50050 mRNA. Translation: BAA08768.1. AK046299 mRNA. Translation: BAC32676.1. BC003239 mRNA. Translation: AAH03239.1.
IPI	IPI00649267.
PIR	I49759.
RefSeq	NP_001152800.1. NM_001159328.1. NP_032270.3. NM_008244.3.
UniGene	Mm.7919.
3D structure databases
ProteinModelPortal	Q99LI8.
SMR	Q99LI8. Positions 6-221, 402-499.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-29102N.
IntAct	Q99LI8. 2 interactions.
MINT	MINT-267768.
STRING	10090.ENSMUSP00000026900.
PTM databases
PhosphoSite	Q99LI8.
Proteomic databases
PaxDb	Q99LI8.
PRIDE	Q99LI8.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	15239.
KEGG	mmu:15239.
UCSC	uc007msx.2. mouse.
Organism-specific databases
CTD	9146.
MGI	MGI:104681. Hgs.
Phylogenomic databases
eggNOG	NOG257212.
HOVERGEN	HBG062917.
InParanoid	Q99LI8.
KO	K12182.
Gene expression databases
ArrayExpress	Q99LI8.
Bgee	Q99LI8.
CleanEx	MM_HGS.
Genevestigator	Q99LI8.
GermOnline	ENSMUSG00000025793. Mus musculus.
Family and domain databases
Gene3D	1.25.40.90. 1 hit. 3.30.40.10. 1 hit.
InterPro	IPR008942. ENTH_VHS. IPR024641. HRS_helical. IPR017073. Ubi-bd_Hrs_VPS27. IPR003903. Ubiquitin-int_motif. IPR002014. VHS. IPR018205. VHS_subgr. IPR000306. Znf_FYVE. IPR017455. Znf_FYVE-rel. IPR011011. Znf_FYVE_PHD. IPR013083. Znf_RING/FYVE/PHD. [Graphical view]
Pfam	PF01363. FYVE. 1 hit. PF12210. Hrs_helical. 1 hit. PF00790. VHS. 1 hit. [Graphical view]
PIRSF	PIRSF036956. Hrs_Vps27. 1 hit.
SMART	SM00064. FYVE. 1 hit. SM00726. UIM. 1 hit. SM00288. VHS. 1 hit. [Graphical view]
SUPFAM	SSF48464. ENTH_VHS. 1 hit. SSF57903. FYVE_PHD_ZnF. 1 hit.
PROSITE	PS50330. UIM. 1 hit. PS50179. VHS. 1 hit. PS50178. ZF_FYVE. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	287839.
SOURCE	Search...

Entry information

Entry name

HGS_MOUSE

Accession

Primary (citable) accession number: Q99LI8
Secondary accession number(s): Q61691, Q8BQW3

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 19, 2005
Last sequence update:	July 19, 2005
Last modified:	April 3, 2013
This is version 102 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program