HAVR2_HUMAN
ID HAVR2_HUMAN Reviewed; 301 AA.
AC Q8TDQ0; B2RAY2; Q8WW60; Q96K94;
DT 27-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2010, sequence version 3.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Hepatitis A virus cellular receptor 2;
DE Short=HAVcr-2;
DE AltName: Full=T-cell immunoglobulin and mucin domain-containing protein 3;
DE Short=TIMD-3;
DE AltName: Full=T-cell immunoglobulin mucin receptor 3;
DE Short=TIM-3;
DE AltName: Full=T-cell membrane protein 3;
DE AltName: CD_antigen=CD366;
DE Flags: Precursor;
GN Name=HAVCR2; Synonyms=TIM3, TIMD3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, VARIANT LEU-140, AND
RP TISSUE SPECIFICITY.
RX PubMed=11823861; DOI=10.1038/415536a;
RA Monney L., Sabatos C.A., Gaglia J.L., Ryu A., Waldner H., Chernova T.,
RA Manning S., Greenfield E.A., Coyle A.J., Sobel R.A., Freeman G.J.,
RA Kuchroo V.K.;
RT "Th1-specific cell surface protein Tim-3 regulates macrophage activation
RT and severity of an autoimmune disease.";
RL Nature 415:536-541(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT LEU-140, AND VARIANT SPTCL
RP ILE-101.
RA Zhang W., Wan T., Li N., Cao X.;
RT "Novel human hepatitis A virus cellular receptor.";
RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT LEU-140.
RC TISSUE=Hepatoma;
RA Kuehn E.W., Ichimura T., Bonventre J.V.;
RT "A homolog to human kidney injury molecule-1 is expressed in hepatoma
RT cells.";
RL Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT LEU-140.
RC TISSUE=Embryo, and Umbilical cord blood;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT LEU-140.
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP LEU-140.
RC TISSUE=Lung, and Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION.
RX PubMed=14556005; DOI=10.1038/ni987;
RA Sanchez-Fueyo A., Tian J., Picarella D., Domenig C., Zheng X.X.,
RA Sabatos C.A., Manlongat N., Bender O., Kamradt T., Kuchroo V.K.,
RA Gutierrez-Ramos J.-C., Coyle A.J., Strom T.B.;
RT "Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and
RT promotes immunological tolerance.";
RL Nat. Immunol. 4:1093-1101(2003).
RN [9]
RP FUNCTION AS A RECEPTOR FOR LGALS9.
RX PubMed=16286920; DOI=10.1038/ni1271;
RA Zhu C., Anderson A.C., Schubart A., Xiong H., Imitola J., Khoury S.J.,
RA Zheng X.X., Strom T.B., Kuchroo V.K.;
RT "The Tim-3 ligand galectin-9 negatively regulates T helper type 1
RT immunity.";
RL Nat. Immunol. 6:1245-1252(2005).
RN [10]
RP PHOSPHORYLATION AT TYR-265, AND TISSUE SPECIFICITY.
RX PubMed=17069754; DOI=10.1016/j.bbrc.2006.10.079;
RA van de Weyer P.S., Muehlfeit M., Klose C., Bonventre J.V., Walz G.,
RA Kuehn E.W.;
RT "A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by
RT its ligand galectin-9.";
RL Biochem. Biophys. Res. Commun. 351:571-576(2006).
RN [11]
RP TISSUE SPECIFICITY.
RX PubMed=18006747; DOI=10.1126/science.1148536;
RA Anderson A.C., Anderson D.E., Bregoli L., Hastings W.D., Kassam N., Lei C.,
RA Chandwaskar R., Karman J., Su E.W., Hirashima M., Bruce J.N., Kane L.P.,
RA Kuchroo V.K., Hafler D.A.;
RT "Promotion of tissue inflammation by the immune receptor Tim-3 expressed on
RT innate immune cells.";
RL Science 318:1141-1143(2007).
RN [12]
RP INVOLVEMENT IN T-CELL EXHAUSTION, AND TISSUE SPECIFICITY.
RX PubMed=19001139; DOI=10.1084/jem.20081398;
RA Jones R.B., Ndhlovu L.C., Barbour J.D., Sheth P.M., Jha A.R., Long B.R.,
RA Wong J.C., Satkunarajah M., Schweneker M., Chapman J.M., Gyenes G.,
RA Vali B., Hyrcza M.D., Yue F.Y., Kovacs C., Sassi A., Loutfy M.,
RA Halpenny R., Persad D., Spotts G., Hecht F.M., Chun T.W., McCune J.M.,
RA Kaul R., Rini J.M., Nixon D.F., Ostrowski M.A.;
RT "Tim-3 expression defines a novel population of dysfunctional T cells with
RT highly elevated frequencies in progressive HIV-1 infection.";
RL J. Exp. Med. 205:2763-2779(2008).
RN [13]
RP INVOLVEMENT IN T-CELL EXHAUSTION, AND TISSUE SPECIFICITY.
RX PubMed=19587053; DOI=10.1128/jvi.00639-09;
RA Golden-Mason L., Palmer B.E., Kassam N., Townshend-Bulson L.,
RA Livingston S., McMahon B.J., Castelblanco N., Kuchroo V., Gretch D.R.,
RA Rosen H.R.;
RT "Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C
RT virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T
RT cells.";
RL J. Virol. 83:9122-9130(2009).
RN [14]
RP PHOSPHATIDYLSERINE-BINDING.
RX PubMed=20083673; DOI=10.4049/jimmunol.0903059;
RA DeKruyff R.H., Bu X., Ballesteros A., Santpiago C., Chim Y.L., Lee H.H.,
RA Karisola P., Pichavant M., Kaplan G.G., Umetsu D.T., Freeman G.J.,
RA Casasnovas J.M.;
RT "T cell/transmembrane, Ig, and mucin-3 allelic variants differentially
RT recognize phosphatidylserine and mediate phagocytosis of apoptotic cells.";
RL J. Immunol. 184:1918-1930(2010).
RN [15]
RP GLYCOSYLATION AT THR-145, STRUCTURE OF CARBOHYDRATES, AND IDENTIFICATION BY
RP MASS SPECTROMETRY.
RX PubMed=22171320; DOI=10.1074/mcp.m111.013649;
RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.;
RT "Human urinary glycoproteomics; attachment site specific analysis of N- and
RT O-linked glycosylations by CID and ECD.";
RL Mol. Cell. Proteomics 11:1-17(2012).
RN [16]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=22323453; DOI=10.1182/blood-2011-06-360321;
RA Gleason M.K., Lenvik T.R., McCullar V., Felices M., O'Brien M.S.,
RA Cooley S.A., Verneris M.R., Cichocki F., Holman C.J.,
RA Panoskaltsis-Mortari A., Niki T., Hirashima M., Blazar B.R., Miller J.S.;
RT "Tim-3 is an inducible human natural killer cell receptor that enhances
RT interferon gamma production in response to galectin-9.";
RL Blood 119:3064-3072(2012).
RN [17]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=22383801; DOI=10.1182/blood-2011-11-392951;
RA Ndhlovu L.C., Lopez-Verges S., Barbour J.D., Jones R.B., Jha A.R.,
RA Long B.R., Schoeffler E.C., Fujita T., Nixon D.F., Lanier L.L.;
RT "Tim-3 marks human natural killer cell maturation and suppresses cell-
RT mediated cytotoxicity.";
RL Blood 119:3734-3743(2012).
RN [18]
RP FUNCTION AS A RECEPTOR FOR LGALS9.
RX PubMed=23555261; DOI=10.1371/journal.ppat.1003253;
RA Leitner J., Rieger A., Pickl W.F., Zlabinger G.,
RA Grabmeier-Pfistershammer K., Steinberger P.;
RT "TIM-3 does not act as a receptor for galectin-9.";
RL PLoS Pathog. 9:E1003253-E1003253(2013).
RN [19]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=24838857; DOI=10.1002/eji.201344392;
RA Gautron A.S., Dominguez-Villar M., de Marcken M., Hafler D.A.;
RT "Enhanced suppressor function of TIM-3+ FoxP3+ regulatory T cells.";
RL Eur. J. Immunol. 44:2703-2711(2014).
RN [20]
RP REVIEW ON FUNCTION IN REGULATING T-CELL RESPONSES.
RX PubMed=24825777; DOI=10.1007/s12026-014-8524-1;
RA Gorman J.V., Colgan J.D.;
RT "Regulation of T cell responses by the receptor molecule Tim-3.";
RL Immunol. Res. 59:56-65(2014).
RN [21]
RP SUBCELLULAR LOCATION, INTERACTION WITH LGALS9 AND LCK, AND PHOSPHORYLATION.
RX PubMed=24337741; DOI=10.4049/jimmunol.1302663;
RA Clayton K.L., Haaland M.S., Douglas-Vail M.B., Mujib S., Chew G.M.,
RA Ndhlovu L.C., Ostrowski M.A.;
RT "T cell Ig and mucin domain-containing protein 3 is recruited to the immune
RT synapse, disrupts stable synapse formation, and associates with receptor
RT phosphatases.";
RL J. Immunol. 192:782-791(2014).
RN [22]
RP FUNCTION, INTERACTION WITH VAV1; AKT; LCP2; ZAP70; SYK; PIK3R1; FYN; SH3BP2
RP AND SH2D2A, AND MUTAGENESIS OF TYR-265 AND TYR-272.
RX PubMed=26492563; DOI=10.1371/journal.pone.0140694;
RA Tomkowicz B., Walsh E., Cotty A., Verona R., Sabins N., Kaplan F.,
RA Santulli-Marotto S., Chin C.N., Mooney J., Lingham R.B., Naso M.,
RA McCabe T.;
RT "TIM-3 Suppresses Anti-CD3/CD28-Induced TCR Activation and IL-2 Expression
RT through the NFAT Signaling Pathway.";
RL PLoS ONE 10:E0140694-E0140694(2015).
RN [23]
RP INVOLVEMENT IN SPTCL, SUBCELLULAR LOCATION, VARIANTS SPTCL CYS-82 AND
RP MET-97, AND CHARACTERIZATION OF VARIANTS SPTCL CYS-82 AND MET-97.
RX PubMed=30374066; DOI=10.1038/s41588-018-0251-4;
RA Gayden T., Sepulveda F.E., Khuong-Quang D.A., Pratt J., Valera E.T.,
RA Garrigue A., Kelso S., Sicheri F., Mikael L.G., Hamel N., Bajic A.,
RA Dali R., Deshmukh S., Dervovic D., Schramek D., Guerin F., Taipale M.,
RA Nikbakht H., Majewski J., Moshous D., Charlebois J., Abish S.,
RA Bole-Feysot C., Nitschke P., Bader-Meunier B., Mitchell D., Thieblemont C.,
RA Battistella M., Gravel S., Nguyen V.H., Conyers R., Diana J.S.,
RA McCormack C., Prince H.M., Besnard M., Blanche S., Ekert P.G., Fraitag S.,
RA Foulkes W.D., Fischer A., Neven B., Michonneau D., de Saint Basile G.,
RA Jabado N.;
RT "Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous
RT panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic
RT syndrome.";
RL Nat. Genet. 50:1650-1657(2018).
RN [24]
RP ERRATUM OF PUBMED:30374066.
RX PubMed=30429576; DOI=10.1038/s41588-018-0304-8;
RA Gayden T., Sepulveda F.E., Khuong-Quang D.A., Pratt J., Valera E.T.,
RA Garrigue A., Kelso S., Sicheri F., Mikael L.G., Hamel N., Bajic A.,
RA Dali R., Deshmukh S., Dervovic D., Schramek D., Guerin F., Taipale M.,
RA Nikbakht H., Majewski J., Moshous D., Charlebois J., Abish S.,
RA Bole-Feysot C., Nitschke P., Bader-Meunier B., Mitchell D., Thieblemont C.,
RA Battistella M., Gravel S., Nguyen V.H., Conyers R., Diana J.S.,
RA McCormack C., Prince H.M., Besnard M., Blanche S., Ekert P.G., Fraitag S.,
RA Foulkes W.D., Fischer A., Neven B., Michonneau D., de Saint Basile G.,
RA Jabado N.;
RL Nat. Genet. 51:196-196(2019).
RN [25]
RP INTERACTION WITH ILF3.
RX PubMed=34110282; DOI=10.7554/elife.66501;
RA Dou S., Li G., Li G., Hou C., Zheng Y., Tang L., Gao Y., Mo R., Li Y.,
RA Wang R., Shen B., Zhang J., Han G.;
RT "Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate
RT immunity.";
RL Elife 10:0-0(2021).
RN [26]
RP INVOLVEMENT IN SPTCL, AND VARIANTS SPTCL CYS-82 AND ILE-101.
RX PubMed=30792187; DOI=10.1182/bloodadvances.2018028340;
RA Polprasert C., Takeuchi Y., Kakiuchi N., Yoshida K., Assanasen T.,
RA Sitthi W., Bunworasate U., Pirunsarn A., Wudhikarn K., Lawasut P.,
RA Uaprasert N., Kongkiatkamon S., Moonla C., Sanada M., Akita N., Takeda J.,
RA Fujii Y., Suzuki H., Nannya Y., Shiraishi Y., Chiba K., Tanaka H.,
RA Miyano S., Rojnuckarin P., Ogawa S., Makishima H.;
RT "Frequent germline mutations of HAVCR2 in sporadic subcutaneous
RT panniculitis-like T-cell lymphoma.";
RL Blood Adv. 3:588-595(2019).
CC -!- FUNCTION: Cell surface receptor implicated in modulating innate and
CC adaptive immune responses. Generally accepted to have an inhibiting
CC function. Reports on stimulating functions suggest that the activity
CC may be influenced by the cellular context and/or the respective ligand
CC (PubMed:24825777). Regulates macrophage activation (PubMed:11823861).
CC Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune
CC responses and promotes immunological tolerance (PubMed:14556005). In
CC CD8+ cells attenuates TCR-induced signaling, specifically by blocking
CC NF-kappaB and NFAT promoter activities resulting in the loss of IL-2
CC secretion. The function may implicate its association with LCK proposed
CC to impair phosphorylation of TCR subunits, and/or LGALS9-dependent
CC recruitment of PTPRC to the immunological synapse (PubMed:24337741,
CC PubMed:26492563). In contrast, shown to activate TCR-induced signaling
CC in T-cells probably implicating ZAP70, LCP2, LCK and FYN (By
CC similarity). Expressed on Treg cells can inhibit Th17 cell responses
CC (PubMed:24838857). Receptor for LGALS9 (PubMed:16286920,
CC PubMed:24337741). Binding to LGALS9 is believed to result in
CC suppression of T-cell responses; the resulting apoptosis of antigen-
CC specific cells may implicate HAVCR2 phosphorylation and disruption of
CC its association with BAG6. Binding to LGALS9 is proposed to be involved
CC in innate immune response to intracellular pathogens. Expressed on Th1
CC cells interacts with LGALS9 expressed on Mycobacterium tuberculosis-
CC infected macrophages to stimulate antibactericidal activity including
CC IL-1 beta secretion and to restrict intracellular bacterial growth (By
CC similarity). However, the function as receptor for LGALS9 has been
CC challenged (PubMed:23555261). Also reported to enhance CD8+ T-cell
CC responses to an acute infection such as by Listeria monocytogenes (By
CC similarity). Receptor for phosphatidylserine (PtSer); PtSer-binding is
CC calcium-dependent. May recognize PtSer on apoptotic cells leading to
CC their phagocytosis. Mediates the engulfment of apoptotic cells by
CC dendritic cells. Expressed on T-cells, promotes conjugation but not
CC engulfment of apoptotic cells. Expressed on dendritic cells (DCs)
CC positively regulates innate immune response and in synergy with Toll-
CC like receptors promotes secretion of TNF-alpha. In tumor-imfiltrating
CC DCs suppresses nucleic acid-mediated innate immune repsonse by
CC interaction with HMGB1 and interfering with nucleic acid-sensing and
CC trafficking of nucleid acids to endosomes (By similarity). Expressed on
CC natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma
CC production in response to LGALS9 (PubMed:22323453). In contrast, shown
CC to suppress NK cell-mediated cytotoxicity (PubMed:22383801). Negatively
CC regulates NK cell function in LPS-induced endotoxic shock (By
CC similarity). {ECO:0000250|UniProtKB:Q8VIM0,
CC ECO:0000269|PubMed:11823861, ECO:0000269|PubMed:14556005,
CC ECO:0000269|PubMed:16286920, ECO:0000269|PubMed:22323453,
CC ECO:0000269|PubMed:23555261, ECO:0000269|PubMed:24838857,
CC ECO:0000269|PubMed:26492563, ECO:0000269|PubMed:30374066,
CC ECO:0000305|PubMed:24825777}.
CC -!- SUBUNIT: Interacts with HMGB1; impairs HMGB1 binding to B-DNA and
CC likely HMGB1-mediated innate immune response (By similarity). Interacts
CC with BAG6 (By similarity). Interacts (phosphorylated) with PIK3R1 and
CC PIK3R2. Interacts (not dependent on its phosphorylation status) with
CC FYN (By similarity). Interacts (in basal state T-cells) with VAV1;
CC AKT1/2, LCP2, ZAP70, SYK, PIK3R1, FYN, SH3BP2 and SH2D2A. Interacts (in
CC activated T-cells) with LCK and PLCG (PubMed:26492563,
CC PubMed:24337741). Interacts with ILF3; this interaction promotes ILF3
CC ubiquitination and degradation (PubMed:34110282).
CC {ECO:0000250|UniProtKB:Q8VIM0, ECO:0000269|PubMed:24337741,
CC ECO:0000269|PubMed:26492563, ECO:0000269|PubMed:34110282}.
CC -!- INTERACTION:
CC Q8TDQ0; P13688: CEACAM1; NbExp=4; IntAct=EBI-11472922, EBI-4314481;
CC Q8TDQ0; Q96IW7: SEC22A; NbExp=3; IntAct=EBI-11472922, EBI-8652744;
CC Q8TDQ0; Q8N2M4: TMEM86A; NbExp=3; IntAct=EBI-11472922, EBI-12015604;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type I
CC membrane protein {ECO:0000305}. Cell junction
CC {ECO:0000269|PubMed:24337741}. Cell membrane
CC {ECO:0000269|PubMed:30374066}. Note=Localizes to the immunological
CC synapse between CD8+ T-cells and target cells.
CC {ECO:0000269|PubMed:24337741}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8TDQ0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8TDQ0-2; Sequence=VSP_017287, VSP_017288;
CC -!- TISSUE SPECIFICITY: Expressed in T-helper type 1 (Th1) lymphocytes.
CC Expressed on regulatory T (Treg) cells after TCR stimulation. Expressed
CC in dendritic cells and natural killer (NK) cells. Expressed in
CC epithelial tissues. Expression is increased on CD4+ and CD8+ T-cells in
CC chronic hepatitis C virus (HCV) infection. In progressive HIV-1
CC infection, expression is up-regulated on HIV-1-specific CD8 T-cells.
CC {ECO:0000269|PubMed:11823861, ECO:0000269|PubMed:17069754,
CC ECO:0000269|PubMed:18006747, ECO:0000269|PubMed:19001139,
CC ECO:0000269|PubMed:19587053, ECO:0000269|PubMed:22323453,
CC ECO:0000269|PubMed:22383801, ECO:0000269|PubMed:24838857}.
CC -!- PTM: O-glycosylated with core 1 or possibly core 8 glycans.
CC {ECO:0000269|PubMed:22171320}.
CC -!- PTM: Phosphorylated on tyrosine residues; modestly increased after
CC TCR/CD28 stimulation. Can be phosphorylated in the cytoplasmatic domain
CC by FYN (By similarity). Phosphorylation at Tyr-265 is increased by
CC stimulation with ligand LGALS9. {ECO:0000250|UniProtKB:Q8VIM0,
CC ECO:0000269|PubMed:17069754, ECO:0000269|PubMed:24337741}.
CC -!- DISEASE: Note=May be involved in T-cell exhaustion associated with
CC chronic viral infections such as with human immunodeficiency virus
CC (HIV) and hepatitic C virus (HCV). {ECO:0000269|PubMed:19001139,
CC ECO:0000269|PubMed:19587053}.
CC -!- DISEASE: T-cell lymphoma, subcutaneous panniculitis-like (SPTCL)
CC [MIM:618398]: An uncommon form of T-cell non-Hodgkin lymphoma, in which
CC cytotoxic CD8+ T-cells infiltrate subcutaneous adipose tissue, and
CC rimming adipocytes in a lace-like pattern. Affected individuals
CC typically present with multiple subcutaneous nodules, systemic B-cell
CC symptoms, and, in a subset of cases, autoimmune disorders, most
CC commonly systemic lupus erythematosus. A subset of patients develop
CC hemophagocytic lymphohistiocytosis. SPTCL transmission pattern is
CC consistent with autosomal recessive inheritance with incomplete
CC penetrance. {ECO:0000269|PubMed:30374066, ECO:0000269|PubMed:30792187,
CC ECO:0000269|Ref.2}. Note=Disease susceptibility is associated with
CC variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the immunoglobulin superfamily. TIM family.
CC {ECO:0000305}.
CC -!- CAUTION: Experimental results based on the injection of HAVCR2/TIM-3
CC antibodies or use of HAVCR2/TIM-3-Fc fusion proteins can reflect
CC changes in the activity of several cell types and pathways as
CC HAVCR2/TIM-3 is expressed by multiple immune cell types.
CC {ECO:0000305|PubMed:24825777}.
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DR EMBL; AF251707; AAM19100.1; -; mRNA.
DR EMBL; AY069944; AAL55401.1; -; mRNA.
DR EMBL; AK027334; BAB55044.1; -; mRNA.
DR EMBL; AK314406; BAG37029.1; -; mRNA.
DR EMBL; AC011377; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471062; EAW61614.1; -; Genomic_DNA.
DR EMBL; BC020843; AAH20843.1; -; mRNA.
DR EMBL; BC063431; AAH63431.1; -; mRNA.
DR CCDS; CCDS4333.1; -. [Q8TDQ0-1]
DR RefSeq; NP_116171.3; NM_032782.4. [Q8TDQ0-1]
DR PDB; 5DZL; X-ray; 3.40 A; A/B=22-126.
DR PDB; 5F71; X-ray; 2.40 A; A/B=22-130.
DR PDB; 6DHB; X-ray; 1.70 A; A=24-130.
DR PDB; 6TXZ; X-ray; 3.06 A; A/B/C/D=22-130.
DR PDB; 7KQL; X-ray; 1.49 A; T=13-132.
DR PDB; 7M3Y; X-ray; 1.69 A; B=22-130.
DR PDB; 7M3Z; X-ray; 1.40 A; A=22-130.
DR PDB; 7M41; X-ray; 1.79 A; A/B=22-130.
DR PDBsum; 5DZL; -.
DR PDBsum; 5F71; -.
DR PDBsum; 6DHB; -.
DR PDBsum; 6TXZ; -.
DR PDBsum; 7KQL; -.
DR PDBsum; 7M3Y; -.
DR PDBsum; 7M3Z; -.
DR PDBsum; 7M41; -.
DR AlphaFoldDB; Q8TDQ0; -.
DR SMR; Q8TDQ0; -.
DR BioGRID; 124313; 82.
DR DIP; DIP-61459N; -.
DR IntAct; Q8TDQ0; 79.
DR STRING; 9606.ENSP00000312002; -.
DR ChEMBL; CHEMBL4630879; -.
DR GlyConnect; 712; 5 O-Linked glycans (1 site).
DR GlyGen; Q8TDQ0; 4 sites, 6 O-linked glycans (3 sites).
DR iPTMnet; Q8TDQ0; -.
DR PhosphoSitePlus; Q8TDQ0; -.
DR BioMuta; HAVCR2; -.
DR DMDM; 311033536; -.
DR jPOST; Q8TDQ0; -.
DR MassIVE; Q8TDQ0; -.
DR PaxDb; Q8TDQ0; -.
DR PeptideAtlas; Q8TDQ0; -.
DR PRIDE; Q8TDQ0; -.
DR ProteomicsDB; 74319; -. [Q8TDQ0-1]
DR ProteomicsDB; 74320; -. [Q8TDQ0-2]
DR ABCD; Q8TDQ0; 3 sequenced antibodies.
DR Antibodypedia; 2450; 1295 antibodies from 46 providers.
DR CPTC; Q8TDQ0; 3 antibodies.
DR DNASU; 84868; -.
DR Ensembl; ENST00000307851.9; ENSP00000312002.4; ENSG00000135077.9. [Q8TDQ0-1]
DR GeneID; 84868; -.
DR KEGG; hsa:84868; -.
DR MANE-Select; ENST00000307851.9; ENSP00000312002.4; NM_032782.5; NP_116171.3.
DR UCSC; uc003lwk.3; human. [Q8TDQ0-1]
DR CTD; 84868; -.
DR DisGeNET; 84868; -.
DR GeneCards; HAVCR2; -.
DR HGNC; HGNC:18437; HAVCR2.
DR HPA; ENSG00000135077; Tissue enhanced (lymphoid).
DR MalaCards; HAVCR2; -.
DR MIM; 606652; gene.
DR MIM; 618398; phenotype.
DR neXtProt; NX_Q8TDQ0; -.
DR OpenTargets; ENSG00000135077; -.
DR Orphanet; 86884; Subcutaneous panniculitis-like T-cell lymphoma.
DR PharmGKB; PA134883425; -.
DR VEuPathDB; HostDB:ENSG00000135077; -.
DR eggNOG; ENOG502S454; Eukaryota.
DR GeneTree; ENSGT00940000154444; -.
DR InParanoid; Q8TDQ0; -.
DR OMA; EHGPAET; -.
DR OrthoDB; 1147868at2759; -.
DR PhylomeDB; Q8TDQ0; -.
DR TreeFam; TF336163; -.
DR PathwayCommons; Q8TDQ0; -.
DR Reactome; R-HSA-451927; Interleukin-2 family signaling.
DR SignaLink; Q8TDQ0; -.
DR BioGRID-ORCS; 84868; 10 hits in 1074 CRISPR screens.
DR ChiTaRS; HAVCR2; human.
DR GeneWiki; HAVCR2; -.
DR GenomeRNAi; 84868; -.
DR Pharos; Q8TDQ0; Tbio.
DR PRO; PR:Q8TDQ0; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q8TDQ0; protein.
DR Bgee; ENSG00000135077; Expressed in granulocyte and 145 other tissues.
DR ExpressionAtlas; Q8TDQ0; baseline and differential.
DR Genevisible; Q8TDQ0; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-SubCell.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005769; C:early endosome; IEA:Ensembl.
DR GO; GO:0001772; C:immunological synapse; IEA:Ensembl.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0002281; P:macrophage activation involved in immune response; IEA:Ensembl.
DR GO; GO:0060135; P:maternal process involved in female pregnancy; IDA:UniProtKB.
DR GO; GO:0002519; P:natural killer cell tolerance induction; IMP:UniProtKB.
DR GO; GO:1900425; P:negative regulation of defense response to bacterium; IEA:Ensembl.
DR GO; GO:0010629; P:negative regulation of gene expression; IMP:UniProtKB.
DR GO; GO:0071656; P:negative regulation of granulocyte colony-stimulating factor production; IDA:UniProtKB.
DR GO; GO:2000521; P:negative regulation of immunological synapse formation; IEA:Ensembl.
DR GO; GO:0032687; P:negative regulation of interferon-alpha production; IDA:UniProtKB.
DR GO; GO:0032689; P:negative regulation of interferon-gamma production; IDA:UniProtKB.
DR GO; GO:0032703; P:negative regulation of interleukin-2 production; IDA:UniProtKB.
DR GO; GO:0032712; P:negative regulation of interleukin-3 production; IDA:UniProtKB.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0030886; P:negative regulation of myeloid dendritic cell activation; IMP:UniProtKB.
DR GO; GO:0032815; P:negative regulation of natural killer cell activation; IEA:Ensembl.
DR GO; GO:0002859; P:negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target; IEA:Ensembl.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:2001189; P:negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell; IDA:UniProtKB.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0002826; P:negative regulation of T-helper 1 type immune response; IEA:Ensembl.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IMP:UniProtKB.
DR GO; GO:0032722; P:positive regulation of chemokine production; IEA:Ensembl.
DR GO; GO:1900426; P:positive regulation of defense response to bacterium; IEA:Ensembl.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0045089; P:positive regulation of innate immune response; IEA:Ensembl.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IEA:Ensembl.
DR GO; GO:0032732; P:positive regulation of interleukin-1 production; IEA:Ensembl.
DR GO; GO:0032753; P:positive regulation of interleukin-4 production; IMP:UniProtKB.
DR GO; GO:0043032; P:positive regulation of macrophage activation; IEA:Ensembl.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IMP:UniProtKB.
DR GO; GO:0002652; P:regulation of tolerance induction dependent upon immune response; IEA:Ensembl.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; IEA:Ensembl.
DR GO; GO:0034154; P:toll-like receptor 7 signaling pathway; IEA:Ensembl.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; IEA:Ensembl.
DR Gene3D; 2.60.40.10; -; 1.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR013106; Ig_V-set.
DR Pfam; PF07686; V-set; 1.
DR SMART; SM00409; IG; 1.
DR SUPFAM; SSF48726; SSF48726; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Adaptive immunity; Alternative splicing; Cell junction;
KW Cell membrane; Disease variant; Disulfide bond; Glycoprotein; Immunity;
KW Immunoglobulin domain; Inflammatory response; Innate immunity; Membrane;
KW Metal-binding; Phosphoprotein; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..301
FT /note="Hepatitis A virus cellular receptor 2"
FT /id="PRO_0000042101"
FT TOPO_DOM 22..202
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 203..223
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 224..301
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 22..124
FT /note="Ig-like V-type"
FT BINDING 111
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT /ligand_id="ChEBI:CHEBI:57262"
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0"
FT BINDING 116
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0"
FT BINDING 118
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT /ligand_id="ChEBI:CHEBI:57262"
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0"
FT BINDING 119
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0"
FT MOD_RES 265
FT /note="Phosphotyrosine; by ITK"
FT /evidence="ECO:0000269|PubMed:17069754"
FT CARBOHYD 145
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:22171320"
FT CARBOHYD 172
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 38..110
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0,
FT ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 52..63
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0,
FT ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 58..109
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0,
FT ECO:0000255|PROSITE-ProRule:PRU00114"
FT VAR_SEQ 132..142
FT /note="AKVTPAPTRQR -> GEWTFACHLYE (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_017287"
FT VAR_SEQ 143..301
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_017288"
FT VARIANT 82
FT /note="Y -> C (in SPTCL; associated with disease
FT susceptibility; results in dysregulated secretion of
FT inflammatory cytokines by macrophages; affects protein
FT folding; decreased localization at the cell membrane;
FT dbSNP:rs184868814)"
FT /evidence="ECO:0000269|PubMed:30374066,
FT ECO:0000269|PubMed:30792187"
FT /id="VAR_082211"
FT VARIANT 97
FT /note="I -> M (in SPTCL; associated with disease
FT susceptibility; affects protein folding; decreased
FT localization at the cell membrane; dbSNP:rs35960726)"
FT /evidence="ECO:0000269|PubMed:30374066"
FT /id="VAR_082212"
FT VARIANT 101
FT /note="T -> I (in SPTCL; may be associated with disease
FT susceptibility; dbSNP:rs147827860)"
FT /evidence="ECO:0000269|PubMed:30792187, ECO:0000269|Ref.2"
FT /id="VAR_082213"
FT VARIANT 140
FT /note="R -> L (in dbSNP:rs1036199)"
FT /evidence="ECO:0000269|PubMed:11823861,
FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15489334,
FT ECO:0000269|Ref.2, ECO:0000269|Ref.3, ECO:0000269|Ref.6"
FT /id="VAR_025342"
FT MUTAGEN 265
FT /note="Y->A: Abolishes TCR-induced NFAT activation; when
FT associated with A-272."
FT /evidence="ECO:0000269|PubMed:26492563"
FT MUTAGEN 265
FT /note="Y->E: No effect on TCR-induced NFAT activation
FT (phosphomimetic mutation); when associated with E-272."
FT /evidence="ECO:0000269|PubMed:26492563"
FT MUTAGEN 272
FT /note="Y->A: Abolishes TCR-induced NFAT activation; when
FT associated with A-265."
FT /evidence="ECO:0000269|PubMed:26492563"
FT MUTAGEN 272
FT /note="Y->E: No effect on TCR-induced NFAT activation
FT (phosphomimetic mutation); when associated with E-265."
FT /evidence="ECO:0000269|PubMed:26492563"
FT STRAND 26..29
FT /evidence="ECO:0007829|PDB:7M3Z"
FT STRAND 34..36
FT /evidence="ECO:0007829|PDB:7M3Z"
FT STRAND 44..46
FT /evidence="ECO:0007829|PDB:5F71"
FT STRAND 51..56
FT /evidence="ECO:0007829|PDB:7M3Z"
FT TURN 61..63
FT /evidence="ECO:0007829|PDB:7M3Z"
FT STRAND 64..70
FT /evidence="ECO:0007829|PDB:7M3Z"
FT STRAND 72..78
FT /evidence="ECO:0007829|PDB:7M3Z"
FT STRAND 82..86
FT /evidence="ECO:0007829|PDB:6DHB"
FT HELIX 88..90
FT /evidence="ECO:0007829|PDB:7M3Z"
FT STRAND 95..97
FT /evidence="ECO:0007829|PDB:7M3Z"
FT HELIX 102..104
FT /evidence="ECO:0007829|PDB:7M3Z"
FT STRAND 106..112
FT /evidence="ECO:0007829|PDB:7M3Z"
FT STRAND 115..118
FT /evidence="ECO:0007829|PDB:7M3Z"
FT STRAND 121..130
FT /evidence="ECO:0007829|PDB:7M3Z"
SQ SEQUENCE 301 AA; 33394 MW; 519A5B0D512B6173 CRC64;
MFSHLPFDCV LLLLLLLLTR SSEVEYRAEV GQNAYLPCFY TPAAPGNLVP VCWGKGACPV
FECGNVVLRT DERDVNYWTS RYWLNGDFRK GDVSLTIENV TLADSGIYCC RIQIPGIMND
EKFNLKLVIK PAKVTPAPTR QRDFTAAFPR MLTTRGHGPA ETQTLGSLPD INLTQISTLA
NELRDSRLAN DLRDSGATIR IGIYIGAGIC AGLALALIFG ALIFKWYSHS KEKIQNLSLI
SLANLPPSGL ANAVAEGIRS EENIYTIEEN VYEVEEPNEY YCYVSSRQQP SQPLGCRFAM
P
