TYOBP_HUMAN
ID TYOBP_HUMAN Reviewed; 113 AA.
AC O43914; A8K2X0; F5H389; Q6FGA5; Q9UMT3;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=TYRO protein tyrosine kinase-binding protein {ECO:0000312|HGNC:HGNC:12449};
DE AltName: Full=DNAX-activation protein 12 {ECO:0000303|PubMed:9490415};
DE AltName: Full=Killer-activating receptor-associated protein;
DE Short=KAR-associated protein;
DE Flags: Precursor;
GN Name=TYROBP {ECO:0000312|HGNC:HGNC:12449};
GN Synonyms=DAP12 {ECO:0000303|PubMed:9490415},
GN KARAP {ECO:0000250|UniProtKB:O54885};
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 [GENOMIC DNA / MRNA] (ISOFORM 1), FUNCTION, AND
RP PHOSPHORYLATION.
RX PubMed=9490415; DOI=10.1038/35642;
RA Lanier L.L., Corliss B.C., Wu J., Leong C., Phillips J.H.;
RT "Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved
RT in activating NK cells.";
RL Nature 391:703-707(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Lymphoid tissue;
RA Cantoni C., Biassoni R.;
RT "Killer activating receptor associated protein isoform b.";
RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Begum N.A., Seya T.;
RT "Dendritic cells express two types of immunoreceptor DAP12 transcripts.";
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Macrophage;
RX PubMed=16344560; DOI=10.1101/gr.4039406;
RA Kimura K., Wakamatsu A., Suzuki Y., Ota T., Nishikawa T., Yamashita R.,
RA Yamamoto J., Sekine M., Tsuritani K., Wakaguri H., Ishii S., Sugiyama T.,
RA Saito K., Isono Y., Irie R., Kushida N., Yoneyama T., Otsuka R., Kanda K.,
RA Yokoi T., Kondo H., Wagatsuma M., Murakawa K., Ishida S., Ishibashi T.,
RA Takahashi-Fujii A., Tanase T., Nagai K., Kikuchi H., Nakai K., Isogai T.,
RA Sugano S.;
RT "Diversification of transcriptional modulation: large-scale identification
RT and characterization of putative alternative promoters of human genes.";
RL Genome Res. 16:55-65(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
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 [10]
RP FUNCTION, INTERACTION WITH KLRD1, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP ASP-50.
RX PubMed=9655483; DOI=10.1016/s1074-7613(00)80574-9;
RA Lanier L.L., Corliss B., Wu J., Phillips J.H.;
RT "Association of DAP12 with activating CD94/NKG2C NK cell receptors.";
RL Immunity 8:693-701(1998).
RN [11]
RP FUNCTION, AND INTERACTION WITH CLECSF5.
RX PubMed=10449773; DOI=10.1073/pnas.96.17.9792;
RA Bakker A.B.H., Baker E., Sutherland G.R., Phillips J.H., Lanier L.L.;
RT "Myeloid DAP12-associating lectin (MDL)-1 is a cell surface receptor
RT involved in the activation of myeloid cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:9792-9796(1999).
RN [12]
RP FUNCTION, AND INTERACTION WITH SIRPB1.
RX PubMed=10604985; DOI=10.4049/jimmunol.164.1.9;
RA Dietrich J., Cella M., Seiffert M., Buehring H.-J., Colonna M.;
RT "Signal-regulatory protein beta 1 is a DAP12-associated activating receptor
RT expressed in myeloid cells.";
RL J. Immunol. 164:9-12(2000).
RN [13]
RP INVOLVEMENT IN PLOSL1.
RX PubMed=10888890; DOI=10.1038/77153;
RA Paloneva J., Kestilae M., Wu J., Salminen A., Boehling T., Ruotsalainen V.,
RA Hakola P., Bakker A.B.H., Phillips J.H., Pekkarinen P., Lanier L.L.,
RA Timonen T., Peltonen L.;
RT "Loss-of-function mutations in TYROBP (DAP12) result in a presenile
RT dementia with bone cysts.";
RL Nat. Genet. 25:357-361(2000).
RN [14]
RP FUNCTION, AND INTERACTION WITH TREM1.
RX PubMed=10799849; DOI=10.4049/jimmunol.164.10.4991;
RA Bouchon A., Dietrich J., Colonna M.;
RT "Inflammatory responses can be triggered by TREM-1, a novel receptor
RT expressed on neutrophils and monocytes.";
RL J. Immunol. 164:4991-4995(2000).
RN [15]
RP FUNCTION, AND INTERACTION WITH TREM2.
RX PubMed=11602640; DOI=10.1084/jem.194.8.1111;
RA Bouchon A., Hernandez-Munain C., Cella M., Colonna M.;
RT "A DAP12-mediated pathway regulates expression of CC chemokine receptor 7
RT and maturation of human dendritic cells.";
RL J. Exp. Med. 194:1111-1122(2001).
RN [16]
RP INVOLVEMENT IN PLOSL1.
RX PubMed=12370476; DOI=10.1212/wnl.59.7.1105;
RA Kondo T., Takahashi K., Kohara N., Takahashi Y., Hayashi S., Takahashi H.,
RA Matsuo H., Yamazaki M., Inoue K., Miyamoto K., Yamamura T.;
RT "Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease):
RT three genetic forms.";
RL Neurology 59:1105-1107(2002).
RN [17]
RP TISSUE SPECIFICITY.
RX PubMed=11922939; DOI=10.1016/s0161-5890(02)00004-4;
RA Gingras M.-C., Lapillonne H., Margolin J.F.;
RT "TREM-1, MDL-1, and DAP12 expression is associated with a mature stage of
RT myeloid development.";
RL Mol. Immunol. 38:817-824(2002).
RN [18]
RP FUNCTION, AND INTERACTION WITH CD300E.
RX PubMed=15557162; DOI=10.4049/jimmunol.173.11.6703;
RA Aguilar H., Alvarez-Errico D., Garcia-Montero A.C., Orfao A., Sayos J.,
RA Lopez-Botet M.;
RT "Molecular characterization of a novel immune receptor restricted to the
RT monocytic lineage.";
RL J. Immunol. 173:6703-6711(2004).
RN [19]
RP INTERACTION WITH KLRD1.
RX PubMed=15940674; DOI=10.1002/eji.200425843;
RA Guma M., Busch L.K., Salazar-Fontana L.I., Bellosillo B., Morte C.,
RA Garcia P., Lopez-Botet M.;
RT "The CD94/NKG2C killer lectin-like receptor constitutes an alternative
RT activation pathway for a subset of CD8+ T cells.";
RL Eur. J. Immunol. 35:2071-2080(2005).
RN [20]
RP INTERACTION WITH SIGLEC14.
RX PubMed=17012248; DOI=10.1096/fj.06-5800com;
RA Angata T., Hayakawa T., Yamanaka M., Varki A., Nakamura M.;
RT "Discovery of Siglec-14, a novel sialic acid receptor undergoing concerted
RT evolution with Siglec-5 in primates.";
RL FASEB J. 20:1964-1973(2006).
RN [21]
RP FUNCTION, AND INTERACTION WITH CD300LB.
RX PubMed=16920917; DOI=10.4049/jimmunol.177.5.2819;
RA Martinez-Barriocanal A., Sayos J.;
RT "Molecular and functional characterization of CD300b, a new activating
RT immunoglobulin receptor able to transduce signals through two different
RT pathways.";
RL J. Immunol. 177:2819-2830(2006).
RN [22]
RP FUNCTION, AND INTERACTION WITH CD300LB.
RX PubMed=17928527; DOI=10.1182/blood-2007-04-085787;
RA Yamanishi Y., Kitaura J., Izawa K., Matsuoka T., Oki T., Lu Y., Shibata F.,
RA Yamazaki S., Kumagai H., Nakajima H., Maeda-Yamamoto M., Tybulewicz V.L.J.,
RA Takai T., Kitamura T.;
RT "Analysis of mouse LMIR5/CLM-7 as an activating receptor: differential
RT regulation of LMIR5/CLM-7 in mouse versus human cells.";
RL Blood 111:688-698(2008).
RN [23]
RP INTERACTION WITH KIR2DS5.
RX PubMed=18624290; DOI=10.1002/eji.200838434;
RA Della Chiesa M., Romeo E., Falco M., Balsamo M., Augugliaro R., Moretta L.,
RA Bottino C., Moretta A., Vitale M.;
RT "Evidence that the KIR2DS5 gene codes for a surface receptor triggering
RT natural killer cell function.";
RL Eur. J. Immunol. 38:2284-2289(2008).
RN [24]
RP FUNCTION.
RX PubMed=18957693; DOI=10.1126/scisignal.1159665;
RA Helming L., Tomasello E., Kyriakides T.R., Martinez F.O., Takai T.,
RA Gordon S., Vivier E.;
RT "Essential role of DAP12 signaling in macrophage programming into a fusion-
RT competent state.";
RL Sci. Signal. 1:RA11-RA11(2008).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [26]
RP FUNCTION.
RX PubMed=21727189; DOI=10.1084/jem.20101623;
RA Nakano-Yokomizo T., Tahara-Hanaoka S., Nakahashi-Oda C., Nabekura T.,
RA Tchao N.K., Kadosaki M., Totsuka N., Kurita N., Nakamagoe K., Tamaoka A.,
RA Takai T., Yasui T., Kikutani H., Honda S., Shibuya K., Lanier L.L.,
RA Shibuya A.;
RT "The immunoreceptor adapter protein DAP12 suppresses B lymphocyte-driven
RT adaptive immune responses.";
RL J. Exp. Med. 208:1661-1671(2011).
RN [27]
RP FUNCTION, INTERACTION WITH KIR2DS1, AND MUTAGENESIS OF ASP-50.
RX PubMed=23715743; DOI=10.1189/jlb.0213093;
RA Mulrooney T.J., Posch P.E., Hurley C.K.;
RT "DAP12 impacts trafficking and surface stability of killer immunoglobulin-
RT like receptors on natural killer cells.";
RL J. Leukoc. Biol. 94:301-313(2013).
RN [28]
RP FUNCTION, INTERACTION WITH TREM2, AND MUTAGENESIS OF ASP-50.
RX PubMed=25957402; DOI=10.1074/jbc.m115.645986;
RA Zhong L., Chen X.F., Zhang Z.L., Wang Z., Shi X.Z., Xu K., Zhang Y.W.,
RA Xu H., Bu G.;
RT "DAP12 stabilizes the C-terminal fragment of the triggering receptor
RT expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro-
RT inflammatory response.";
RL J. Biol. Chem. 290:15866-15877(2015).
RN [29]
RP FUNCTION, AND INTERACTION WITH CD300H.
RX PubMed=26221034; DOI=10.1074/jbc.m115.643361;
RA Niizuma K., Tahara-Hanaoka S., Noguchi E., Shibuya A.;
RT "Identification and Characterization of CD300H, a New Member of the Human
RT CD300 Immunoreceptor Family.";
RL J. Biol. Chem. 290:22298-22308(2015).
RN [30]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [31]
RP STRUCTURE BY NMR OF 35-67 IN COMPLEX WITH KLRC2, SUBUNIT, DISULFIDE BOND,
RP MUTAGENESIS OF THR-54, AND INTERACTION WITH KLRC2 AND KIR2DS3.
RX PubMed=20890284; DOI=10.1038/ni.1943;
RA Call M.E., Wucherpfennig K.W., Chou J.J.;
RT "The structural basis for intramembrane assembly of an activating
RT immunoreceptor complex.";
RL Nat. Immunol. 11:1023-1029(2010).
RN [32] {ECO:0007744|PDB:4WO1, ECO:0007744|PDB:4WOL}
RP X-RAY CRYSTALLOGRAPHY (1.77 ANGSTROMS) OF 35-67, SUBUNIT, TRANSMEMBRANE
RP DOMAIN, METAL-BINDING, DISULFIDE BOND, AND MUTAGENESIS OF GLY-41; GLY-45;
RP GLY-49; ASP-50 AND THR-54.
RX PubMed=25981043; DOI=10.1016/j.celrep.2015.04.045;
RA Knoblich K., Park S., Lutfi M., van 't Hag L., Conn C.E., Seabrook S.A.,
RA Newman J., Czabotar P.E., Im W., Call M.E., Call M.J.;
RT "Transmembrane complexes of DAP12 crystallized in lipid membranes provide
RT insights into control of oligomerization in immunoreceptor assembly.";
RL Cell Rep. 11:1184-1192(2015).
RN [33]
RP VARIANTS GLU-2; CYS-23; ALA-47;
RP PRO-ALA-ASP-GLY-ARG-LEU-VAL-LEU-GLY-ASP-ARG-ASP-GLY-ARG-50 INS; LEU-55;
RP TRP-80; VAL-84 AND LEU-89.
RX PubMed=27658901; DOI=10.1016/j.neurobiolaging.2016.07.028;
RA Pottier C., Ravenscroft T.A., Brown P.H., Finch N.A., Baker M., Parsons M.,
RA Asmann Y.W., Ren Y., Christopher E., Levitch D., van Blitterswijk M.,
RA Cruchaga C., Campion D., Nicolas G., Richard A.C., Guerreiro R., Bras J.T.,
RA Zuchner S., Gonzalez M.A., Bu G., Younkin S., Knopman D.S., Josephs K.A.,
RA Parisi J.E., Petersen R.C., Ertekin-Taner N., Graff-Radford N.R.,
RA Boeve B.F., Dickson D.W., Rademakers R.;
RT "TYROBP genetic variants in early-onset Alzheimer's disease.";
RL Neurobiol. Aging 48:222.E9-222.E15(2016).
RN [34]
RP VARIANT LEU-55.
RX PubMed=28716534; DOI=10.1016/j.neurobiolaging.2017.06.019;
RA Darwent L., Carmona S., Lohmann E., Guven G., Kun-Rodrigues C., Bilgic B.,
RA Hanagasi H., Gurvit H., Erginel-Unaltuna N., Pak M., Hardy J.,
RA Singleton A., Bras J., Guerreiro R.;
RT "Mutations in TYROBP are not a common cause of dementia in a Turkish
RT cohort.";
RL Neurobiol. Aging 58:240.E1-240.E3(2017).
CC -!- FUNCTION: Adapter protein which non-covalently associates with
CC activating receptors found on the surface of a variety of immune cells
CC to mediate signaling and cell activation following ligand binding by
CC the receptors (PubMed:9490415, PubMed:9655483, PubMed:10604985). TYROBP
CC is tyrosine-phosphorylated in the ITAM domain following ligand binding
CC by the associated receptors which leads to activation of additional
CC tyrosine kinases and subsequent cell activation (PubMed:9490415). Also
CC has an inhibitory role in some cells (PubMed:21727189). Non-covalently
CC associates with activating receptors of the CD300 family to mediate
CC cell activation (PubMed:15557162, PubMed:16920917, PubMed:17928527;
CC PubMed:26221034). Also mediates cell activation through association
CC with activating receptors of the CD200R family (By similarity).
CC Required for neutrophil activation mediated by integrin (By
CC similarity). Required for the activation of myeloid cells mediated by
CC the CLEC5A/MDL1 receptor (PubMed:10449773). Associates with natural
CC killer (NK) cell receptors such as KIR2DS2 and the KLRD1/KLRC2
CC heterodimer to mediate NK cell activation (PubMed:9490415,
CC PubMed:9655483, PubMed:23715743). Also enhances trafficking and cell
CC surface expression of NK cell receptors KIR2DS1, KIR2DS2 and KIR2DS4
CC and ensures their stability at the cell surface (PubMed:23715743).
CC Associates with SIRPB1 to mediate activation of myeloid cells such as
CC monocytes and dendritic cells (PubMed:10604985). Associates with TREM1
CC to mediate activation of neutrophils and monocytes (PubMed:10799849).
CC Associates with TREM2 on monocyte-derived dendritic cells to mediate
CC up-regulation of chemokine receptor CCR7 and dendritic cell maturation
CC and survival (PubMed:11602640). Association with TREM2 mediates
CC cytokine-induced formation of multinucleated giant cells which are
CC formed by the fusion of macrophages (PubMed:18957693). Stabilizes the
CC TREM2 C-terminal fragment (TREM2-CTF) produced by TREM2 ectodomain
CC shedding which suppresses the release of pro-inflammatory cytokines
CC (PubMed:25957402). In microglia, required with TREM2 for phagocytosis
CC of apoptotic neurons (By similarity). Required with ITGAM/CD11B in
CC microglia to control production of microglial superoxide ions which
CC promote the neuronal apoptosis that occurs during brain development (By
CC similarity). Promotes pro-inflammatory responses in microglia following
CC nerve injury which accelerates degeneration of injured neurons (By
CC similarity). Positively regulates the expression of the IRAK3/IRAK-M
CC kinase and IL10 production by liver dendritic cells and inhibits their
CC T cell allostimulatory ability (By similarity). Negatively regulates B
CC cell proliferation (PubMed:21727189). Required for CSF1-mediated
CC osteoclast cytoskeletal organization (By similarity). Positively
CC regulates multinucleation during osteoclast development (By
CC similarity). {ECO:0000250|UniProtKB:O54885,
CC ECO:0000269|PubMed:10449773, ECO:0000269|PubMed:10604985,
CC ECO:0000269|PubMed:10799849, ECO:0000269|PubMed:11602640,
CC ECO:0000269|PubMed:15557162, ECO:0000269|PubMed:16920917,
CC ECO:0000269|PubMed:17928527, ECO:0000269|PubMed:18957693,
CC ECO:0000269|PubMed:21727189, ECO:0000269|PubMed:23715743,
CC ECO:0000269|PubMed:25957402, ECO:0000269|PubMed:26221034,
CC ECO:0000269|PubMed:9490415, ECO:0000269|PubMed:9655483}.
CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:20890284). Homotrimer;
CC disulfide-linked (PubMed:25981043). Homotetramer; disulfide-linked
CC (PubMed:25981043). Homotrimers and homotetramers form when low levels
CC of partner receptors are available and are competitive with assembly
CC with interacting receptors (PubMed:25981043). They may represent
CC alternative oligomerization states or may be intermediates in the
CC receptor assembly process (PubMed:25981043). Binding of a metal cation
CC aids in homooligomerization through coordination of the metal ion by
CC the subunits of the oligomer (PubMed:25981043). Interacts with TREM1
CC (PubMed:10799849). Interacts with TREM2 (PubMed:11602640,
CC PubMed:25957402). Interacts with SIRPB1 (PubMed:10604985). Interacts
CC with CLECSF5 (PubMed:10449773). Interacts with SIGLEC14
CC (PubMed:17012248). Interacts with CD300LB and CD300E (PubMed:15557162,
CC PubMed:16920917, PubMed:17928527). Interacts with CD300C2 (By
CC similarity). Interacts (via ITAM domain) with SYK (via SH2 domains);
CC activates SYK mediating neutrophil and macrophage integrin-mediated
CC activation (By similarity). Interacts with KLRC2, KIR2DS3 and KIR2DS5
CC (PubMed:18624290, PubMed:20890284). Interacts with CD300H
CC (PubMed:26221034). Interacts with KIR2DS1 (PubMed:23715743). Interacts
CC with KLRD1 (PubMed:9655483, PubMed:15940674).
CC {ECO:0000250|UniProtKB:O54885, ECO:0000269|PubMed:10449773,
CC ECO:0000269|PubMed:10604985, ECO:0000269|PubMed:10799849,
CC ECO:0000269|PubMed:11602640, ECO:0000269|PubMed:15557162,
CC ECO:0000269|PubMed:16920917, ECO:0000269|PubMed:17012248,
CC ECO:0000269|PubMed:17928527, ECO:0000269|PubMed:18624290,
CC ECO:0000269|PubMed:20890284, ECO:0000269|PubMed:23715743,
CC ECO:0000269|PubMed:25957402, ECO:0000269|PubMed:25981043,
CC ECO:0000269|PubMed:26221034, ECO:0000269|PubMed:9655483}.
CC -!- INTERACTION:
CC O43914; Q14953: KIR2DS5; NbExp=3; IntAct=EBI-2214794, EBI-16823921;
CC O43914; O95944: NCR2; NbExp=2; IntAct=EBI-2214794, EBI-14058375;
CC O43914; O00241: SIRPB1; NbExp=4; IntAct=EBI-2214794, EBI-2615458;
CC O43914; Q969S0: SLC35B4; NbExp=3; IntAct=EBI-2214794, EBI-10281213;
CC O43914; Q8N2M4: TMEM86A; NbExp=3; IntAct=EBI-2214794, EBI-12015604;
CC O43914; Q9NZC2: TREM2; NbExp=4; IntAct=EBI-2214794, EBI-14036387;
CC O43914; O43914: TYROBP; NbExp=2; IntAct=EBI-2214794, EBI-2214794;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:9655483};
CC Single-pass type I membrane protein {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=KARAP-a;
CC IsoId=O43914-1; Sequence=Displayed;
CC Name=2; Synonyms=KARAP-b;
CC IsoId=O43914-2; Sequence=VSP_012909;
CC Name=3;
CC IsoId=O43914-3; Sequence=VSP_046066;
CC -!- TISSUE SPECIFICITY: Expressed at low levels in the early development of
CC the hematopoietic system and in the promonocytic stage and at high
CC levels in mature monocytes. Expressed in hematological cells and
CC tissues such as peripheral blood leukocytes and spleen. Also found in
CC bone marrow, lymph nodes, placenta, lung and liver. Expressed at lower
CC levels in different parts of the brain especially in the basal ganglia
CC and corpus callosum. {ECO:0000269|PubMed:11922939}.
CC -!- PTM: Following ligand binding by associated receptors, tyrosine
CC phosphorylated in the ITAM domain which leads to activation of
CC additional tyrosine kinases and subsequent cell activation.
CC {ECO:0000269|PubMed:9490415}.
CC -!- DISEASE: Polycystic lipomembranous osteodysplasia with sclerosing
CC leukoencephalopathy 1 (PLOSL1) [MIM:221770]: A recessively inherited
CC disease characterized by presenile dementia along with large-scale
CC destruction of cancellous bones. Initial symptoms, starting in the
CC twenties, are pain and swelling resulting from cysts in the wrists and
CC ankles. Extremity bone fractures could occur with minor trauma. At
CC around 30 years of age, patients gradually develop neuropsychiatric
CC symptoms, including epileptic seizures, agnosia, apraxia, speech
CC disorder, memory disturbance, euphoria, and loss of social inhibitions.
CC The disorder usually leads to death in the fifth decade of life.
CC {ECO:0000269|PubMed:10888890, ECO:0000269|PubMed:12370476}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the TYROBP family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
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DR EMBL; AF019562; AAD09436.1; -; mRNA.
DR EMBL; AF019563; AAD09437.1; -; Genomic_DNA.
DR EMBL; AJ010098; CAB52288.1; -; mRNA.
DR EMBL; AY074782; AAL74017.1; -; mRNA.
DR EMBL; BT009851; AAP88853.1; -; mRNA.
DR EMBL; AK290385; BAF83074.1; -; mRNA.
DR EMBL; CR450342; CAG29338.1; -; mRNA.
DR EMBL; CR542202; CAG46999.1; -; mRNA.
DR EMBL; BP295666; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AD000833; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AD000864; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC011175; AAH11175.1; -; mRNA.
DR CCDS; CCDS12482.1; -. [O43914-1]
DR CCDS; CCDS46058.1; -. [O43914-2]
DR CCDS; CCDS54255.1; -. [O43914-3]
DR RefSeq; NP_001166985.1; NM_001173514.1. [O43914-3]
DR RefSeq; NP_003323.1; NM_003332.3. [O43914-1]
DR RefSeq; NP_937758.1; NM_198125.2. [O43914-2]
DR PDB; 2L34; NMR; -; A/B=35-67.
DR PDB; 2L35; NMR; -; A=35-67, B=35-66.
DR PDB; 4WO1; X-ray; 2.14 A; A/B/C/D=35-67.
DR PDB; 4WOL; X-ray; 1.77 A; A/B/C=35-67.
DR PDB; 7Q5W; X-ray; 2.20 A; GGG/HHH/III/JJJ/KKK/LLL=88-107.
DR PDBsum; 2L34; -.
DR PDBsum; 2L35; -.
DR PDBsum; 4WO1; -.
DR PDBsum; 4WOL; -.
DR PDBsum; 7Q5W; -.
DR AlphaFoldDB; O43914; -.
DR SMR; O43914; -.
DR BioGRID; 113155; 88.
DR CORUM; O43914; -.
DR IntAct; O43914; 18.
DR STRING; 9606.ENSP00000262629; -.
DR TCDB; 8.A.128.1.1; the signaling adaptor protein karap/dap12/tyrobp (sap) family.
DR iPTMnet; O43914; -.
DR PhosphoSitePlus; O43914; -.
DR BioMuta; TYROBP; -.
DR EPD; O43914; -.
DR jPOST; O43914; -.
DR MassIVE; O43914; -.
DR PaxDb; O43914; -.
DR PeptideAtlas; O43914; -.
DR PRIDE; O43914; -.
DR ProteomicsDB; 26198; -.
DR ProteomicsDB; 49229; -. [O43914-1]
DR ProteomicsDB; 49230; -. [O43914-2]
DR Antibodypedia; 4010; 298 antibodies from 38 providers.
DR DNASU; 7305; -.
DR Ensembl; ENST00000262629.9; ENSP00000262629.3; ENSG00000011600.12. [O43914-1]
DR Ensembl; ENST00000544690.6; ENSP00000445332.1; ENSG00000011600.12. [O43914-3]
DR Ensembl; ENST00000589517.1; ENSP00000468447.1; ENSG00000011600.12. [O43914-2]
DR GeneID; 7305; -.
DR KEGG; hsa:7305; -.
DR MANE-Select; ENST00000262629.9; ENSP00000262629.3; NM_003332.4; NP_003323.1.
DR UCSC; uc002ocm.4; human. [O43914-1]
DR CTD; 7305; -.
DR DisGeNET; 7305; -.
DR GeneCards; TYROBP; -.
DR GeneReviews; TYROBP; -.
DR HGNC; HGNC:12449; TYROBP.
DR HPA; ENSG00000011600; Tissue enhanced (bone marrow, lymphoid tissue).
DR MalaCards; TYROBP; -.
DR MIM; 221770; phenotype.
DR MIM; 604142; gene.
DR neXtProt; NX_O43914; -.
DR OpenTargets; ENSG00000011600; -.
DR Orphanet; 2770; Nasu-Hakola disease.
DR PharmGKB; PA37100; -.
DR VEuPathDB; HostDB:ENSG00000011600; -.
DR eggNOG; ENOG502SCVI; Eukaryota.
DR GeneTree; ENSGT00390000016786; -.
DR HOGENOM; CLU_141718_0_0_1; -.
DR InParanoid; O43914; -.
DR OMA; VFCFATH; -.
DR OrthoDB; 1508977at2759; -.
DR PhylomeDB; O43914; -.
DR TreeFam; TF336898; -.
DR PathwayCommons; O43914; -.
DR Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR Reactome; R-HSA-2172127; DAP12 interactions.
DR Reactome; R-HSA-2424491; DAP12 signaling.
DR Reactome; R-HSA-391160; Signal regulatory protein family interactions.
DR Reactome; R-HSA-416700; Other semaphorin interactions.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR SignaLink; O43914; -.
DR SIGNOR; O43914; -.
DR BioGRID-ORCS; 7305; 16 hits in 1075 CRISPR screens.
DR ChiTaRS; TYROBP; human.
DR EvolutionaryTrace; O43914; -.
DR GeneWiki; TYROBP; -.
DR GenomeRNAi; 7305; -.
DR Pharos; O43914; Tbio.
DR PRO; PR:O43914; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; O43914; protein.
DR Bgee; ENSG00000011600; Expressed in monocyte and 185 other tissues.
DR ExpressionAtlas; O43914; baseline and differential.
DR Genevisible; O43914; HS.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; TAS:ARUK-UCL.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0030667; C:secretory granule membrane; TAS:Reactome.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0005102; F:signaling receptor binding; IPI:UniProtKB.
DR GO; GO:0030036; P:actin cytoskeleton organization; ISS:UniProtKB.
DR GO; GO:0043277; P:apoptotic cell clearance; ISS:UniProtKB.
DR GO; GO:0097190; P:apoptotic signaling pathway; ISS:ARUK-UCL.
DR GO; GO:0006968; P:cellular defense response; TAS:ProtInc.
DR GO; GO:0030900; P:forebrain development; ISS:ARUK-UCL.
DR GO; GO:0035556; P:intracellular signal transduction; TAS:ProtInc.
DR GO; GO:0002282; P:microglial cell activation involved in immune response; ISS:UniProtKB.
DR GO; GO:0002274; P:myeloid leukocyte activation; IDA:UniProtKB.
DR GO; GO:0030889; P:negative regulation of B cell proliferation; IMP:UniProtKB.
DR GO; GO:0032693; P:negative regulation of interleukin-10 production; ISS:ARUK-UCL.
DR GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; ISS:ARUK-UCL.
DR GO; GO:0032911; P:negative regulation of transforming growth factor beta1 production; ISS:ARUK-UCL.
DR GO; GO:0002283; P:neutrophil activation involved in immune response; IBA:GO_Central.
DR GO; GO:0030316; P:osteoclast differentiation; IMP:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; ISS:ARUK-UCL.
DR GO; GO:0110090; P:positive regulation of hippocampal neuron apoptotic process; ISS:ARUK-UCL.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISS:ARUK-UCL.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:ARUK-UCL.
DR GO; GO:0034241; P:positive regulation of macrophage fusion; IMP:UniProtKB.
DR GO; GO:1904151; P:positive regulation of microglial cell mediated cytotoxicity; ISS:UniProtKB.
DR GO; GO:0032816; P:positive regulation of natural killer cell activation; IBA:GO_Central.
DR GO; GO:1901216; P:positive regulation of neuron death; ISS:ARUK-UCL.
DR GO; GO:2001206; P:positive regulation of osteoclast development; ISS:UniProtKB.
DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; IMP:UniProtKB.
DR GO; GO:1902685; P:positive regulation of receptor localization to synapse; ISS:ARUK-UCL.
DR GO; GO:0032930; P:positive regulation of superoxide anion generation; ISS:ARUK-UCL.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:ARUK-UCL.
DR GO; GO:0050821; P:protein stabilization; IDA:UniProtKB.
DR GO; GO:0048678; P:response to axon injury; ISS:ARUK-UCL.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0002223; P:stimulatory C-type lectin receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0002222; P:stimulatory killer cell immunoglobulin-like receptor signaling pathway; IDA:UniProtKB.
DR InterPro; IPR026200; Tyrobp.
DR PANTHER; PTHR17554; PTHR17554; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Calcium; Cell membrane; Disulfide bond;
KW Immunity; Membrane; Metal-binding; Phosphoprotein; Reference proteome;
KW Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..113
FT /note="TYRO protein tyrosine kinase-binding protein"
FT /id="PRO_0000022603"
FT TOPO_DOM 22..40
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:25981043"
FT TRANSMEM 41..61
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:25981043"
FT TOPO_DOM 62..113
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:25981043"
FT DOMAIN 80..108
FT /note="ITAM"
FT REGION 75..113
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 88..113
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 50
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_note="ligand shared between two neighboring
FT subunits in homooligomer"
FT /evidence="ECO:0000269|PubMed:25981043"
FT SITE 54
FT /note="Important for interaction with transmembrane
FT receptors"
FT /evidence="ECO:0000269|PubMed:20890284"
FT MOD_RES 91
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O54885"
FT MOD_RES 102
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O54885"
FT DISULFID 35
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:20890284,
FT ECO:0000269|PubMed:25981043, ECO:0007744|PDB:2L34,
FT ECO:0007744|PDB:2L35, ECO:0007744|PDB:4WOL"
FT VAR_SEQ 20..30
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:16344560"
FT /id="VSP_046066"
FT VAR_SEQ 77
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.2,
FT ECO:0000303|Ref.3"
FT /id="VSP_012909"
FT VARIANT 2
FT /note="G -> E (found in patients with early-onset Alzheimer
FT disease; unknown pathological significance; associated in
FT cis with L-55 in some patients; dbSNP:rs200649978)"
FT /evidence="ECO:0000269|PubMed:27658901"
FT /id="VAR_081398"
FT VARIANT 23
FT /note="R -> C (found in patients with early-onset Alzheimer
FT disease; unknown pathological significance;
FT dbSNP:rs769635655)"
FT /evidence="ECO:0000269|PubMed:27658901"
FT /id="VAR_081399"
FT VARIANT 47
FT /note="V -> A (found in patients with early-onset Alzheimer
FT disease; unknown pathological significance;
FT dbSNP:rs372140827)"
FT /evidence="ECO:0000269|PubMed:27658901"
FT /id="VAR_081400"
FT VARIANT 50
FT /note="D -> DPADGRLVLGDRDGR (found in patients with early-
FT onset Alzheimer disease; unknown pathological significance;
FT causes reduced expression; also leads to reduced expression
FT of TREM2)"
FT /evidence="ECO:0000269|PubMed:27658901"
FT /id="VAR_081401"
FT VARIANT 55
FT /note="V -> L (found in patients with early-onset Alzheimer
FT disease; unknown pathological significance; associated in
FT cis with E-2 in some patients; dbSNP:rs77782321)"
FT /evidence="ECO:0000269|PubMed:27658901,
FT ECO:0000269|PubMed:28716534"
FT /id="VAR_081402"
FT VARIANT 80
FT /note="R -> W (found in patients with early-onset Alzheimer
FT disease; unknown pathological significance;
FT dbSNP:rs140188939)"
FT /evidence="ECO:0000269|PubMed:27658901"
FT /id="VAR_081403"
FT VARIANT 84
FT /note="I -> V (found in patients with early-onset Alzheimer
FT disease; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:27658901"
FT /id="VAR_081404"
FT VARIANT 89
FT /note="S -> L (found in patients with early-onset Alzheimer
FT disease; unknown pathological significance;
FT dbSNP:rs557854792)"
FT /evidence="ECO:0000269|PubMed:27658901"
FT /id="VAR_081405"
FT VARIANT 111
FT /note="Y -> H (in dbSNP:rs14714)"
FT /id="VAR_011985"
FT MUTAGEN 41
FT /note="G->L: Does not significantly alter the formation of
FT homotrimers or homotetramers; when associated with L-45 and
FT L-49."
FT /evidence="ECO:0000269|PubMed:25981043"
FT MUTAGEN 45
FT /note="G->L: Does not significantly alter the formation of
FT homotrimers or homotetramers; when associated with L-41 and
FT L-49."
FT /evidence="ECO:0000269|PubMed:25981043"
FT MUTAGEN 49
FT /note="G->L: Does not significantly alter the formation of
FT homotrimers or homotetramers; when associated with L-41 and
FT L-45."
FT /evidence="ECO:0000269|PubMed:25981043"
FT MUTAGEN 50
FT /note="D->A: Reduced cell surface expression of KIR2DS1.
FT Severely impairs formation of homotrimers and
FT homotetramers. Abolishes interaction with TREM2 and
FT stabilization of TREM2-CTF. Impairs the expression of
FT KLRD1-KLRC2 on the cell surface."
FT /evidence="ECO:0000269|PubMed:23715743,
FT ECO:0000269|PubMed:25957402, ECO:0000269|PubMed:25981043,
FT ECO:0000269|PubMed:9655483"
FT MUTAGEN 50
FT /note="D->E,Q: Severely impairs formation of homotrimers
FT and homotetramers."
FT /evidence="ECO:0000269|PubMed:25981043"
FT MUTAGEN 50
FT /note="D->N: Reduces formation of homotrimers and
FT homotetramers."
FT /evidence="ECO:0000269|PubMed:25981043"
FT MUTAGEN 54
FT /note="T->A: Reduced interaction with KLRC2 and KIR2DS3.
FT Reduces homotrimer formation and increases homotetramer
FT formation."
FT /evidence="ECO:0000269|PubMed:20890284,
FT ECO:0000269|PubMed:25981043"
FT HELIX 40..65
FT /evidence="ECO:0007829|PDB:4WOL"
SQ SEQUENCE 113 AA; 12179 MW; 267CB1C1756F89F0 CRC64;
MGGLEPCSRL LLLPLLLAVS GLRPVQAQAQ SDCSCSTVSP GVLAGIVMGD LVLTVLIALA
VYFLGRLVPR GRGAAEAATR KQRITETESP YQELQGQRSD VYSDLNTQRP YYK
