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 27-NOV-2024, entry version 190. 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 INTERACTION WITH SIGLEC1. RX PubMed=26358190; DOI=10.1038/cr.2015.108; RA Zheng Q., Hou J., Zhou Y., Yang Y., Xie B., Cao X.; RT "Siglec1 suppresses antiviral innate immune response by inducing TBK1 RT degradation via the ubiquitin ligase TRIM27."; RL Cell Res. 25:1121-1136(2015). RN [32] 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 [33] {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 [34] 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 [35] 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:10604985, PubMed:9490415, PubMed:9655483). 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:23715743, CC PubMed:9490415, PubMed:9655483). 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:15940674, PubMed:9655483). Interacts with SIGLEC1 CC (PubMed:26358190). {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:17012248, ECO:0000269|PubMed:17928527, CC ECO:0000269|PubMed:18624290, ECO:0000269|PubMed:20890284, CC ECO:0000269|PubMed:23715743, ECO:0000269|PubMed:25957402, CC ECO:0000269|PubMed:25981043, ECO:0000269|PubMed:26221034, CC ECO:0000269|PubMed:26358190, 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 --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 84. 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 jPOST; O43914; -. DR MassIVE; O43914; -. DR PaxDb; 9606-ENSP00000262629; -. DR PeptideAtlas; O43914; -. DR ProteomicsDB; 26198; -. DR ProteomicsDB; 49229; -. [O43914-1] DR ProteomicsDB; 49230; -. [O43914-2] DR Antibodypedia; 4010; 286 antibodies from 37 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 AGR; HGNC:12449; -. 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; FPECNCS; -. DR OrthoDB; 4557845at2759; -. 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; 18 hits in 1151 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 186 other cell types or tissues. DR ExpressionAtlas; O43914; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; TAS:ARUK-UCL. 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:0060090; F:molecular adaptor activity; IDA:UniProt. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IDA:UniProt. DR GO; GO:0005102; F:signaling receptor binding; IPI:UniProtKB. DR GO; GO:0030036; P:actin cytoskeleton organization; ISS:UniProtKB. DR GO; GO:0097242; P:amyloid-beta clearance; IDA:UniProt. DR GO; GO:0043277; P:apoptotic cell clearance; ISS:UniProtKB. DR GO; GO:0006968; P:cellular defense response; TAS:ProtInc. DR GO; GO:1904646; P:cellular response to amyloid-beta; IDA:UniProt. 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:0032480; P:negative regulation of type I interferon production; IDA:UniProt. 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: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: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:0071526; P:semaphorin-plexin signaling pathway; ISS:UniProtKB. 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 GO; GO:0002291; P:T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell; ISS:UniProtKB. DR FunFam; 1.10.287.770:FF:000004; TYRO protein tyrosine kinase-binding protein; 1. DR Gene3D; 1.10.287.770; YojJ-like; 1. DR InterPro; IPR026200; Tyrobp. DR PANTHER; PTHR17554; TYRO PROTEIN TYROSINE KINASE-BINDING PROTEIN; 1. DR PANTHER; PTHR17554:SF2; TYRO PROTEIN TYROSINE KINASE-BINDING PROTEIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Calcium; Cell membrane; Disulfide bond; KW Immunity; Membrane; Metal-binding; Phosphoprotein; KW Proteomics identification; Reference proteome; Signal; Transmembrane; KW 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; uncertain significance; associated in cis with L- FT 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; uncertain significance; 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; uncertain significance; 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; uncertain significance; causes FT reduced expression; also leads to reduced expression of FT 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; uncertain significance; associated in cis with E-2 FT 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; uncertain significance; 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; uncertain 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; uncertain significance; 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 //