SH21A_HUMAN
ID SH21A_HUMAN Reviewed; 128 AA.
AC O60880; A8MSW0; O95383; O95384; O95385; O95386; Q6FGS6; Q9UNR0;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1998, sequence version 1.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=SH2 domain-containing protein 1A;
DE AltName: Full=Duncan disease SH2-protein;
DE AltName: Full=Signaling lymphocytic activation molecule-associated protein;
DE Short=SLAM-associated protein;
DE AltName: Full=T-cell signal transduction molecule SAP;
GN Name=SH2D1A; Synonyms=DSHP, SAP;
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], AND VARIANTS XLP1 THR-32; ILE-68 AND LEU-101.
RX PubMed=9771704; DOI=10.1038/2424;
RA Coffey A.J., Brooksbank R.A., Brandau O., Oohashi T., Howell G.R.,
RA Bye J.M., Cahn A.P., Durham J., Heath P., Wray P., Pavitt R., Wilkinson J.,
RA Leversha M., Huckle E., Shaw-Smith C.J., Dunham A., Rhodes S., Schuster V.,
RA Porta G., Yin L., Serafini P., Sylla B., Zollo M., Franco B., Bentley D.R.;
RT "Host response to EBV infection in X-linked lymphoproliferative disease
RT results from mutations in an SH2-domain encoding gene.";
RL Nat. Genet. 20:129-135(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9774102; DOI=10.1038/26683;
RA Sayos J., Wu C., Morra M., Wang N., Zhang X., Allen D., van Schaik S.,
RA Notarangelo L., Geha R., Roncarolo M.G., Oettgen H., de Vries J.E.,
RA Aversa G., Terhorst C.;
RT "The X-linked lymphoproliferative-disease gene product SAP regulates
RT signals induced through the co-receptor SLAM.";
RL Nature 395:462-469(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=11282995; DOI=10.1093/intimm/13.4.559;
RA Takei M., Ishiwata T., Mitamura K., Fujiwara S., Sasaki K., Nishi T.,
RA Kuga T., Ookubo T., Horie T., Ryu J., Ohi H., Sawada S.;
RT "Decreased expression of signaling lymphocytic-activation molecule-
RT associated protein (SAP) transcripts in T cells from patients with
RT rheumatoid arthritis.";
RL Int. Immunol. 13:559-565(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE SPLICING.
RA Amemiya C.T., Halevi A.;
RT "The Duncan's disease gene is preferentially expressed in lymphoid cell
RT lineages and undergoes high levels of alternative splicing.";
RL Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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].
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P.,
RA Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y.,
RA LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
RC TISSUE=Lung;
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 INTERACTION WITH CD84.
RX PubMed=11389028; DOI=10.1182/blood.v97.12.3867;
RA Sayos J., Martin M., Chen A., Simarro M., Howie D., Morra M., Engel P.,
RA Terhorst C.;
RT "Cell surface receptors Ly-9 and CD84 recruit the X-linked
RT lymphoproliferative disease gene product SAP.";
RL Blood 97:3867-3874(2001).
RN [11]
RP FUNCTION, AND INTERACTION WITH SLAMF1.
RX PubMed=11806999; DOI=10.1182/blood.v99.3.957;
RA Howie D., Simarro M., Sayos J., Guirado M., Sancho J., Terhorst C.;
RT "Molecular dissection of the signaling and costimulatory functions of CD150
RT (SLAM): CD150/SAP binding and CD150-mediated costimulation.";
RL Blood 99:957-965(2002).
RN [12]
RP INTERACTION WITH CD84.
RX PubMed=12115647;
RX DOI=10.1002/1521-4141(200206)32:6<1640::aid-immu1640>3.0.co;2-s;
RA Tangye S.G., van de Weerdt B.C.M., Avery D.T., Hodgkin P.D.;
RT "CD84 is up-regulated on a major population of human memory B cells and
RT recruits the SH2 domain containing proteins SAP and EAT-2.";
RL Eur. J. Immunol. 32:1640-1649(2002).
RN [13]
RP FUNCTION, INTERACTION WITH SLAMF1; CD244; CD84 AND FYN, AND
RP CHARACTERIZATION OF VARIANTS XLP1 CYS-7; PRO-99; LEU-101 AND GLY-102.
RX PubMed=12458214; DOI=10.1074/jbc.m206649200;
RA Li C., Iosef C., Jia C.Y., Han V.K., Li S.S.;
RT "Dual functional roles for the X-linked lymphoproliferative syndrome gene
RT product SAP/SH2D1A in signaling through the signaling lymphocyte activation
RT molecule (SLAM) family of immune receptors.";
RL J. Biol. Chem. 278:3852-3859(2003).
RN [14]
RP INTERACTION WITH FYN.
RX PubMed=12545173; DOI=10.1038/ncb919;
RA Latour S., Roncagalli R., Chen R., Bakinowski M., Shi X.,
RA Schwartzberg P.L., Davidson D., Veillette A.;
RT "Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of
RT receptor signalling in immune regulation.";
RL Nat. Cell Biol. 5:149-154(2003).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-89, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
RP REVIEW.
RX PubMed=21219180; DOI=10.1146/annurev-immunol-030409-101302;
RA Cannons J.L., Tangye S.G., Schwartzberg P.L.;
RT "SLAM family receptors and SAP adaptors in immunity.";
RL Annu. Rev. Immunol. 29:665-705(2011).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.1 ANGSTROMS) OF 1-104.
RX PubMed=10549287; DOI=10.1016/s1097-2765(00)80206-3;
RA Poy F., Yaffe M.B., Sayos J., Saxena K., Morra M., Sumegi J., Cantley L.C.,
RA Terhorst C., Eck M.J.;
RT "Crystal structures of the XLP protein SAP reveal a class of SH2 domains
RT with extended, phosphotyrosine-independent sequence recognition.";
RL Mol. Cell 4:555-561(1999).
RN [18]
RP STRUCTURE BY NMR IN COMPLEX WITH SLAMF1, CHARACTERIZATION OF VARIANTS XLP1
RP CYS-7; ARG-28; ILE-53; ILE-68; PRO-99; LEU-101 AND GLY-102, AND MUTAGENESIS
RP OF ARG-32.
RX PubMed=11823424; DOI=10.1093/emboj/21.3.314;
RA Hwang P.M., Li C., Morra M., Lillywhite J., Muhandiram D.R., Gertler F.,
RA Terhorst C., Kay L.E., Pawson T., Forman-Kay J.D., Li S.-C.;
RT "A 'three-pronged' binding mechanism for the SAP/SH2D1A SH2 domain:
RT structural basis and relevance to the XLP syndrome.";
RL EMBO J. 21:314-323(2002).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-104 IN COMPLEX WITH SLAMF1 AND
RP FYN, AND MUTAGENESIS OF ARG-78.
RX PubMed=12545174; DOI=10.1038/ncb920;
RA Chan B., Lanyi A., Song H.K., Griesbach J., Simarro-Grande M., Poy F.,
RA Howie D., Sumegi J., Terhorst C., Eck M.J.;
RT "SAP couples Fyn to SLAM immune receptors.";
RL Nat. Cell Biol. 5:155-160(2003).
RN [20]
RP VARIANT XLP1 THR-32.
RX PubMed=10598819; DOI=10.1007/s004390051137;
RA Yin L., Ferrand V., Lavoue M.-F., Hayoz D., Philippe N., Souillet G.,
RA Seri M., Giacchino R., Castagnola E., Hodgson S., Sylla B.S., Romeo G.;
RT "SH2D1A mutation analysis for diagnosis of XLP in typical and atypical
RT patients.";
RL Hum. Genet. 105:501-505(1999).
RN [21]
RP VARIANTS XLP1 CYS-7; ARG-28; PRO-31; TRP-42; ILE-53; CYS-54; SER-87; PRO-99
RP AND GLY-102.
RX PubMed=11049992;
RA Sumegi J., Huang D., Lanyi A., Davis J.D., Seemayer T.A., Maeda A.,
RA Klein G., Seri M., Wakiguchi H., Purtilo D.T., Gross T.G.;
RT "Correlation of mutations of the SH2D1A gene and Epstein-Barr virus
RT infection with clinical phenotype and outcome in X-linked
RT lymphoproliferative disease.";
RL Blood 96:3118-3125(2000).
RN [22]
RP VARIANT XLP1 LEU-55.
RX PubMed=11034354; DOI=10.4049/jimmunol.165.7.3549;
RA Benoit L., Wang X., Pabst H.F., Dutz J., Tan R.;
RT "Defective NK cell activation in X-linked lymphoproliferative disease.";
RL J. Immunol. 165:3549-3553(2000).
RN [23]
RP VARIANTS XLP1 ASP-8; SER-27; TYR-33 AND VAL-49.
RX PubMed=11493483; DOI=10.1182/blood.v98.4.1268;
RA Sumazaki R., Kanegane H., Osaki M., Fukushima T., Tsuchida M.,
RA Matsukura H., Shinozaki K., Kimura H., Matsui A., Miyawaki T.;
RT "SH2D1A mutations in Japanese males with severe Epstein-Barr virus-
RT associated illnesses.";
RL Blood 98:1268-1270(2001).
RN [24]
RP CHARACTERIZATION OF VARIANTS XLP1 CYS-7; ARG-28; TRP-42; ILE-53; ILE-68;
RP PRO-99; LEU-101 AND GLY-102, AND INTERACTION WITH CD244; SLAMF1; CD84 AND
RP LY9.
RX PubMed=11477068; DOI=10.1074/jbc.m101305200;
RA Morra M., Simarro-Grande M., Martin M., Chen A.S.-I., Lanyi A.,
RA Silander O., Calpe S., Davis J., Pawson T., Eck M.J., Sumegi J., Engel P.,
RA Li S.-C., Terhorst C.;
RT "Characterization of SH2D1A missense mutations identified in X-linked
RT lymphoproliferative disease patients.";
RL J. Biol. Chem. 276:36809-36816(2001).
RN [25]
RP CHARACTERIZATION OF VARIANTS XLP1 PRO-31; CYS-54; LEU-55 AND SER-87.
RX PubMed=14674764; DOI=10.1021/bi034798l;
RA Li C., Iosef C., Jia C.Y.H., Gkourasas T., Han V.K.M., Li S.-C.;
RT "Disease-causing SAP mutants are defective in ligand binding and protein
RT folding.";
RL Biochemistry 42:14885-14892(2003).
RN [26]
RP VARIANT PRO-57.
RX PubMed=14583885; DOI=10.1086/379126;
RA Halasa N.B., Whitlock J.A., McCurley T.L., Smith J.A., Zhu Q., Ochs H.,
RA Dermody T.S., Crowe J.E. Jr.;
RT "Fatal hemophagocytic lymphohistiocytosis associated with Epstein-Barr
RT virus infection in a patient with a novel mutation in the signaling
RT lymphocytic activation molecule-associated protein.";
RL Clin. Infect. Dis. 37:E136-E141(2003).
RN [27]
RP VARIANT XLP1 ASP-16, AND CHARACTERIZATION OF VARIANT XLP1 ASP-16.
RX PubMed=15841490; DOI=10.1002/humu.9339;
RA Erdos M., Uzvoelgyi E., Nemes Z., Toeroek O., Rakoczi E., Went-Suemegi N.,
RA Suemegi J., Marodi L.;
RT "Characterization of a new disease-causing mutation of SH2D1A in a family
RT with X-linked lymphoproliferative disease.";
RL Hum. Mutat. 25:506-506(2005).
RN [28]
RP VARIANTS XLP1 CYS-54; THR-84 AND SER-87, AND CHARACTERIZATION OF VARIANTS
RP XLP1 CYS-54; THR-84 AND SER-87.
RX PubMed=16720617; DOI=10.1093/intimm/dxl039;
RA Hare N.J., Ma C.S., Alvaro F., Nichols K.E., Tangye S.G.;
RT "Missense mutations in SH2D1A identified in patients with X-linked
RT lymphoproliferative disease differentially affect the expression and
RT function of SAP.";
RL Int. Immunol. 18:1055-1065(2006).
CC -!- FUNCTION: Cytoplasmic adapter regulating receptors of the signaling
CC lymphocytic activation molecule (SLAM) family such as SLAMF1, CD244,
CC LY9, CD84, SLAMF6 and SLAMF7. In SLAM signaling seems to cooperate with
CC SH2D1B/EAT-2. Initially it has been proposed that association with
CC SLAMF1 prevents SLAMF1 binding to inhibitory effectors including
CC INPP5D/SHIP1 and PTPN11/SHP-2 (PubMed:11806999). However, by
CC simultaneous interactions, recruits FYN which subsequently
CC phosphorylates and activates SLAMF1 (PubMed:12458214). Positively
CC regulates CD244/2B4- and CD84-mediated natural killer (NK) cell
CC functions. Can also promote CD48-, SLAMF6 -, LY9-, and SLAMF7-mediated
CC NK cell activation. In the context of NK cell-mediated cytotoxicity
CC enhances conjugate formation with target cells (By similarity). May
CC also regulate the activity of the neurotrophin receptors NTRK1, NTRK2
CC and NTRK3. {ECO:0000250|UniProtKB:O88890, ECO:0000269|PubMed:11806999,
CC ECO:0000269|PubMed:12458214, ECO:0000305|PubMed:21219180}.
CC -!- SUBUNIT: Interacts with NTRK1, NTRK2 and NTRK3 (By similarity).
CC Interacts with CD84, CD244, LY9, SLAMF1 and FYN. {ECO:0000250,
CC ECO:0000269|PubMed:11389028, ECO:0000269|PubMed:11477068,
CC ECO:0000269|PubMed:11806999, ECO:0000269|PubMed:11823424,
CC ECO:0000269|PubMed:12115647, ECO:0000269|PubMed:12458214,
CC ECO:0000269|PubMed:12545174}.
CC -!- INTERACTION:
CC O60880; Q9BZW8: CD244; NbExp=10; IntAct=EBI-6983382, EBI-1580565;
CC O60880; P20963: CD247; NbExp=5; IntAct=EBI-6983382, EBI-1165705;
CC O60880; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-6983382, EBI-742054;
CC O60880; P01100: FOS; NbExp=3; IntAct=EBI-6983382, EBI-852851;
CC O60880; Q9UBR4-2: LHX3; NbExp=3; IntAct=EBI-6983382, EBI-12039345;
CC O60880; Q969G2: LHX4; NbExp=7; IntAct=EBI-6983382, EBI-2865388;
CC O60880; P08581: MET; NbExp=3; IntAct=EBI-6983382, EBI-1039152;
CC O60880; Q13291: SLAMF1; NbExp=12; IntAct=EBI-6983382, EBI-4315002;
CC O60880; Q96DU3: SLAMF6; NbExp=12; IntAct=EBI-6983382, EBI-14058448;
CC O60880; P12931: SRC; NbExp=3; IntAct=EBI-6983382, EBI-621482;
CC O60880; Q07912: TNK2; NbExp=3; IntAct=EBI-6983382, EBI-603457;
CC O60880; Q07912-2: TNK2; NbExp=3; IntAct=EBI-6983382, EBI-11994780;
CC O60880-1; Q15052: ARHGEF6; NbExp=3; IntAct=EBI-15552052, EBI-1642523;
CC O60880-1; Q14155: ARHGEF7; NbExp=5; IntAct=EBI-15552052, EBI-717515;
CC O60880-1; Q9BZW8: CD244; NbExp=2; IntAct=EBI-15552052, EBI-1580565;
CC O60880-1; Q13291: SLAMF1; NbExp=2; IntAct=EBI-15552052, EBI-4315002;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=A;
CC IsoId=O60880-1; Sequence=Displayed;
CC Name=B;
CC IsoId=O60880-2; Sequence=VSP_004386;
CC Name=C;
CC IsoId=O60880-3; Sequence=VSP_004387;
CC Name=D;
CC IsoId=O60880-4; Sequence=VSP_004390;
CC Name=E;
CC IsoId=O60880-5; Sequence=VSP_004388;
CC Name=F;
CC IsoId=O60880-6; Sequence=VSP_004389;
CC -!- TISSUE SPECIFICITY: Expressed at a high level in thymus and lung, with
CC a lower level of expression in spleen and liver. Expressed in
CC peripheral blood leukocytes, including T-lymphocytes. Tends to be
CC expressed at lower levels in peripheral blood leukocytes in patients
CC with rheumatoid arthritis. {ECO:0000269|PubMed:11282995}.
CC -!- DISEASE: Lymphoproliferative syndrome, X-linked, 1 (XLP1) [MIM:308240]:
CC A rare immunodeficiency characterized by extreme susceptibility to
CC infection with Epstein-Barr virus (EBV). Symptoms include severe or
CC fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and
CC malignant lymphoma. {ECO:0000269|PubMed:10598819,
CC ECO:0000269|PubMed:11034354, ECO:0000269|PubMed:11049992,
CC ECO:0000269|PubMed:11477068, ECO:0000269|PubMed:11493483,
CC ECO:0000269|PubMed:11823424, ECO:0000269|PubMed:12458214,
CC ECO:0000269|PubMed:14674764, ECO:0000269|PubMed:15841490,
CC ECO:0000269|PubMed:16720617, ECO:0000269|PubMed:9771704}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- WEB RESOURCE: Name=SH2D1Abase; Note=SH2D1A mutation db;
CC URL="http://structure.bmc.lu.se/idbase/SH2D1Abase/";
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DR EMBL; AL023657; CAA19222.1; -; mRNA.
DR EMBL; AF073019; AAC62631.1; -; mRNA.
DR EMBL; AF072930; AAC62630.1; -; mRNA.
DR EMBL; AB586694; BAJ19023.1; -; mRNA.
DR EMBL; AF100539; AAC79712.1; -; mRNA.
DR EMBL; AF100540; AAC79713.1; -; mRNA.
DR EMBL; AF100541; AAC79714.1; -; mRNA.
DR EMBL; AF100542; AAC79715.1; -; mRNA.
DR EMBL; AF100543; AAC79716.1; -; mRNA.
DR EMBL; AK311911; BAG34852.1; -; mRNA.
DR EMBL; CR542031; CAG46828.1; -; mRNA.
DR EMBL; CR542043; CAG46840.1; -; mRNA.
DR EMBL; AL022718; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471107; EAX11848.1; -; Genomic_DNA.
DR EMBL; CH471107; EAX11849.1; -; Genomic_DNA.
DR EMBL; BC020732; AAH20732.1; -; mRNA.
DR CCDS; CCDS14608.1; -. [O60880-1]
DR CCDS; CCDS48162.1; -. [O60880-4]
DR RefSeq; NP_001108409.1; NM_001114937.2. [O60880-4]
DR RefSeq; NP_002342.1; NM_002351.4. [O60880-1]
DR PDB; 1D1Z; X-ray; 1.40 A; A/B/C/D=1-104.
DR PDB; 1D4T; X-ray; 1.10 A; A=1-104.
DR PDB; 1D4W; X-ray; 1.80 A; A/B=1-104.
DR PDB; 1KA6; NMR; -; A=1-128.
DR PDB; 1KA7; NMR; -; A=1-128.
DR PDB; 1M27; X-ray; 2.50 A; A=1-104.
DR PDBsum; 1D1Z; -.
DR PDBsum; 1D4T; -.
DR PDBsum; 1D4W; -.
DR PDBsum; 1KA6; -.
DR PDBsum; 1KA7; -.
DR PDBsum; 1M27; -.
DR AlphaFoldDB; O60880; -.
DR SMR; O60880; -.
DR BioGRID; 110246; 35.
DR DIP; DIP-40768N; -.
DR IntAct; O60880; 34.
DR MINT; O60880; -.
DR STRING; 9606.ENSP00000360181; -.
DR BindingDB; O60880; -.
DR ChEMBL; CHEMBL2321636; -.
DR iPTMnet; O60880; -.
DR PhosphoSitePlus; O60880; -.
DR BioMuta; SH2D1A; -.
DR jPOST; O60880; -.
DR MassIVE; O60880; -.
DR MaxQB; O60880; -.
DR PaxDb; O60880; -.
DR PeptideAtlas; O60880; -.
DR PRIDE; O60880; -.
DR ProteomicsDB; 49642; -. [O60880-1]
DR ProteomicsDB; 49643; -. [O60880-2]
DR ProteomicsDB; 49644; -. [O60880-3]
DR ProteomicsDB; 49645; -. [O60880-4]
DR ProteomicsDB; 49646; -. [O60880-5]
DR ProteomicsDB; 49647; -. [O60880-6]
DR Antibodypedia; 30053; 469 antibodies from 41 providers.
DR DNASU; 4068; -.
DR Ensembl; ENST00000360027.4; ENSP00000353126.4; ENSG00000183918.17. [O60880-4]
DR Ensembl; ENST00000371139.9; ENSP00000360181.5; ENSG00000183918.17. [O60880-1]
DR Ensembl; ENST00000477673.2; ENSP00000477094.1; ENSG00000183918.17. [O60880-5]
DR GeneID; 4068; -.
DR KEGG; hsa:4068; -.
DR MANE-Select; ENST00000371139.9; ENSP00000360181.5; NM_002351.5; NP_002342.1.
DR UCSC; uc004euf.6; human. [O60880-1]
DR CTD; 4068; -.
DR DisGeNET; 4068; -.
DR GeneCards; SH2D1A; -.
DR GeneReviews; SH2D1A; -.
DR HGNC; HGNC:10820; SH2D1A.
DR HPA; ENSG00000183918; Tissue enriched (lymphoid).
DR MalaCards; SH2D1A; -.
DR MIM; 300490; gene.
DR MIM; 308240; phenotype.
DR neXtProt; NX_O60880; -.
DR OpenTargets; ENSG00000183918; -.
DR Orphanet; 538931; X-linked lymphoproliferative disease due to SH2D1A deficiency.
DR PharmGKB; PA35728; -.
DR VEuPathDB; HostDB:ENSG00000183918; -.
DR eggNOG; KOG0565; Eukaryota.
DR GeneTree; ENSGT00940000155920; -.
DR HOGENOM; CLU_125532_1_0_1; -.
DR InParanoid; O60880; -.
DR OMA; CVLCNGY; -.
DR OrthoDB; 1417830at2759; -.
DR PhylomeDB; O60880; -.
DR TreeFam; TF343096; -.
DR PathwayCommons; O60880; -.
DR Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR SignaLink; O60880; -.
DR BioGRID-ORCS; 4068; 8 hits in 691 CRISPR screens.
DR ChiTaRS; SH2D1A; human.
DR EvolutionaryTrace; O60880; -.
DR GeneWiki; SH2D1A; -.
DR GenomeRNAi; 4068; -.
DR Pharos; O60880; Tbio.
DR PRO; PR:O60880; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; O60880; protein.
DR Bgee; ENSG00000183918; Expressed in thymus and 122 other tissues.
DR ExpressionAtlas; O60880; baseline and differential.
DR Genevisible; O60880; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0007267; P:cell-cell signaling; IEA:InterPro.
DR GO; GO:0006968; P:cellular defense response; IEA:InterPro.
DR GO; GO:0006959; P:humoral immune response; IEA:Ensembl.
DR GO; GO:0042267; P:natural killer cell mediated cytotoxicity; IEA:Ensembl.
DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0045954; P:positive regulation of natural killer cell mediated cytotoxicity; IBA:GO_Central.
DR GO; GO:0050776; P:regulation of immune response; IMP:UniProtKB.
DR GO; GO:0009966; P:regulation of signal transduction; IBA:GO_Central.
DR CDD; cd10400; SH2_SAP1a; 1.
DR DisProt; DP02714; -.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR017289; SH2_prot_1A.
DR InterPro; IPR035876; SH2D1A_SH2.
DR Pfam; PF00017; SH2; 1.
DR PIRSF; PIRSF037828; SH2_p1A; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00252; SH2; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Adaptive immunity; Alternative splicing;
KW Cytoplasm; Disease variant; Immunity; Innate immunity; Reference proteome;
KW SH2 domain.
FT CHAIN 1..128
FT /note="SH2 domain-containing protein 1A"
FT /id="PRO_0000097722"
FT DOMAIN 6..104
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT REGION 67..92
FT /note="Interaction with FYN SH3 domain"
FT /evidence="ECO:0000250|UniProtKB:O88890"
FT REGION 106..128
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 89
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT VAR_SEQ 40..128
FT /note="VYCLCVLYHGYIYTYRVSQTETGSWSAETAPGVHKRYFRKIKNLISAFQKPD
FT QGIVIPLQYPVEKKSSARSTQGTTGIREDPDVCLKAP -> ITVTFIHTECPRQKQVLG
FT VLSISEARSRHCNTSAVSS (in isoform E)"
FT /evidence="ECO:0000305"
FT /id="VSP_004388"
FT VAR_SEQ 47..128
FT /note="YHGYIYTYRVSQTETGSWSAETAPGVHKRYFRKIKNLISAFQKPDQGIVIPL
FT QYPVEKKSSARSTQGTTGIREDPDVCLKAP -> QHLGYIKDISGK (in isoform
FT C)"
FT /evidence="ECO:0000305"
FT /id="VSP_004387"
FT VAR_SEQ 47..128
FT /note="YHGYIYTYRVSQTETGSWSAETAPGVHKRYFRKIKNLISAFQKPDQGIVIPL
FT QYPVEKKSSARSTQGTTGIREDPDVCLKAP -> ISEARSRHCNTSAVSS (in
FT isoform F)"
FT /evidence="ECO:0000305"
FT /id="VSP_004389"
FT VAR_SEQ 68..128
FT /note="TAPGVHKRYFRKIKNLISAFQKPDQGIVIPLQYPVEKKSSARSTQGTTGIRE
FT DPDVCLKAP -> HFRSQIKA (in isoform B)"
FT /evidence="ECO:0000305"
FT /id="VSP_004386"
FT VAR_SEQ 114..116
FT /note="Missing (in isoform D)"
FT /evidence="ECO:0000305"
FT /id="VSP_004390"
FT VARIANT 7
FT /note="Y -> C (in XLP1; reduced protein stability and
FT reduced affinity for SLAMF1, decreases interaction with
FT FYN; dbSNP:rs1569527111)"
FT /evidence="ECO:0000269|PubMed:11049992,
FT ECO:0000269|PubMed:11477068, ECO:0000269|PubMed:11823424,
FT ECO:0000269|PubMed:12458214"
FT /id="VAR_048005"
FT VARIANT 8
FT /note="H -> D (in XLP1)"
FT /evidence="ECO:0000269|PubMed:11493483"
FT /id="VAR_048006"
FT VARIANT 16
FT /note="G -> D (in XLP1; abolishes interaction with SLAMF1)"
FT /evidence="ECO:0000269|PubMed:15841490"
FT /id="VAR_048007"
FT VARIANT 27
FT /note="G -> S (in XLP1)"
FT /evidence="ECO:0000269|PubMed:11493483"
FT /id="VAR_048008"
FT VARIANT 28
FT /note="S -> R (in XLP1; reduced protein stability)"
FT /evidence="ECO:0000269|PubMed:11049992,
FT ECO:0000269|PubMed:11477068, ECO:0000269|PubMed:11823424"
FT /id="VAR_048009"
FT VARIANT 31
FT /note="L -> P (in XLP1; reduced protein stability and
FT reduced affinity for SLAMF1 and FYN)"
FT /evidence="ECO:0000269|PubMed:11049992,
FT ECO:0000269|PubMed:14674764"
FT /id="VAR_048010"
FT VARIANT 32
FT /note="R -> T (in XLP1; dbSNP:rs111033624)"
FT /evidence="ECO:0000269|PubMed:10598819,
FT ECO:0000269|PubMed:9771704"
FT /id="VAR_005612"
FT VARIANT 33
FT /note="D -> Y (in XLP1)"
FT /evidence="ECO:0000269|PubMed:11493483"
FT /id="VAR_048011"
FT VARIANT 42
FT /note="C -> W (in XLP1; loss of interaction with CD84 and
FT reduced affinity for SLAMF1)"
FT /evidence="ECO:0000269|PubMed:11049992,
FT ECO:0000269|PubMed:11477068"
FT /id="VAR_048012"
FT VARIANT 49
FT /note="G -> V (in XLP1)"
FT /evidence="ECO:0000269|PubMed:11493483"
FT /id="VAR_048013"
FT VARIANT 53
FT /note="T -> I (in XLP1; loss of interaction with CD84; loss
FT of interaction with non-phosphorylated SLAMF1)"
FT /evidence="ECO:0000269|PubMed:11049992,
FT ECO:0000269|PubMed:11477068, ECO:0000269|PubMed:11823424"
FT /id="VAR_048014"
FT VARIANT 54
FT /note="Y -> C (in XLP1; reduced protein stability and
FT reduced affinity for SLAMF1 and FYN)"
FT /evidence="ECO:0000269|PubMed:11049992,
FT ECO:0000269|PubMed:14674764, ECO:0000269|PubMed:16720617"
FT /id="VAR_048015"
FT VARIANT 55
FT /note="R -> L (in XLP1; reduced affinity for SLAMF1 and
FT FYN; dbSNP:rs111033630)"
FT /evidence="ECO:0000269|PubMed:11034354,
FT ECO:0000269|PubMed:14674764"
FT /id="VAR_018307"
FT VARIANT 57
FT /note="S -> P (in one XLP1 patient; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:14583885"
FT /id="VAR_048016"
FT VARIANT 68
FT /note="T -> I (in XLP1; loss of interaction with CD84;
FT strongly reduced affinity for SLAMF1; dbSNP:rs111033627)"
FT /evidence="ECO:0000269|PubMed:11477068,
FT ECO:0000269|PubMed:11823424, ECO:0000269|PubMed:9771704"
FT /id="VAR_005613"
FT VARIANT 84
FT /note="I -> T (in XLP1; reduced protein stability)"
FT /evidence="ECO:0000269|PubMed:16720617"
FT /id="VAR_048017"
FT VARIANT 87
FT /note="F -> S (in XLP1; reduced protein stability and
FT reduced affinity for SLAMF1 and FYN)"
FT /evidence="ECO:0000269|PubMed:11049992,
FT ECO:0000269|PubMed:14674764, ECO:0000269|PubMed:16720617"
FT /id="VAR_048018"
FT VARIANT 99
FT /note="Q -> P (in XLP1; reduced protein stability and
FT strongly reduced affinity for SLAMF1, disrupts interaction
FT with FYN)"
FT /evidence="ECO:0000269|PubMed:11049992,
FT ECO:0000269|PubMed:11477068, ECO:0000269|PubMed:11823424,
FT ECO:0000269|PubMed:12458214"
FT /id="VAR_048019"
FT VARIANT 101
FT /note="P -> L (in XLP1; reduced protein stability and
FT reduced affinity for SLAMF1, decreases interaction with
FT FYN; dbSNP:rs111033626)"
FT /evidence="ECO:0000269|PubMed:11282995,
FT ECO:0000269|PubMed:11477068, ECO:0000269|PubMed:11823424,
FT ECO:0000269|PubMed:9771704"
FT /id="VAR_005614"
FT VARIANT 102
FT /note="V -> G (in XLP1; reduced protein stability and
FT strongly reduced affinity for SLAMF1, decreases interaction
FT with FYN)"
FT /evidence="ECO:0000269|PubMed:11049992,
FT ECO:0000269|PubMed:11477068, ECO:0000269|PubMed:11823424,
FT ECO:0000269|PubMed:12458214"
FT /id="VAR_048020"
FT MUTAGEN 32
FT /note="R->Q: Strongly reduced affinity for SLAMF1."
FT /evidence="ECO:0000269|PubMed:11823424"
FT MUTAGEN 78
FT /note="R->E: Disrupts interaction with FYN."
FT /evidence="ECO:0000269|PubMed:12545174"
FT STRAND 5..7
FT /evidence="ECO:0007829|PDB:1KA6"
FT HELIX 13..23
FT /evidence="ECO:0007829|PDB:1D4T"
FT STRAND 28..33
FT /evidence="ECO:0007829|PDB:1D4T"
FT STRAND 35..37
FT /evidence="ECO:0007829|PDB:1D4T"
FT STRAND 41..47
FT /evidence="ECO:0007829|PDB:1D4T"
FT STRAND 50..58
FT /evidence="ECO:0007829|PDB:1D4T"
FT STRAND 64..66
FT /evidence="ECO:0007829|PDB:1D4T"
FT STRAND 77..79
FT /evidence="ECO:0007829|PDB:1D4T"
FT HELIX 80..87
FT /evidence="ECO:0007829|PDB:1D4T"
FT STRAND 89..96
FT /evidence="ECO:0007829|PDB:1D4T"
SQ SEQUENCE 128 AA; 14187 MW; 90234E7A6614EE3D CRC64;
MDAVAVYHGK ISRETGEKLL LATGLDGSYL LRDSESVPGV YCLCVLYHGY IYTYRVSQTE
TGSWSAETAP GVHKRYFRKI KNLISAFQKP DQGIVIPLQY PVEKKSSARS TQGTTGIRED
PDVCLKAP
