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Tyrosine-protein kinase ZAP-70 (EC 2.7.10.2) (70 kDa zeta-chain associated protein) (Syk-related tyrosine kinase)

 ZAP70_HUMAN             Reviewed;         619 AA.
P43403; A6NFP4; Q6PIA4; Q8IXD6; Q9UBS6;
01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
01-NOV-1995, sequence version 1.
25-OCT-2017, entry version 207.
RecName: Full=Tyrosine-protein kinase ZAP-70;
EC=2.7.10.2;
AltName: Full=70 kDa zeta-chain associated protein;
AltName: Full=Syk-related tyrosine kinase;
Name=ZAP70; Synonyms=SRK;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH
CD247, TISSUE SPECIFICITY, AND PHOSPHORYLATION.
PubMed=1423621; DOI=10.1016/0092-8674(92)90598-7;
Chan A.C., Iwashima M., Turck C.W., Weiss A.;
"ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR
zeta chain.";
Cell 71:649-662(1992).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
TISSUE=Leukocyte;
PubMed=14985102; DOI=10.1016/j.bbrc.2004.01.127;
Kuroyama H., Ikeda T., Kasai M., Yamasaki S., Tatsumi M., Utsuyama M.,
Saito T., Hirokawa K.;
"Identification of a novel isoform of ZAP-70, truncated ZAP kinase.";
Biochem. Biophys. Res. Commun. 315:935-941(2004).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15815621; DOI=10.1038/nature03466;
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
Waterston R.H., Wilson R.K.;
"Generation and annotation of the DNA sequences of human chromosomes 2
and 4.";
Nature 434:724-731(2005).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
TISSUE=Blood, and Brain;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[5]
NUCLEOTIDE SEQUENCE [MRNA] OF 521-547, VARIANT IMD48 LEU-GLU-GLN-541
INS, FUNCTION, AND INVOLVEMENT IN IMD48.
TISSUE=Lymphoid tissue;
PubMed=8124727; DOI=10.1016/0092-8674(94)90368-9;
Arpaia E., Shahar M., Dadi H., Cohen A., Roifman C.M.;
"Defective T cell receptor signaling and CD8+ thymic selection in
humans lacking zap-70 kinase.";
Cell 76:947-958(1994).
[6]
CHARACTERIZATION OF TAM-BINDING.
PubMed=7528772; DOI=10.1084/jem.181.1.375;
Isakov N., Wange R.L., Burgess W.H., Watts J.D., Aebersold R.,
Samelson L.E.;
"ZAP-70 binding specificity to T cell receptor tyrosine-based
activation motifs: the tandem SH2 domains of ZAP-70 bind distinct
tyrosine-based activation motifs with varying affinity.";
J. Exp. Med. 181:375-380(1995).
[7]
PHOSPHORYLATION AT TYR-492 AND TYR-493, AND MUTAGENESIS OF TYR-492 AND
TYR-493.
PubMed=7781602;
Chan A.C., Dalton M., Johnson R., Kong G.H., Wang T., Thoma R.,
Kurosaki T.;
"Activation of ZAP-70 kinase activity by phosphorylation of tyrosine
493 is required for lymphocyte antigen receptor function.";
EMBO J. 14:2499-2508(1995).
[8]
FUNCTION IN PHOSPHORYLATION OF LCP2.
PubMed=8702662; DOI=10.1074/jbc.271.33.19641;
Bubeck Wardenburg J., Fu C., Jackman J.K., Flotow H., Wilkinson S.E.,
Williams D.H., Johnson R., Kong G., Chan A.C., Findell P.R.;
"Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is
required for T-cell receptor function.";
J. Biol. Chem. 271:19641-19644(1996).
[9]
PHOSPHORYLATION AT TYR-292, AND MUTAGENESIS OF TYR-292.
PubMed=8943331; DOI=10.1128/MCB.16.12.6765;
Zhao Q., Weiss A.;
"Enhancement of lymphocyte responsiveness by a gain-of-function
mutation of ZAP-70.";
Mol. Cell. Biol. 16:6765-6774(1996).
[10]
INTERACTION WITH VAV1, AND MUTAGENESIS OF TYR-315.
PubMed=9151714; DOI=10.1084/jem.185.10.1877;
Wu J., Zhao Q., Kurosaki T., Weiss A.;
"The Vav binding site (Y315) in ZAP-70 is critical for antigen
receptor-mediated signal transduction.";
J. Exp. Med. 185:1877-1882(1997).
[11]
TISSUE SPECIFICITY.
PubMed=9378960;
Gary-Gouy H., Lang V., Sarun S., Boumsell L., Bismuth G.;
"In vivo association of CD5 with tyrosine-phosphorylated ZAP-70 and
p21 phospho-zeta molecules in human CD3+ thymocytes.";
J. Immunol. 159:3739-3747(1997).
[12]
FUNCTION IN PHOSPHORYLATION OF LAT.
PubMed=9489702; DOI=10.1016/S0092-8674(00)80901-0;
Zhang W., Sloan-Lancaster J., Kitchen J., Trible R.P., Samelson L.E.;
"LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor
to cellular activation.";
Cell 92:83-92(1998).
[13]
SUBCELLULAR LOCATION.
PubMed=9813084; DOI=10.1083/jcb.143.3.613;
Sloan-Lancaster J., Presley J., Ellenberg J., Yamazaki T.,
Lippincott-Schwartz J., Samelson L.E.;
"ZAP-70 association with T cell receptor zeta (TCRzeta): fluorescence
imaging of dynamic changes upon cellular stimulation.";
J. Cell Biol. 143:613-624(1998).
[14]
PHOSPHORYLATION AT TYR-315 AND TYR-319, AND MUTAGENESIS OF TYR-315 AND
TYR-319.
PubMed=10037717; DOI=10.1074/jbc.274.10.6285;
Di Bartolo V., Mege D., Germain V., Pelosi M., Dufour E., Michel F.,
Magistrelli G., Isacchi A., Acuto O.;
"Tyrosine 319, a newly identified phosphorylation site of ZAP-70,
plays a critical role in T cell antigen receptor signaling.";
J. Biol. Chem. 274:6285-6294(1999).
[15]
INTERACTION WITH CBL AND SLA.
PubMed=10449770; DOI=10.1073/pnas.96.17.9775;
Tang J., Sawasdikosol S., Chang J.-H., Burakoff S.J.;
"SLAP, a dimeric adapter protein, plays a functional role in T cell
receptor signaling.";
Proc. Natl. Acad. Sci. U.S.A. 96:9775-9780(1999).
[16]
FUNCTION IN CD3Z UBIQUITINATION.
PubMed=11353765; DOI=10.1074/jbc.M010738200;
Wang H.Y., Altman Y., Fang D., Elly C., Dai Y., Shao Y., Liu Y.C.;
"Cbl promotes ubiquitination of the T cell receptor zeta through an
adaptor function of Zap-70.";
J. Biol. Chem. 276:26004-26011(2001).
[17]
INTERACTION WITH FCRL3.
PubMed=12051764; DOI=10.1016/S0006-291X(02)00332-7;
Xu M.-J., Zhao R., Cao H., Zhao Z.J.;
"SPAP2, an Ig family receptor containing both ITIMs and ITAMs.";
Biochem. Biophys. Res. Commun. 293:1037-1046(2002).
[18]
MUTAGENESIS OF TYR-315.
PubMed=11828374;
DOI=10.1002/1521-4141(200202)32:2<568::AID-IMMU568>3.0.CO;2-Q;
Di Bartolo V., Malissen M., Dufour E., Sechet E., Malissen B.,
Acuto O.;
"Tyrosine 315 determines optimal recruitment of ZAP-70 to the T cell
antigen receptor.";
Eur. J. Immunol. 32:568-575(2002).
[19]
INTERACTION WITH SHB.
PubMed=12084069; DOI=10.1046/j.1432-1033.2002.03008.x;
Lindholm C.K., Henriksson M.L., Hallberg B., Welsh M.;
"Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells.";
Eur. J. Biochem. 269:3279-3288(2002).
[20]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=12522270; DOI=10.1073/pnas.2436191100;
Salomon A.R., Ficarro S.B., Brill L.M., Brinker A., Phung Q.T.,
Ericson C., Sauer K., Brock A., Horn D.M., Schultz P.G., Peters E.C.;
"Profiling of tyrosine phosphorylation pathways in human cells using
mass spectrometry.";
Proc. Natl. Acad. Sci. U.S.A. 100:443-448(2003).
[21]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-289, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Leukemic T-cell;
PubMed=15144186; DOI=10.1021/ac035352d;
Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M.,
Peters E.C.;
"Robust phosphoproteomic profiling of tyrosine phosphorylation sites
from human T cells using immobilized metal affinity chromatography and
tandem mass spectrometry.";
Anal. Chem. 76:2763-2772(2004).
[22]
INTERACTION WITH NFAM1.
PubMed=15143214; DOI=10.1073/pnas.0401119101;
Ohtsuka M., Arase H., Takeuchi A., Yamasaki S., Shiina R., Suenaga T.,
Sakurai D., Yokosuka T., Arase N., Iwashima M., Kitamura T.,
Moriya H., Saito T.;
"NFAM1, an immunoreceptor tyrosine-based activation motif-bearing
molecule that regulates B cell development and signaling.";
Proc. Natl. Acad. Sci. U.S.A. 101:8126-8131(2004).
[23]
PHOSPHORYLATION BY LCK.
PubMed=16339550; DOI=10.4049/jimmunol.175.12.8123;
Gelkop S., Gish G.D., Babichev Y., Pawson T., Isakov N.;
"T cell activation-induced CrkII binding to the Zap70 protein tyrosine
kinase is mediated by Lck-dependent phosphorylation of Zap70 tyrosine
315.";
J. Immunol. 175:8123-8132(2005).
[24]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-248, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=15592455; DOI=10.1038/nbt1046;
Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
Zha X.-M., Polakiewicz R.D., Comb M.J.;
"Immunoaffinity profiling of tyrosine phosphorylation in cancer
cells.";
Nat. Biotechnol. 23:94-101(2005).
[25]
TISSUE SPECIFICITY.
PubMed=16467082; DOI=10.1158/1078-0432.CCR-05-1531;
Crespo M., Villamor N., Gine E., Muntanola A., Colomer D.,
Marafioti T., Jones M., Camos M., Campo E., Montserrat E., Bosch F.;
"ZAP-70 expression in normal pro/pre B cells, mature B cells, and in
B-cell acute lymphoblastic leukemia.";
Clin. Cancer Res. 12:726-734(2006).
[26]
DEPHOSPHORYLATION BY PTN22.
PubMed=16461343; DOI=10.1074/jbc.M600498200;
Wu J., Katrekar A., Honigberg L.A., Smith A.M., Conn M.T., Tang J.,
Jeffery D., Mortara K., Sampang J., Williams S.R., Buggy J.,
Clark J.M.;
"Identification of substrates of human protein-tyrosine phosphatase
PTPN22.";
J. Biol. Chem. 281:11002-11010(2006).
[27]
REVIEW ON FUNCTION.
PubMed=19290920; DOI=10.1111/j.1600-065X.2008.00753.x;
Au-Yeung B.B., Deindl S., Hsu L.Y., Palacios E.H., Levin S.E.,
Kuriyan J., Weiss A.;
"The structure, regulation, and function of ZAP-70.";
Immunol. Rev. 228:41-57(2009).
[28]
INTERACTION WITH FCRL3.
PubMed=19843936; DOI=10.4049/jimmunol.0901982;
Kochi Y., Myouzen K., Yamada R., Suzuki A., Kurosaki T., Nakamura Y.,
Yamamoto K.;
"FCRL3, an autoimmune susceptibility gene, has inhibitory potential on
B-cell receptor-mediated signaling.";
J. Immunol. 183:5502-5510(2009).
[29]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-292, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Leukemic T-cell;
PubMed=19690332; DOI=10.1126/scisignal.2000007;
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
Rodionov V., Han D.K.;
"Quantitative phosphoproteomic analysis of T cell receptor signaling
reveals system-wide modulation of protein-protein interactions.";
Sci. Signal. 2:RA46-RA46(2009).
[30]
ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-603, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=19608861; DOI=10.1126/science.1175371;
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
Walther T.C., Olsen J.V., Mann M.;
"Lysine acetylation targets protein complexes and co-regulates major
cellular functions.";
Science 325:834-840(2009).
[31]
FUNCTION, AND DOMAIN.
PubMed=20135127; DOI=10.1007/s00281-010-0196-x;
Fischer A., Picard C., Chemin K., Dogniaux S., le Deist F., Hivroz C.;
"ZAP70: a master regulator of adaptive immunity.";
Semin. Immunopathol. 32:107-116(2010).
[32]
FUNCTION, INTERACTION WITH OTUD7B AND UBASH3B, UBIQUITINATION AT
LYS-544, IDENTIFICATION BY MASS SPECTROMETRY, AND MUTAGENESIS OF
LYS-304; LYS-538 AND LYS-544.
PubMed=26903241; DOI=10.1084/jem.20151426;
Hu H., Wang H., Xiao Y., Jin J., Chang J.H., Zou Q., Xie X., Cheng X.,
Sun S.C.;
"Otud7b facilitates T cell activation and inflammatory responses by
regulating Zap70 ubiquitination.";
J. Exp. Med. 213:399-414(2016).
[33]
X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 3-256 IN COMPLEX WITH CD247,
AND INTERACTION WITH CD247.
PubMed=7659156; DOI=10.1038/377032a0;
Hatada M.H., Lu X., Laird E.R., Green J., Morgenstern J.P., Lou M.,
Marr C.S., Phillips T.B., Ram M.K., Theriault K., Zoller M.J.,
Karas L.K.;
"Molecular basis for interaction of the protein tyrosine kinase ZAP-70
with the T-cell receptor.";
Nature 377:32-38(1995).
[34]
X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 286-297 IN COMPLEX WITH CBL,
AND INTERACTION WITH CBL.
PubMed=10078535; DOI=10.1038/18050;
Meng W., Sawasdikosol S., Burakoff S.J., Eck M.J.;
"Structure of the amino-terminal domain of Cbl complexed to its
binding site on ZAP-70 kinase.";
Nature 398:84-90(1999).
[35]
X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 289-297 IN COMPLEX WITH CBL
AND UBE2L3.
PubMed=10966114; DOI=10.1016/S0092-8674(00)00057-X;
Zheng N., Wang P., Jeffrey P.D., Pavletich N.P.;
"Structure of a c-Cbl-UbcH7 complex: RING domain function in
ubiquitin-protein ligases.";
Cell 102:533-539(2000).
[36]
X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-256.
PubMed=12450381; DOI=10.1021/bi026465e;
Folmer R.H., Geschwindner S., Xue Y.;
"Crystal structure and NMR studies of the apo SH2 domains of ZAP-70:
two bikes rather than a tandem.";
Biochemistry 41:14176-14184(2002).
[37]
X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 327-606 IN COMPLEX WITH
STAUROSPORINE, CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF
ASP-479, AND ENZYME REGULATION.
PubMed=15292186; DOI=10.1074/jbc.M407096200;
Jin L., Pluskey S., Petrella E.C., Cantin S.M., Gorga J.C.,
Rynkiewicz M.J., Pandey P., Strickler J.E., Babine R.E., Weaver D.T.,
Seidl K.J.;
"The three-dimensional structure of the ZAP-70 kinase domain in
complex with staurosporine: implications for the design of selective
inhibitors.";
J. Biol. Chem. 279:42818-42825(2004).
[38]
X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 1-606 OF MUTANT ASN-461 IN
COMPLEX WITH MAGNESIUM AND ATP ANALOG, ACTIVE SITE, AND MUTAGENESIS OF
TRP-131; LEU-133; ALA-141; SER-144; GLN-145; PRO-147; TYR-315;
TYR-319; ASP-461; TYR-597 AND TYR-598.
PubMed=17512407; DOI=10.1016/j.cell.2007.03.039;
Deindl S., Kadlecek T.A., Brdicka T., Cao X., Weiss A., Kuriyan J.;
"Structural basis for the inhibition of tyrosine kinase activity of
ZAP-70.";
Cell 129:735-746(2007).
[39]
VARIANT IMD48 ARG-518.
PubMed=8202713; DOI=10.1126/science.8202713;
Chan A.C., Kadlecek T.A., Elder M.E., Filipovich A.H., Kuo W.-L.,
Iwashima M., Parslow T.G., Weiss A.;
"ZAP-70 deficiency in an autosomal recessive form of severe combined
immunodeficiency.";
Science 264:1599-1601(1994).
[40]
VARIANT IMD48 HIS-465.
PubMed=11412303; DOI=10.1046/j.1365-2567.2001.01246.x;
Toyabe S., Watanabe A., Harada W., Karasawa T., Uchiyama M.;
"Specific immunoglobulin E responses in ZAP-70-deficient patients are
mediated by Syk-dependent T-cell receptor signalling.";
Immunology 103:164-171(2001).
[41]
VARIANT IMD48 CYS-465.
PubMed=11123350; DOI=10.4049/jimmunol.166.1.656;
Elder M.E., Skoda-Smith S., Kadlecek T.A., Wang F., Wu J., Weiss A.;
"Distinct T cell developmental consequences in humans and mice
expressing identical mutations in the DLAARN motif of ZAP-70.";
J. Immunol. 166:656-661(2001).
[42]
VARIANTS [LARGE SCALE ANALYSIS] LEU-175; LEU-191; GLU-448 AND LEU-523.
PubMed=17344846; DOI=10.1038/nature05610;
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
"Patterns of somatic mutation in human cancer genomes.";
Nature 446:153-158(2007).
[43]
VARIANTS IMD48 ARG-337; VAL-507 AND ARG-564.
PubMed=18509675; DOI=10.1007/s00431-008-0718-x;
Turul T., Tezcan I., Artac H., de Bruin-Versteeg S., Barendregt B.H.,
Reisli I., Sanal O., van Dongen J.J., van der Burg M.;
"Clinical heterogeneity can hamper the diagnosis of patients with
ZAP70 deficiency.";
Eur. J. Pediatr. 168:87-93(2009).
[44]
VARIANTS ADMIO2 TRP-192 AND PRO-360, CHARACTERIZATION OF VARIANTS
ADMIO2 TRP-192 AND PRO-360, INVOLVEMENT IN ADMIO2, INTERACTION WITH
CD247, AND MUTAGENESIS OF ARG-37; ARG-190; 315-TYR--TYR-319; ASP-327
AND LYS-362.
PubMed=26783323; DOI=10.1084/jem.20150888;
Chan A.Y., Punwani D., Kadlecek T.A., Cowan M.J., Olson J.L.,
Mathes E.F., Sunderam U., Fu S.M., Srinivasan R., Kuriyan J.,
Brenner S.E., Weiss A., Puck J.M.;
"A novel human autoimmune syndrome caused by combined hypomorphic and
activating mutations in ZAP-70.";
J. Exp. Med. 213:155-165(2016).
-!- FUNCTION: Tyrosine kinase that plays an essential role in
regulation of the adaptive immune response. Regulates motility,
adhesion and cytokine expression of mature T-cells, as well as
thymocyte development. Contributes also to the development and
activation of primary B-lymphocytes. When antigen presenting cells
(APC) activate T-cell receptor (TCR), a serie of phosphorylations
lead to the recruitment of ZAP70 to the doubly phosphorylated TCR
component CD247/CD3Z through ITAM motif at the plasma membrane.
This recruitment serves to localization to the stimulated TCR and
to relieve its autoinhibited conformation. Release of ZAP70 active
conformation is further stabilized by phosphorylation mediated by
LCK. Subsequently, ZAP70 phosphorylates at least 2 essential
adapter proteins: LAT and LCP2. In turn, a large number of
signaling molecules are recruited and ultimately lead to
lymphokine production, T-cell proliferation and differentiation.
Furthermore, ZAP70 controls cytoskeleton modifications, adhesion
and mobility of T-lymphocytes, thus ensuring correct delivery of
effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z
internalization and degradation through interaction with the E3
ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2.
Thus, ZAP70 regulates both T-cell activation switch on and switch
off by modulating TCR expression at the T-cell surface. During
thymocyte development, ZAP70 promotes survival and cell-cycle
progression of developing thymocytes before positive selection
(when cells are still CD4/CD8 double negative). Additionally,
ZAP70-dependent signaling pathway may also contribute to primary
B-cells formation and activation through B-cell receptor (BCR).
{ECO:0000269|PubMed:11353765, ECO:0000269|PubMed:12051764,
ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:20135127,
ECO:0000269|PubMed:26903241, ECO:0000269|PubMed:8124727,
ECO:0000269|PubMed:8702662, ECO:0000269|PubMed:9489702}.
-!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
[protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE-
ProRule:PRU10028, ECO:0000269|PubMed:15292186}.
-!- ENZYME REGULATION: Activated by phosphorylation at Tyr-493 in the
activation loop. Inhibited by staurosporine.
{ECO:0000269|PubMed:15292186}.
-!- SUBUNIT: Interacts with CD247/CD3Z; this interaction docks ZAP70
at the stimulated TCR (PubMed:1423621, PubMed:7659156,
PubMed:26783323). Interacts with NFAM1 (PubMed:15143214).
Interacts with adapter protein SLA; this interaction negatively
regulates T-cell receptor signaling (PubMed:10449770). Interacts
with FCRL3 (PubMed:12051764, PubMed:19843936). Interacts with VAV1
(PubMed:9151714). Interacts with CBL; this interaction promotes
ubiquitination, internalization and subsequent degradation of
CD247/CD3Z (PubMed:10449770, PubMed:10078535). Identified in a
complex with CBL and UBE2L3 (PubMed:10966114). Interacts with SHB
(PubMed:12084069). Interacts with adapter protein SLA2; this
interaction negatively regulates T-cell receptor signaling.
Interacts with CBLB. Interacts (via SH2 domains) with RHOH; this
interaction regulates ZAP70 subcellular localization. Interacts
with DEF6 (By similarity). Interacts (ubiquitinated form) with
OTUD7B and UBASH3B (PubMed:26903241).
{ECO:0000250|UniProtKB:P43404, ECO:0000269|PubMed:10078535,
ECO:0000269|PubMed:10449770, ECO:0000269|PubMed:10966114,
ECO:0000269|PubMed:12051764, ECO:0000269|PubMed:12084069,
ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:15143214,
ECO:0000269|PubMed:19843936, ECO:0000269|PubMed:26783323,
ECO:0000269|PubMed:26903241, ECO:0000269|PubMed:7659156,
ECO:0000269|PubMed:9151714}.
-!- INTERACTION:
P22681:CBL; NbExp=3; IntAct=EBI-1211276, EBI-518228;
P20963:CD247; NbExp=22; IntAct=EBI-1211276, EBI-1165705;
P07766:CD3E; NbExp=3; IntAct=EBI-1211276, EBI-1211297;
P00533:EGFR; NbExp=2; IntAct=EBI-1211276, EBI-297353;
P10721:KIT; NbExp=2; IntAct=EBI-1211276, EBI-1379503;
P06239:LCK; NbExp=2; IntAct=EBI-1211276, EBI-1348;
P08581:MET; NbExp=2; IntAct=EBI-1211276, EBI-1039152;
Q9Y2R2:PTPN22; NbExp=4; IntAct=EBI-1211276, EBI-1211241;
Q8N1K5-1:THEMIS; NbExp=3; IntAct=EBI-1211276, EBI-15102259;
Q8BGG7:Ubash3b (xeno); NbExp=10; IntAct=EBI-1211276, EBI-8846415;
-!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:9813084}. Cell
membrane {ECO:0000269|PubMed:9813084}; Peripheral membrane protein
{ECO:0000269|PubMed:9813084}. Note=In quiescent T-lymphocytes, it
is cytoplasmic. Upon TCR activation, it is recruited at the plasma
membrane by interacting with CD247/CD3Z. Colocalizes together with
RHOH in the immunological synapse. RHOH is required for its proper
localization to the cell membrane and cytoskeleton fractions in
the thymocytes (By similarity). {ECO:0000250}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=3;
Name=1;
IsoId=P43403-1; Sequence=Displayed;
Name=2; Synonyms=TZK;
IsoId=P43403-2; Sequence=VSP_031156;
Name=3;
IsoId=P43403-3; Sequence=VSP_031157, VSP_031158;
Note=No experimental confirmation available.;
-!- TISSUE SPECIFICITY: Expressed in T- and natural killer cells. Also
present in early thymocytes and pro/pre B-cells.
{ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:16467082,
ECO:0000269|PubMed:9378960}.
-!- DOMAIN: Composed of 2 N-terminal SH2 domains and a C-terminal
kinase domain. The tandem SH2 domains bind to the doubly
phosphorylated tyrosine-based activation motif (ITAM) of
CD247/CD3Z and the non-canonical phosphorylated tyrosine-based
activation motif (TAM) of RHOH (By similarity). The interdomain B
located between the second SH2 and the kinase domain contains 3
tyrosines (Tyr-292, Tyr-315, Tyr-319) that are phosphorylated
following TCR activation. These sites have been implicated in
binding to other signaling molecules including CBL or VAV1. Thus,
ZAP70 can also function as a scaffold by recruiting additional
factors to the stimulated TCR complex. {ECO:0000250,
ECO:0000269|PubMed:20135127}.
-!- PTM: Phosphorylated on tyrosine residues upon T-cell antigen
receptor (TCR) stimulation. Phosphorylation of Tyr-315 and Tyr-319
are essential for ZAP70 positive function on T-lymphocyte
activation whereas Tyr-292 has a negative regulatory role. Within
the C-terminal kinase domain, Tyr-492 and Tyr-493 are
phosphorylated after TCR induction, Tyr-492 playing a negative
regulatory role and Tyr-493 a positive. Tyr-493 is
dephosphorylated by PTN22. {ECO:0000269|PubMed:10037717,
ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:16339550,
ECO:0000269|PubMed:8943331}.
-!- PTM: Ubiquitinated in response to T cell activation.
Deubiquitinated by OTUD7B. {ECO:0000269|PubMed:26903241}.
-!- DISEASE: Immunodeficiency 48 (IMD48) [MIM:269840]: A form of
severe immunodeficiency characterized by a selective absence of
CD8+ T-cells. {ECO:0000269|PubMed:11123350,
ECO:0000269|PubMed:11412303, ECO:0000269|PubMed:18509675,
ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8202713}. Note=The
disease is caused by mutations affecting the gene represented in
this entry.
-!- DISEASE: Autoimmune disease, multisystem, infantile-onset, 2
(ADMIO2) [MIM:617006]: An autosomal recessive, autoimmune disorder
characterized by systemic manifestations including blistering skin
disease, uncontrollable bullous pemphigoid, inflammatory colitis,
autoimmune hypothyroidism, proteinuria and nephrotic syndrome.
{ECO:0000269|PubMed:26783323}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
kinase family. SYK/ZAP-70 subfamily. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
-!- WEB RESOURCE: Name=ZAP70base; Note=ZAP70 mutation db;
URL="http://structure.bmc.lu.se/idbase/ZAP70base/";
-----------------------------------------------------------------------
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EMBL; L05148; -; NOT_ANNOTATED_CDS; mRNA.
EMBL; AB083211; BAC43747.1; -; mRNA.
EMBL; AC016699; AAX93187.1; -; Genomic_DNA.
EMBL; BC039039; AAH39039.1; -; mRNA.
EMBL; BC053878; AAH53878.1; -; mRNA.
CCDS; CCDS33254.1; -. [P43403-1]
CCDS; CCDS33255.1; -. [P43403-2]
PIR; A44266; A44266.
PIR; A49955; A49955.
RefSeq; NP_001070.2; NM_001079.3. [P43403-1]
RefSeq; NP_997402.1; NM_207519.1. [P43403-2]
UniGene; Hs.234569; -.
PDB; 1FBV; X-ray; 2.90 A; B=289-297.
PDB; 1M61; X-ray; 2.50 A; A=1-256.
PDB; 1U59; X-ray; 2.30 A; A=327-606.
PDB; 2CBL; X-ray; 2.10 A; B=286-297.
PDB; 2OQ1; X-ray; 1.90 A; A=3-256.
PDB; 2OZO; X-ray; 2.60 A; A=1-606.
PDB; 2Y1N; X-ray; 2.00 A; B/D=286-297.
PDB; 3ZNI; X-ray; 2.21 A; B/F/J/N=286-297.
PDB; 4A4B; X-ray; 2.79 A; B=286-297.
PDB; 4A4C; X-ray; 2.70 A; B=286-297.
PDB; 4K2R; X-ray; 3.00 A; A=1-606.
PDB; 4XZ0; X-ray; 2.00 A; A=1-259.
PDB; 4XZ1; X-ray; 2.80 A; A=1-259.
PDBsum; 1FBV; -.
PDBsum; 1M61; -.
PDBsum; 1U59; -.
PDBsum; 2CBL; -.
PDBsum; 2OQ1; -.
PDBsum; 2OZO; -.
PDBsum; 2Y1N; -.
PDBsum; 3ZNI; -.
PDBsum; 4A4B; -.
PDBsum; 4A4C; -.
PDBsum; 4K2R; -.
PDBsum; 4XZ0; -.
PDBsum; 4XZ1; -.
ProteinModelPortal; P43403; -.
SMR; P43403; -.
BioGrid; 113367; 52.
CORUM; P43403; -.
DIP; DIP-38781N; -.
ELM; P43403; -.
IntAct; P43403; 22.
MINT; MINT-110540; -.
STRING; 9606.ENSP00000264972; -.
BindingDB; P43403; -.
ChEMBL; CHEMBL2803; -.
DrugBank; DB02010; Staurosporine.
GuidetoPHARMACOLOGY; 2285; -.
iPTMnet; P43403; -.
PhosphoSitePlus; P43403; -.
BioMuta; ZAP70; -.
DMDM; 1177044; -.
MaxQB; P43403; -.
PaxDb; P43403; -.
PeptideAtlas; P43403; -.
PRIDE; P43403; -.
DNASU; 7535; -.
Ensembl; ENST00000264972; ENSP00000264972; ENSG00000115085. [P43403-1]
Ensembl; ENST00000451498; ENSP00000400475; ENSG00000115085. [P43403-2]
GeneID; 7535; -.
KEGG; hsa:7535; -.
UCSC; uc002syd.2; human. [P43403-1]
CTD; 7535; -.
DisGeNET; 7535; -.
EuPathDB; HostDB:ENSG00000115085.13; -.
GeneCards; ZAP70; -.
GeneReviews; ZAP70; -.
HGNC; HGNC:12858; ZAP70.
HPA; CAB002625; -.
HPA; HPA003134; -.
MalaCards; ZAP70; -.
MIM; 176947; gene.
MIM; 269840; phenotype.
MIM; 617006; phenotype.
neXtProt; NX_P43403; -.
OpenTargets; ENSG00000115085; -.
Orphanet; 911; Combined immunodeficiency due to ZAP70 deficiency.
PharmGKB; PA37447; -.
eggNOG; ENOG410IH0T; Eukaryota.
eggNOG; COG0515; LUCA.
GeneTree; ENSGT00760000118799; -.
HOGENOM; HOG000113264; -.
HOVERGEN; HBG001540; -.
InParanoid; P43403; -.
KO; K07360; -.
OMA; ADKDEMM; -.
OrthoDB; EOG091G07KU; -.
PhylomeDB; P43403; -.
TreeFam; TF351629; -.
BRENDA; 2.7.10.2; 2681.
Reactome; R-HSA-202430; Translocation of ZAP-70 to Immunological synapse.
Reactome; R-HSA-202433; Generation of second messenger molecules.
SignaLink; P43403; -.
SIGNOR; P43403; -.
EvolutionaryTrace; P43403; -.
GeneWiki; ZAP70; -.
GenomeRNAi; 7535; -.
PMAP-CutDB; P43403; -.
PRO; PR:P43403; -.
Proteomes; UP000005640; Chromosome 2.
Bgee; ENSG00000115085; -.
CleanEx; HS_ZAP70; -.
Genevisible; P43403; HS.
GO; GO:0005911; C:cell-cell junction; IEA:Ensembl.
GO; GO:0005737; C:cytoplasm; TAS:HGNC.
GO; GO:0005829; C:cytosol; TAS:Reactome.
GO; GO:0031234; C:extrinsic component of cytoplasmic side of plasma membrane; IBA:GO_Central.
GO; GO:0001772; C:immunological synapse; IEA:Ensembl.
GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL.
GO; GO:0042101; C:T cell receptor complex; IDA:MGI.
GO; GO:0005524; F:ATP binding; NAS:UniProtKB.
GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; TAS:UniProtKB.
GO; GO:0004713; F:protein tyrosine kinase activity; IDA:UniProtKB.
GO; GO:0005102; F:receptor binding; IBA:GO_Central.
GO; GO:0002250; P:adaptive immune response; TAS:UniProtKB.
GO; GO:0042113; P:B cell activation; TAS:UniProtKB.
GO; GO:0043366; P:beta selection; IEA:Ensembl.
GO; GO:0006955; P:immune response; IDA:UniProtKB.
GO; GO:0045087; P:innate immune response; IBA:GO_Central.
GO; GO:0035556; P:intracellular signal transduction; NAS:UniProtKB.
GO; GO:0045060; P:negative thymic T cell selection; IEA:Ensembl.
GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; IBA:GO_Central.
GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:MGI.
GO; GO:0046638; P:positive regulation of alpha-beta T cell differentiation; IEA:Ensembl.
GO; GO:0046641; P:positive regulation of alpha-beta T cell proliferation; IEA:Ensembl.
GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IEA:Ensembl.
GO; GO:0045582; P:positive regulation of T cell differentiation; IDA:MGI.
GO; GO:0045059; P:positive thymic T cell selection; IDA:MGI.
GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
GO; GO:0042127; P:regulation of cell proliferation; IBA:GO_Central.
GO; GO:0042110; P:T cell activation; TAS:UniProtKB.
GO; GO:0070489; P:T cell aggregation; TAS:UniProtKB.
GO; GO:0030217; P:T cell differentiation; NAS:UniProtKB.
GO; GO:0072678; P:T cell migration; TAS:UniProtKB.
GO; GO:0050852; P:T cell receptor signaling pathway; TAS:UniProtKB.
GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
CDD; cd09938; SH2_N-SH2_Zap70_Syk_like; 1.
Gene3D; 1.10.930.10; -; 1.
Gene3D; 3.30.505.10; -; 2.
InterPro; IPR011009; Kinase-like_dom.
InterPro; IPR023420; Kinase_SYK/ZAP-70_inter-SH2.
InterPro; IPR000719; Prot_kinase_dom.
InterPro; IPR017441; Protein_kinase_ATP_BS.
InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
InterPro; IPR000980; SH2.
InterPro; IPR036860; SH2_dom_sf.
InterPro; IPR035838; SYK/ZAP-70_N_SH2.
InterPro; IPR008266; Tyr_kinase_AS.
InterPro; IPR020635; Tyr_kinase_cat_dom.
InterPro; IPR012234; Tyr_kinase_non-rcpt_SYK/ZAP70.
Pfam; PF07714; Pkinase_Tyr; 1.
Pfam; PF00017; SH2; 2.
PIRSF; PIRSF000604; TyrPK_SYK; 1.
PRINTS; PR00401; SH2DOMAIN.
PRINTS; PR00109; TYRKINASE.
SMART; SM00252; SH2; 2.
SMART; SM00219; TyrKc; 1.
SUPFAM; SSF55550; SSF55550; 2.
SUPFAM; SSF56112; SSF56112; 1.
PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
PROSITE; PS50001; SH2; 2.
1: Evidence at protein level;
3D-structure; Acetylation; Adaptive immunity; Alternative splicing;
ATP-binding; Cell membrane; Complete proteome; Cytoplasm;
Disease mutation; Immunity; Isopeptide bond; Kinase; Membrane;
Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome;
Repeat; SCID; SH2 domain; Transferase; Tyrosine-protein kinase;
Ubl conjugation.
CHAIN 1 619 Tyrosine-protein kinase ZAP-70.
/FTId=PRO_0000088168.
DOMAIN 10 102 SH2 1. {ECO:0000255|PROSITE-
ProRule:PRU00191}.
DOMAIN 163 254 SH2 2. {ECO:0000255|PROSITE-
ProRule:PRU00191}.
DOMAIN 338 600 Protein kinase. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
NP_BIND 345 352 ATP.
REGION 103 162 Interdomain A.
REGION 255 337 Interdomain B.
ACT_SITE 461 461 Proton acceptor. {ECO:0000255|PROSITE-
ProRule:PRU00159, ECO:0000255|PROSITE-
ProRule:PRU10028,
ECO:0000269|PubMed:15292186,
ECO:0000269|PubMed:17512407}.
BINDING 369 369 ATP.
MOD_RES 248 248 Phosphotyrosine.
{ECO:0000244|PubMed:15592455}.
MOD_RES 289 289 Phosphoserine.
{ECO:0000244|PubMed:15144186}.
MOD_RES 292 292 Phosphotyrosine.
{ECO:0000244|PubMed:19690332,
ECO:0000269|PubMed:8943331}.
MOD_RES 315 315 Phosphotyrosine; by LCK.
{ECO:0000269|PubMed:10037717}.
MOD_RES 319 319 Phosphotyrosine.
{ECO:0000269|PubMed:10037717}.
MOD_RES 492 492 Phosphotyrosine.
{ECO:0000269|PubMed:7781602}.
MOD_RES 493 493 Phosphotyrosine.
{ECO:0000269|PubMed:7781602}.
MOD_RES 603 603 N6-acetyllysine.
{ECO:0000244|PubMed:19608861}.
CROSSLNK 544 544 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in ubiquitin).
{ECO:0000269|PubMed:26903241}.
VAR_SEQ 1 307 Missing (in isoform 2).
{ECO:0000303|PubMed:14985102}.
/FTId=VSP_031156.
VAR_SEQ 1 126 Missing (in isoform 3).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_031157.
VAR_SEQ 127 134 VRQTWKLE -> MRLGPRWK (in isoform 3).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_031158.
VARIANT 175 175 R -> L (in dbSNP:rs55964305).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_041846.
VARIANT 191 191 P -> L (in dbSNP:rs56403250).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_041847.
VARIANT 192 192 R -> W (in ADMIO2; decreases interaction
with phosphorylated CD247; decreases
ZAP70 phosphorylation; no effect on
subcellular localization of CD69 at the
cell surface; dbSNP:rs199840952).
{ECO:0000269|PubMed:26783323}.
/FTId=VAR_077137.
VARIANT 337 337 L -> R (in IMD48).
{ECO:0000269|PubMed:18509675}.
/FTId=VAR_065623.
VARIANT 360 360 R -> P (in ADMIO2; no effect on
interaction with phosphorylated CD247;
increases TCR-induced Y-319 and Y-493
phosphorylation of ZAP70 and
phosphorylation of LAT and LCP2;
increases subcellular localization of
CD69 at the cell surface; weakly
decreases autoinhibition conformation;
dbSNP:rs869025224).
{ECO:0000269|PubMed:26783323}.
/FTId=VAR_077138.
VARIANT 448 448 G -> E (in a head and neck squamous cell
carcinoma sample; somatic mutation).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_041848.
VARIANT 465 465 R -> C (in IMD48; dbSNP:rs113994174).
{ECO:0000269|PubMed:11123350}.
/FTId=VAR_065624.
VARIANT 465 465 R -> H (in IMD48; dbSNP:rs137853201).
{ECO:0000269|PubMed:11412303}.
/FTId=VAR_015538.
VARIANT 507 507 A -> V (in IMD48).
{ECO:0000269|PubMed:18509675}.
/FTId=VAR_065625.
VARIANT 518 518 S -> R (in IMD48; dbSNP:rs104893674).
{ECO:0000269|PubMed:8202713}.
/FTId=VAR_006351.
VARIANT 523 523 W -> L (in dbSNP:rs56189815).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_041849.
VARIANT 541 541 K -> KLEQ (in IMD48).
{ECO:0000269|PubMed:8124727}.
/FTId=VAR_038688.
VARIANT 564 564 C -> R (in IMD48).
{ECO:0000269|PubMed:18509675}.
/FTId=VAR_065626.
MUTAGEN 37 37 R->K: Decreases interaction with
phosphorylated CD247; when associated
with K-190.
{ECO:0000269|PubMed:26783323}.
MUTAGEN 131 131 W->A: Increased constitutive kinase
activity. {ECO:0000269|PubMed:17512407}.
MUTAGEN 133 133 L->A: Increased constitutive kinase
activity. {ECO:0000269|PubMed:17512407}.
MUTAGEN 141 141 A->E: Increased constitutive kinase
activity. {ECO:0000269|PubMed:17512407}.
MUTAGEN 144 144 S->A: Increased kinase activity after
activation by LCK.
{ECO:0000269|PubMed:17512407}.
MUTAGEN 145 145 Q->A: Increased kinase activity after
activation by LCK.
{ECO:0000269|PubMed:17512407}.
MUTAGEN 147 147 P->A: Increased kinase activity after
activation by LCK.
{ECO:0000269|PubMed:17512407}.
MUTAGEN 190 190 R->K: Decreases interaction with
phosphorylated CD247; when associated
with K-37. {ECO:0000269|PubMed:26783323}.
MUTAGEN 292 292 Y->F: Induces constitutive TCR
stimulation-independent NFAT induction.
{ECO:0000269|PubMed:8943331}.
MUTAGEN 304 304 K->R: No effect on ubiquitination.
{ECO:0000269|PubMed:26903241}.
MUTAGEN 314 314 V->A: Increased constitutive kinase
activity.
MUTAGEN 315 319 YESPY->AESPA: Increases strongly
constitutive kinase activity on LAT
phosphorylation.
{ECO:0000269|PubMed:26783323}.
MUTAGEN 315 315 Y->A: Increased constitutive kinase
activity; when associated with F-319.
{ECO:0000269|PubMed:10037717,
ECO:0000269|PubMed:11828374,
ECO:0000269|PubMed:17512407,
ECO:0000269|PubMed:9151714}.
MUTAGEN 315 315 Y->F: Increased constitutive kinase
activity; when associated with F-319.
About 75% loss of CD247/CD3Z-binding in
stimulated TCR and complete loss of VAV1
interaction.
{ECO:0000269|PubMed:10037717,
ECO:0000269|PubMed:11828374,
ECO:0000269|PubMed:17512407,
ECO:0000269|PubMed:9151714}.
MUTAGEN 319 319 Y->A: Increased constitutive kinase
activity; when associated with F-315.
{ECO:0000269|PubMed:10037717,
ECO:0000269|PubMed:17512407}.
MUTAGEN 319 319 Y->F: Increased constitutive kinase
activity; when associated with F-315.
About 80% loss of TCR-induced NFAT
activation. {ECO:0000269|PubMed:10037717,
ECO:0000269|PubMed:17512407}.
MUTAGEN 327 327 D->P: Increases constitutive kinase
activity on LAT phosphorylation, strongly
increases subcellular localization of
CD69 at the cell surface and decreases
autoinhibition conformation.
{ECO:0000269|PubMed:26783323}.
MUTAGEN 362 362 K->E: Increases constitutive kinase
activity on LAT phosphorylation, strongly
increases subcellular localization of
CD69 at the cell surface and decreases
autoinhibition conformation.
{ECO:0000269|PubMed:26783323}.
MUTAGEN 461 461 D->N: Abolishes kinase activity.
{ECO:0000269|PubMed:17512407}.
MUTAGEN 479 479 D->N: Abolishes kinase activity.
{ECO:0000269|PubMed:15292186}.
MUTAGEN 492 492 Y->F: Increases kinase activity.
{ECO:0000269|PubMed:7781602}.
MUTAGEN 493 493 Y->F: Impairs kinase activity.
{ECO:0000269|PubMed:7781602}.
MUTAGEN 538 538 K->R: No effect on ubiquitination.
{ECO:0000269|PubMed:26903241}.
MUTAGEN 544 544 K->R: Strongly decreased ubiquitination.
{ECO:0000269|PubMed:26903241}.
MUTAGEN 597 597 Y->A: Increased kinase activity after
activation by LCK.
{ECO:0000269|PubMed:17512407}.
MUTAGEN 598 598 Y->A: Increased kinase activity after
activation by LCK.
{ECO:0000269|PubMed:17512407}.
TURN 4 7 {ECO:0000244|PDB:2OQ1}.
STRAND 11 14 {ECO:0000244|PDB:1M61}.
HELIX 17 26 {ECO:0000244|PDB:2OQ1}.
STRAND 34 38 {ECO:0000244|PDB:2OQ1}.
STRAND 40 42 {ECO:0000244|PDB:2OQ1}.
STRAND 46 52 {ECO:0000244|PDB:2OQ1}.
STRAND 55 63 {ECO:0000244|PDB:2OQ1}.
STRAND 69 71 {ECO:0000244|PDB:2OQ1}.
STRAND 77 79 {ECO:0000244|PDB:2OQ1}.
HELIX 80 89 {ECO:0000244|PDB:2OQ1}.
STRAND 94 96 {ECO:0000244|PDB:2OQ1}.
HELIX 114 131 {ECO:0000244|PDB:2OQ1}.
HELIX 135 156 {ECO:0000244|PDB:2OQ1}.
HELIX 157 160 {ECO:0000244|PDB:2OQ1}.
HELIX 170 178 {ECO:0000244|PDB:2OQ1}.
TURN 179 181 {ECO:0000244|PDB:1M61}.
STRAND 186 191 {ECO:0000244|PDB:2OQ1}.
STRAND 197 204 {ECO:0000244|PDB:2OQ1}.
STRAND 207 215 {ECO:0000244|PDB:2OQ1}.
TURN 217 219 {ECO:0000244|PDB:4XZ1}.
STRAND 221 223 {ECO:0000244|PDB:2OQ1}.
STRAND 229 231 {ECO:0000244|PDB:2OQ1}.
HELIX 232 241 {ECO:0000244|PDB:2OQ1}.
STRAND 246 248 {ECO:0000244|PDB:2OQ1}.
HELIX 309 311 {ECO:0000244|PDB:4K2R}.
STRAND 316 320 {ECO:0000244|PDB:2OZO}.
HELIX 322 326 {ECO:0000244|PDB:4K2R}.
HELIX 334 336 {ECO:0000244|PDB:1U59}.
STRAND 337 345 {ECO:0000244|PDB:1U59}.
STRAND 350 357 {ECO:0000244|PDB:1U59}.
STRAND 364 371 {ECO:0000244|PDB:1U59}.
HELIX 377 392 {ECO:0000244|PDB:1U59}.
STRAND 401 415 {ECO:0000244|PDB:1U59}.
HELIX 422 426 {ECO:0000244|PDB:1U59}.
TURN 430 432 {ECO:0000244|PDB:1U59}.
HELIX 435 454 {ECO:0000244|PDB:1U59}.
HELIX 464 466 {ECO:0000244|PDB:1U59}.
STRAND 467 471 {ECO:0000244|PDB:1U59}.
STRAND 474 477 {ECO:0000244|PDB:1U59}.
TURN 482 485 {ECO:0000244|PDB:2OZO}.
HELIX 503 505 {ECO:0000244|PDB:1U59}.
HELIX 508 513 {ECO:0000244|PDB:1U59}.
HELIX 518 533 {ECO:0000244|PDB:1U59}.
TURN 534 536 {ECO:0000244|PDB:4K2R}.
TURN 539 542 {ECO:0000244|PDB:1U59}.
HELIX 546 553 {ECO:0000244|PDB:1U59}.
HELIX 566 574 {ECO:0000244|PDB:1U59}.
HELIX 580 582 {ECO:0000244|PDB:1U59}.
HELIX 586 601 {ECO:0000244|PDB:1U59}.
SEQUENCE 619 AA; 69872 MW; D1E1A8EC66FA116F CRC64;
MPDPAAHLPF FYGSISRAEA EEHLKLAGMA DGLFLLRQCL RSLGGYVLSL VHDVRFHHFP
IERQLNGTYA IAGGKAHCGP AELCEFYSRD PDGLPCNLRK PCNRPSGLEP QPGVFDCLRD
AMVRDYVRQT WKLEGEALEQ AIISQAPQVE KLIATTAHER MPWYHSSLTR EEAERKLYSG
AQTDGKFLLR PRKEQGTYAL SLIYGKTVYH YLISQDKAGK YCIPEGTKFD TLWQLVEYLK
LKADGLIYCL KEACPNSSAS NASGAAAPTL PAHPSTLTHP QRRIDTLNSD GYTPEPARIT
SPDKPRPMPM DTSVYESPYS DPEELKDKKL FLKRDNLLIA DIELGCGNFG SVRQGVYRMR
KKQIDVAIKV LKQGTEKADT EEMMREAQIM HQLDNPYIVR LIGVCQAEAL MLVMEMAGGG
PLHKFLVGKR EEIPVSNVAE LLHQVSMGMK YLEEKNFVHR DLAARNVLLV NRHYAKISDF
GLSKALGADD SYYTARSAGK WPLKWYAPEC INFRKFSSRS DVWSYGVTMW EALSYGQKPY
KKMKGPEVMA FIEQGKRMEC PPECPPELYA LMSDCWIYKW EDRPDFLTVE QRMRACYYSL
ASKVEGPPGS TQKAEAACA


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