ID KSYK_HUMAN Reviewed; 635 AA.
AC P43405;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 01-MAY-2013, entry version 157.
DE RecName: Full=Tyrosine-protein kinase SYK;
DE EC=2.7.10.2;
DE AltName: Full=Spleen tyrosine kinase;
DE AltName: Full=p72-Syk;
GN Name=SYK;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7513161; DOI=10.1006/bbrc.1994.1409;
RA Yagi S., Suzuki K., Hasegawa A., Okumura K., Ra C.;
RT "Cloning of the cDNA for the deleted syk kinase homologous to ZAP-70
RT from human basophilic leukemia cell line (KU812).";
RL Biochem. Biophys. Res. Commun. 200:28-34(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND
RP AUTOPHOSPHORYLATION.
RX PubMed=8163536;
RA Law C.-L., Sidorenko S.P., Chandran K.A., Draves K.E., Chan A.C.,
RA Weiss A., Edelhoff S., Disteche C.M., Clark E.A.;
RT "Molecular cloning of human Syk. A B cell protein-tyrosine kinase
RT associated with the surface immunoglobulin M-B cell receptor
RT complex.";
RL J. Biol. Chem. 269:12310-12319(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS LONG AND SHORT).
RC TISSUE=Eye, and Lymph;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 6-635.
RC TISSUE=Tonsil;
RX PubMed=8168854; DOI=10.1007/BF00189234;
RA Mueller B., Cooper L., Terhorst C.;
RT "Molecular cloning of the human homologue to the pig protein-tyrosine
RT kinase syk.";
RL Immunogenetics 39:359-362(1994).
RN [6]
RP INTERACTION WITH EPSTEIN-BARR VIRUS LMP2A.
RX PubMed=7895172; DOI=10.1016/S1074-7613(95)80040-9;
RA Miller C.L., Burkhardt A.L., Lee J.H., Stealey B., Longnecker R.,
RA Bolen J.B., Kieff E.;
RT "Integral membrane protein 2 of Epstein-Barr virus regulates
RT reactivation from latency through dominant negative effects on
RT protein-tyrosine kinases.";
RL Immunity 2:155-166(1995).
RN [7]
RP INTERACTION WITH VAV1.
RX PubMed=8986718; DOI=10.1016/S1074-7613(00)80273-3;
RA Deckert M., Tartare-Deckert S., Couture C., Mustelin T., Altman A.;
RT "Functional and physical interactions of Syk family kinases with the
RT Vav proto-oncogene product.";
RL Immunity 5:591-604(1996).
RN [8]
RP FUNCTION IN PHOSPHORYLATION OF PLCG1, AND INTERACTION WITH PLCG1.
RX PubMed=8657103;
RA Law C.L., Chandran K.A., Sidorenko S.P., Clark E.A.;
RT "Phospholipase C-gamma1 interacts with conserved phosphotyrosyl
RT residues in the linker region of Syk and is a substrate for Syk.";
RL Mol. Cell. Biol. 16:1305-1315(1996).
RN [9]
RP FUNCTION IN PHOSPHORYLATION OF CBL, AND INTERACTION WITH CBL.
RX PubMed=9535867; DOI=10.1074/jbc.273.15.8867;
RA Deckert M., Elly C., Altman A., Liu Y.C.;
RT "Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn
RT and Syk tyrosine kinases.";
RL J. Biol. Chem. 273:8867-8874(1998).
RN [10]
RP ENZYME REGULATION, AND INTERACTION WITH CBL.
RX PubMed=9857068; DOI=10.1074/jbc.273.52.35273;
RA Lupher M.L. Jr., Rao N., Lill N.L., Andoniou C.E., Miyake S.,
RA Clark E.A., Druker B., Band H.;
RT "Cbl-mediated negative regulation of the Syk tyrosine kinase. A
RT critical role for Cbl phosphotyrosine-binding domain binding to Syk
RT phosphotyrosine 323.";
RL J. Biol. Chem. 273:35273-35281(1998).
RN [11]
RP PHOSPHORYLATION, DEPHOSPHORYLATION BY PTPN6, AND ENZYME REGULATION.
RX PubMed=10458769;
RX DOI=10.1002/(SICI)1521-4141(199908)29:08<2539::AID-IMMU2539>3.0.CO;2-M;
RA Brockdorff J., Williams S., Couture C., Mustelin T.;
RT "Dephosphorylation of ZAP-70 and inhibition of T cell activation by
RT activated SHP1.";
RL Eur. J. Immunol. 29:2539-2550(1999).
RN [12]
RP INTERACTION WITH SLA.
RX PubMed=10449770; DOI=10.1073/pnas.96.17.9775;
RA Tang J., Sawasdikosol S., Chang J.-H., Burakoff S.J.;
RT "SLAP, a dimeric adapter protein, plays a functional role in T cell
RT receptor signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:9775-9780(1999).
RN [13]
RP INTERACTION WITH FCRL3.
RX PubMed=11162587; DOI=10.1006/bbrc.2000.4213;
RA Xu M.-J., Zhao R., Zhao Z.J.;
RT "Molecular cloning and characterization of SPAP1, an inhibitory
RT receptor.";
RL Biochem. Biophys. Res. Commun. 280:768-775(2001).
RN [14]
RP FUNCTION IN B-CELL RECEPTOR SIGNALING PATHWAY, AND FUNCTION IN
RP PHOSPHORYLATION OF BLNK.
RX PubMed=12456653; DOI=10.1093/emboj/cdf658;
RA Chiu C.W., Dalton M., Ishiai M., Kurosaki T., Chan A.C.;
RT "BLNK: molecular scaffolding through 'cis'-mediated organization of
RT signaling proteins.";
RL EMBO J. 21:6461-6472(2002).
RN [15]
RP FUNCTION IN CELL ADHESION, AND INTERACTION WITH SELPLG AND MSN.
RX PubMed=12387735; DOI=10.1016/S1074-7613(02)00420-X;
RA Urzainqui A., Serrador J.M., Viedma F., Yanez-Mo M., Rodriguez A.,
RA Corbi A.L., Alonso-Lebrero J.L., Luque A., Deckert M., Vazquez J.,
RA Sanchez-Madrid F.;
RT "ITAM-based interaction of ERM proteins with Syk mediates signaling by
RT the leukocyte adhesion receptor PSGL-1.";
RL Immunity 17:401-412(2002).
RN [16]
RP INTERACTION WITH ITGB3.
RX PubMed=11940607; DOI=10.1083/jcb.200112113;
RA Obergfell A., Eto K., Mocsai A., Buensuceso C., Moores S.L.,
RA Brugge J.S., Lowell C.A., Shattil S.J.;
RT "Coordinate interactions of Csk, Src, and Syk kinases with
RT [alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton.";
RL J. Cell Biol. 157:265-275(2002).
RN [17]
RP FUNCTION IN PHOSPHORYLATION OF LCP2.
RX PubMed=15388330; DOI=10.1016/j.febslet.2004.07.090;
RA Shim E.K., Moon C.S., Lee G.Y., Ha Y.J., Chae S.K., Lee J.R.;
RT "Association of the Src homology 2 domain-containing leukocyte
RT phosphoprotein of 76 kD (SLP-76) with the p85 subunit of
RT phosphoinositide 3-kinase.";
RL FEBS Lett. 575:35-40(2004).
RN [18]
RP INTERACTION WITH BLNK, ENZYME REGULATION, MUTAGENESIS OF TYR-630, AND
RP PHOSPHORYLATION AT TYR-630.
RX PubMed=18369315; DOI=10.1038/emboj.2008.62;
RA Kulathu Y., Hobeika E., Turchinovich G., Reth M.;
RT "The kinase Syk as an adaptor controlling sustained calcium signalling
RT and B-cell development.";
RL EMBO J. 27:1333-1344(2008).
RN [19]
RP ENZYME REGULATION.
RX PubMed=18818202; DOI=10.1074/jbc.M806340200;
RA Tsang E., Giannetti A.M., Shaw D., Dinh M., Tse J.K., Gandhi S.,
RA Ho H., Wang S., Papp E., Bradshaw J.M.;
RT "Molecular mechanism of the Syk activation switch.";
RL J. Biol. Chem. 283:32650-32659(2008).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-323, AND MASS
RP SPECTROMETRY.
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 [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-28, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [23]
RP INTERACTION WITH CLEC1B.
RX PubMed=20154219; DOI=10.1182/blood-2009-08-237834;
RA Hughes C.E., Pollitt A.Y., Mori J., Eble J.A., Tomlinson M.G.,
RA Hartwig J.H., O'Callaghan C.A., Fuetterer K., Watson S.P.;
RT "CLEC-2 activates Syk through dimerization.";
RL Blood 115:2947-2955(2010).
RN [24]
RP INTERACTION WITH USP25, AND FUNCTION.
RX PubMed=19909739; DOI=10.1016/j.yexcr.2009.10.023;
RA Cholay M., Reverdy C., Benarous R., Colland F., Daviet L.;
RT "Functional interaction between the ubiquitin-specific protease 25 and
RT the SYK tyrosine kinase.";
RL Exp. Cell Res. 316:667-675(2010).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [26]
RP PHOSPHORYLATION AT TYR-28; SER-44; TYR-47; TYR-131; SER-202; THR-256;
RP SER-295; TYR-296; SER-297; SER-316; THR-317; SER-319; TYR-323;
RP THR-345; TYR-348; SER-350; TYR-352; TYR-364; SER-379; THR-384;
RP TYR-484; TYR-507; TYR-525; TYR-526; THR-530; SER-579; THR-582;
RP TYR-629; TYR-630 AND TYR-631, INTERACTION WITH YWHAG, AND MUTAGENESIS
RP OF SER-297.
RC TISSUE=B-cell;
RX PubMed=21469132; DOI=10.1002/eji.201041326;
RA Bohnenberger H., Oellerich T., Engelke M., Hsiao H.H., Urlaub H.,
RA Wienands J.;
RT "Complex phosphorylation dynamics control the composition of the Syk
RT interactome in B cells.";
RL Eur. J. Immunol. 41:1550-1562(2011).
RN [27]
RP STRUCTURE BY NMR OF 163-265.
RX PubMed=8590001; DOI=10.1016/S0969-2126(01)00242-8;
RA Narula S.S., Yuan R.W., Adams S.E., Green O.M., Green J.,
RA Philips T.B., Zydowsky L.D., Botfield M.C., Hatada M., Laird E.R.,
RA Zoller M.J., Karas J.L., Dalgarno D.C.;
RT "Solution structure of the C-terminal SH2 domain of the human tyrosine
RT kinase Syk complexed with a phosphotyrosine pentapeptide.";
RL Structure 3:1061-1073(1995).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF SH2 DOMAINS IN COMPLEX WITH
RP CD3E PHOSPHORYLATED ITAM DOMAIN.
RX PubMed=9698567; DOI=10.1006/jmbi.1998.1964;
RA Fuetterer K., Wong J., Grucza R.A., Chan A.C., Waksman G.;
RT "Structural basis for Syk tyrosine kinase ubiquity in signal
RT transduction pathways revealed by the crystal structure of its
RT regulatory SH2 domains bound to a dually phosphorylated ITAM
RT peptide.";
RL J. Mol. Biol. 281:523-537(1998).
CC -!- FUNCTION: Non-receptor tyrosine kinase which mediates signal
CC transduction downstream of a variety of transmembrane receptors
CC including classical immunoreceptors like the B-cell receptor
CC (BCR). Regulates several biological processes including innate and
CC adaptive immunity, cell adhesion, osteoclast maturation, platelet
CC activation and vascular development. Assembles into signaling
CC complexes with activated receptors at the plasma membrane via
CC interaction between its SH2 domains and the receptor tyrosine-
CC phosphorylated ITAM domains. The association with the receptor can
CC also be indirect and mediated by adapter proteins containing ITAM
CC or partial hemITAM domains. The phosphorylation of the ITAM
CC domains is generally mediated by SRC subfamily kinases upon
CC engagement of the receptor. More rarely signal transduction via
CC SYK could be ITAM-independent. Direct downstream effectors
CC phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and
CC BLNK. Initially identified as essential in B-cell receptor (BCR)
CC signaling, it is necessary for the maturation of B-cells most
CC probably at the pro-B to pre-B transition. Activated upon BCR
CC engagement, it phosphorylates and activates BLNK an adapter
CC linking the activated BCR to downstream signaling adapters and
CC effectors. It also phosphorylates and activates PLCG1 and the PKC
CC signaling pathway. It also phosphorylates BTK and regulates its
CC activity in B-cell antigen receptor (BCR)-coupled signaling.
CC Beside its function downstream of BCR plays also a role in T-cell
CC receptor signaling. Plays also a crucial role in the innate immune
CC response to fungal, bacterial and viral pathogens. It is for
CC instance activated by the membrane lectin CLEC7A. Upon stimulation
CC by fungal proteins, CLEC7A together with SYK activates immune
CC cells inducing the production of ROS. Also activates the
CC inflammasome and NF-kappa-B-mediated transcription of chemokines
CC and cytokines in presence of pathogens. Regulates neutrophil
CC degranulation and phagocytosis through activation of the MAPK
CC signaling cascade. Also mediates the activation of dendritic cells
CC by cell necrosis stimuli. Also involved in mast cells activation.
CC Also functions downstream of receptors mediating cell adhesion.
CC Relays for instance, integrin-mediated neutrophils and macrophages
CC activation and P-selectin receptor/SELPG-mediated recruitment of
CC leukocytes to inflammatory loci. Plays also a role in non-immune
CC processes. It is for instance involved in vascular development
CC where it may regulate blood and lymphatic vascular separation. It
CC is also required for osteoclast development and function.
CC Functions in the activation of platelets by collagen, mediating
CC PLCG2 phosphorylation and activation. May be coupled to the
CC collagen receptor by the ITAM domain-containing FCER1G. Also
CC activated by the membrane lectin CLEC1B that is required for
CC activation of platelets by PDPN/podoplanin. Involved in platelet
CC adhesion being activated by ITGB3 engaged by fibrinogen.
CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC [protein]-L-tyrosine phosphate.
CC -!- ENZYME REGULATION: Autoinhibited. Intramolecular binding of the
CC interdomains A and B (also called linker region) to parts of the
CC catalytic domain keep the catalytic center in an inactive
CC conformation. The phosphorylation of the interdomains or the
CC binding of the SH2 domains with dually phosphorylated ITAM domains
CC on transmembrane proteins disrupt those intramolecular
CC interactions allowing the kinase domain to adopt an active
CC conformation. The phosphorylation of SYK and of the ITAM domains
CC which is responsible for SYK activation is essentially mediated by
CC SRC subfamily kinases, like LYN, upon transmembrane receptors
CC engagement. May also be negatively regulated by PTPN6 through
CC dephosphorylation. Downstream signaling adapters and intermediates
CC like BLNK or RHOH may mediate positive and/or negative feedback
CC regulation. Negatively regulated by CBL and CBLB through
CC ubiquitination and probable degradation. Phosphorylates SH3BP2
CC which in turn may regulate SYK through LYN (By similarity).
CC -!- SUBUNIT: Interacts with LYN; phosphorylates SYK (By similarity).
CC Interacts with RHOH (phosphorylated); regulates mast cells
CC activation (By similarity). Interacts with NFAM1 (phosphorylated);
CC probably involved in BCR signaling (By similarity). Interacts with
CC VAV1 (via SH2 domain); phosphorylates VAV1 upon BCR activation.
CC Interacts with GAB2 (phosphorylated); probably involved in IgE Fc
CC receptor signaling (By similarity). Interacts (via its SH2
CC domains) with CD79A (via its phosphorylated ITAM domain); the
CC interaction stimulates SYK autophosphorylation and activation (By
CC similarity). Interacts with FCRL3. Interacts (via SH2 domains)
CC with FCER1G (via ITAM domain); activates SYK and mediates
CC neutrophils and macrophages integrin-mediated activation (By
CC similarity). Interacts with ITGB2 and FGR; involved in ITGB2
CC downstream signaling (By similarity). Interacts with ITGB3; upon
CC activation by ITGB3 promotes platelet adhesion. Interacts (via SH2
CC domains) with TYROBP (via ITAM domain); involved in neutrophils
CC and macrophages integrin-mediated activation (By similarity).
CC Interacts with MSN and SELPLG; mediates the selectin-dependent
CC activation of SYK by SELPLG. Interacts with BLNK (via SH2 domain).
CC Interacts (via the second SH2 domain) with USP25 (via C-terminus);
CC phosphorylates USP25 and regulates USP25 intracellular levels.
CC Interacts (via SH2 domains) with CLEC1B (dimer). Interacts with
CC CLEC7A; participates in leukocyte activation in presence of fungal
CC pathogens. Interacts (phosphorylated) with SLA; may regulate SYK
CC through CBL recruitment. Interacts with YWHAG; attenuates BCR-
CC induced membrane translocation and activation of SYK. Interacts
CC with Epstein-Barr virus LMP2A.
CC -!- INTERACTION:
CC P20273:CD22; NbExp=4; IntAct=EBI-78302, EBI-78277;
CC P11049:CD37; NbExp=3; IntAct=EBI-78302, EBI-6139068;
CC -!- SUBCELLULAR LOCATION: Cell membrane (Probable). Cytoplasm, cytosol
CC (Probable).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long;
CC IsoId=P43405-1; Sequence=Displayed;
CC Name=Short;
CC IsoId=P43405-2; Sequence=VSP_005010;
CC -!- TISSUE SPECIFICITY: Widely expressed in hematopoietic cells (at
CC protein level). Within the B-cells compartment it is for instance
CC expressed for pro-B-cells to plasma cells.
CC -!- DOMAIN: The SH2 domains mediate the interaction of SYK with the
CC phosphorylated ITAM domains of transmembrane proteins. Some
CC proteins like CLEC1B have a partial ITAM domain (also called
CC hemITAM) containing a single YxxL motif. The interaction with SYK
CC requires CLEC1B homodimerization.
CC -!- PTM: Ubiquitinated by CBLB after BCR activation; which promotes
CC proteasomal degradation (By similarity).
CC -!- PTM: Autophosphorylated. Phosphorylated on tyrosine residues by
CC LYN following receptors engagement. Phosphorylation on Tyr-323
CC creates a binding site for CBL, an adapter protein that serves as
CC a negative regulator of BCR-stimulated calcium ion signaling.
CC Phosphorylation at Tyr-348 creates a binding site for VAV1.
CC Phosphorylation on Tyr-348 and Tyr-352 enhances the
CC phosphorylation and activation of phospholipase C-gamma and the
CC early phase of calcium ion mobilization via a phosphoinositide 3-
CC kinase-independent pathway (By similarity). Phosphorylation on
CC Ser-297 is very common, it peaks 5 minutes after BCR stimulation,
CC and creates a binding site for YWHAG. Phosphorylation at Tyr-630
CC creates a binding site for BLNK. Dephosphorylated by PTPN6.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. SYK/ZAP-70 subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 2 SH2 domains.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SYKID394.html";
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DR EMBL; Z29630; CAA82737.1; -; mRNA.
DR EMBL; L28824; AAA36526.1; -; mRNA.
DR EMBL; AL354862; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC001645; AAH01645.1; -; mRNA.
DR EMBL; BC011399; AAH11399.1; -; mRNA.
DR EMBL; BC002962; AAH02962.1; -; mRNA.
DR EMBL; X73568; CAA51970.1; -; mRNA.
DR IPI; IPI00018597; -.
DR IPI; IPI00218278; -.
DR PIR; A53596; A53596.
DR RefSeq; NP_001128524.1; NM_001135052.2.
DR RefSeq; NP_001167638.1; NM_001174167.1.
DR RefSeq; NP_001167639.1; NM_001174168.1.
DR RefSeq; NP_003168.2; NM_003177.5.
DR UniGene; Hs.371720; -.
DR PDB; 1A81; X-ray; 3.00 A; A/C/E/G/I/K=9-262.
DR PDB; 1CSY; NMR; -; A=163-265.
DR PDB; 1CSZ; NMR; -; A=163-265.
DR PDB; 1XBA; X-ray; 2.00 A; A=356-635.
DR PDB; 1XBB; X-ray; 1.57 A; A=356-635.
DR PDB; 1XBC; X-ray; 2.00 A; A=356-635.
DR PDB; 3BUW; X-ray; 1.45 A; A/C=317-329.
DR PDB; 3EMG; X-ray; 2.60 A; A=349-635.
DR PDB; 3FQE; X-ray; 2.50 A; A=356-635.
DR PDB; 3FQH; X-ray; 2.26 A; A/B=356-635.
DR PDB; 3FQS; X-ray; 2.10 A; A=356-635.
DR PDB; 3SRV; X-ray; 1.95 A; A/B=360-635.
DR PDB; 3TUB; X-ray; 2.23 A; A=343-635.
DR PDB; 3TUC; X-ray; 2.10 A; A=343-635.
DR PDB; 3TUD; X-ray; 2.33 A; A=343-635.
DR PDB; 3VF8; X-ray; 2.08 A; A=343-635.
DR PDB; 3VF9; X-ray; 2.30 A; A=343-635.
DR PDB; 4DFL; X-ray; 1.98 A; A=363-635.
DR PDB; 4DFN; X-ray; 2.48 A; A=363-635.
DR PDB; 4F4P; X-ray; 2.37 A; A=365-635.
DR PDB; 4FL1; X-ray; 1.79 A; A=356-635.
DR PDB; 4FL2; X-ray; 2.19 A; A=1-635.
DR PDB; 4FL3; X-ray; 1.90 A; A=1-635.
DR PDB; 4FYN; X-ray; 2.32 A; A=356-635.
DR PDB; 4FYO; X-ray; 1.40 A; A=356-635.
DR PDB; 4FZ6; X-ray; 1.85 A; A=356-635.
DR PDBsum; 1A81; -.
DR PDBsum; 1CSY; -.
DR PDBsum; 1CSZ; -.
DR PDBsum; 1XBA; -.
DR PDBsum; 1XBB; -.
DR PDBsum; 1XBC; -.
DR PDBsum; 3BUW; -.
DR PDBsum; 3EMG; -.
DR PDBsum; 3FQE; -.
DR PDBsum; 3FQH; -.
DR PDBsum; 3FQS; -.
DR PDBsum; 3SRV; -.
DR PDBsum; 3TUB; -.
DR PDBsum; 3TUC; -.
DR PDBsum; 3TUD; -.
DR PDBsum; 3VF8; -.
DR PDBsum; 3VF9; -.
DR PDBsum; 4DFL; -.
DR PDBsum; 4DFN; -.
DR PDBsum; 4F4P; -.
DR PDBsum; 4FL1; -.
DR PDBsum; 4FL2; -.
DR PDBsum; 4FL3; -.
DR PDBsum; 4FYN; -.
DR PDBsum; 4FYO; -.
DR PDBsum; 4FZ6; -.
DR ProteinModelPortal; P43405; -.
DR DIP; DIP-253N; -.
DR IntAct; P43405; 9.
DR MINT; MINT-148486; -.
DR STRING; 9606.ENSP00000364898; -.
DR PhosphoSite; P43405; -.
DR DMDM; 1174527; -.
DR PaxDb; P43405; -.
DR PeptideAtlas; P43405; -.
DR PRIDE; P43405; -.
DR DNASU; 6850; -.
DR Ensembl; ENST00000375746; ENSP00000364898; ENSG00000165025.
DR Ensembl; ENST00000375747; ENSP00000364899; ENSG00000165025.
DR Ensembl; ENST00000375751; ENSP00000364904; ENSG00000165025.
DR Ensembl; ENST00000375754; ENSP00000364907; ENSG00000165025.
DR GeneID; 6850; -.
DR KEGG; hsa:6850; -.
DR UCSC; uc004aqz.3; human.
DR UCSC; uc004ara.3; human.
DR CTD; 6850; -.
DR GeneCards; GC09P093564; -.
DR HGNC; HGNC:11491; SYK.
DR HPA; CAB007773; -.
DR HPA; HPA001384; -.
DR MIM; 600085; gene.
DR neXtProt; NX_P43405; -.
DR PharmGKB; PA36273; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000113264; -.
DR HOVERGEN; HBG001540; -.
DR InParanoid; P43405; -.
DR KO; K05855; -.
DR OMA; PKEVYLD; -.
DR OrthoDB; EOG4WSW93; -.
DR PhylomeDB; P43405; -.
DR BRENDA; 2.7.10.2; 2681.
DR Pathway_Interaction_DB; alphasynuclein_pathway; Alpha-synuclein signaling.
DR Pathway_Interaction_DB; nfkappabatypicalpathway; Atypical NF-kappaB pathway.
DR Pathway_Interaction_DB; bcr_5pathway; BCR signaling pathway.
DR Pathway_Interaction_DB; pi3kcipathway; Class I PI3K signaling events.
DR Pathway_Interaction_DB; fcer1pathway; Fc-epsilon receptor I signaling in mast cells.
DR Pathway_Interaction_DB; il2_1pathway; IL2-mediated signaling events.
DR Pathway_Interaction_DB; avb3_opn_pathway; Osteopontin-mediated events.
DR Pathway_Interaction_DB; txa2pathway; Thromboxane A2 receptor signaling.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR BindingDB; P43405; -.
DR ChEMBL; CHEMBL2599; -.
DR EvolutionaryTrace; P43405; -.
DR GenomeRNAi; 6850; -.
DR NextBio; 26739; -.
DR Bgee; P43405; -.
DR CleanEx; HS_SYK; -.
DR Genevestigator; P43405; -.
DR GermOnline; ENSG00000165025; Homo sapiens.
DR GO; GO:0019815; C:B cell receptor complex; IEA:Compara.
DR GO; GO:0005829; C:cytosol; IC:UniProtKB.
DR GO; GO:0032009; C:early phagosome; ISS:UniProtKB.
DR GO; GO:0042101; C:T cell receptor complex; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IDA:UniProtKB.
DR GO; GO:0004716; F:receptor signaling protein tyrosine kinase activity; IEA:Compara.
DR GO; GO:0007257; P:activation of JUN kinase activity; IEA:Compara.
DR GO; GO:0002250; P:adaptive immune response; ISS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0050853; P:B cell receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0043366; P:beta selection; IEA:Compara.
DR GO; GO:0048514; P:blood vessel morphogenesis; ISS:UniProtKB.
DR GO; GO:0008283; P:cell proliferation; TAS:ProtInc.
DR GO; GO:0071226; P:cellular response to molecule of fungal origin; ISS:UniProtKB.
DR GO; GO:0042742; P:defense response to bacterium; ISS:UniProtKB.
DR GO; GO:0007167; P:enzyme linked receptor protein signaling pathway; IEA:Compara.
DR GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0007159; P:leukocyte cell-cell adhesion; IDA:UniProtKB.
DR GO; GO:0019370; P:leukotriene biosynthetic process; IEA:Compara.
DR GO; GO:0001945; P:lymph vessel development; ISS:UniProtKB.
DR GO; GO:0002281; P:macrophage activation involved in immune response; ISS:UniProtKB.
DR GO; GO:0002283; P:neutrophil activation involved in immune response; ISS:UniProtKB.
DR GO; GO:0030593; P:neutrophil chemotaxis; IDA:UniProtKB.
DR GO; GO:0009887; P:organ morphogenesis; TAS:ProtInc.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:Compara.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0046638; P:positive regulation of alpha-beta T cell differentiation; IEA:Compara.
DR GO; GO:0046641; P:positive regulation of alpha-beta T cell proliferation; IEA:Compara.
DR GO; GO:0045579; P:positive regulation of B cell differentiation; IEA:Compara.
DR GO; GO:0045780; P:positive regulation of bone resorption; ISS:UniProtKB.
DR GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IEA:Compara.
DR GO; GO:0033630; P:positive regulation of cell adhesion mediated by integrin; ISS:UniProtKB.
DR GO; GO:0050715; P:positive regulation of cytokine secretion; IEA:Compara.
DR GO; GO:0045588; P:positive regulation of gamma-delta T cell differentiation; IEA:Compara.
DR GO; GO:0045425; P:positive regulation of granulocyte macrophage colony-stimulating factor biosynthetic process; IEA:Compara.
DR GO; GO:0045401; P:positive regulation of interleukin-3 biosynthetic process; IEA:Compara.
DR GO; GO:0043306; P:positive regulation of mast cell degranulation; IEA:Compara.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IEA:Compara.
DR GO; GO:0046777; P:protein autophosphorylation; IEA:Compara.
DR GO; GO:0090237; P:regulation of arachidonic acid secretion; ISS:UniProtKB.
DR GO; GO:0070372; P:regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0043313; P:regulation of neutrophil degranulation; ISS:UniProtKB.
DR GO; GO:0050764; P:regulation of phagocytosis; ISS:UniProtKB.
DR GO; GO:0090330; P:regulation of platelet aggregation; ISS:UniProtKB.
DR GO; GO:0032928; P:regulation of superoxide anion generation; ISS:UniProtKB.
DR GO; GO:0002554; P:serotonin secretion by platelet; ISS:UniProtKB.
DR GO; GO:0019048; P:virus-host interaction; IEA:UniProtKB-KW.
DR Gene3D; 1.10.930.10; -; 1.
DR Gene3D; 3.30.505.10; -; 2.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR023420; Kinase_SYK/ZAP-70_inter-SH2.
DR InterPro; IPR000719; Prot_kinase_cat_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR012234; Tyr_kinase_non-rcpt_SYK/ZAP70.
DR Pfam; PF07714; Pkinase_Tyr; 1.
DR Pfam; PF00017; SH2; 2.
DR PIRSF; PIRSF000604; TyrPK_SYK; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00252; SH2; 2.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF56112; Kinase_like; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS50001; SH2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Adaptive immunity; Alternative splicing; Angiogenesis;
KW ATP-binding; Cell membrane; Complete proteome; Cytoplasm;
KW Host-virus interaction; Immunity; Innate immunity; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome;
KW Repeat; SH2 domain; Transferase; Tyrosine-protein kinase;
KW Ubl conjugation.
FT CHAIN 1 635 Tyrosine-protein kinase SYK.
FT /FTId=PRO_0000088165.
FT DOMAIN 15 107 SH2 1.
FT DOMAIN 168 259 SH2 2.
FT DOMAIN 371 631 Protein kinase.
FT NP_BIND 377 385 ATP (By similarity).
FT REGION 108 167 Interdomain A.
FT REGION 260 370 Interdomain B.
FT ACT_SITE 494 494 Proton acceptor (By similarity).
FT BINDING 402 402 ATP (By similarity).
FT MOD_RES 28 28 Phosphotyrosine.
FT MOD_RES 44 44 Phosphoserine.
FT MOD_RES 47 47 Phosphotyrosine.
FT MOD_RES 131 131 Phosphotyrosine.
FT MOD_RES 202 202 Phosphoserine.
FT MOD_RES 256 256 Phosphothreonine.
FT MOD_RES 295 295 Phosphoserine.
FT MOD_RES 296 296 Phosphotyrosine.
FT MOD_RES 297 297 Phosphoserine.
FT MOD_RES 316 316 Phosphoserine.
FT MOD_RES 317 317 Phosphothreonine.
FT MOD_RES 319 319 Phosphoserine.
FT MOD_RES 323 323 Phosphotyrosine; by LYN.
FT MOD_RES 345 345 Phosphothreonine.
FT MOD_RES 348 348 Phosphotyrosine.
FT MOD_RES 350 350 Phosphoserine.
FT MOD_RES 352 352 Phosphotyrosine.
FT MOD_RES 364 364 Phosphotyrosine.
FT MOD_RES 379 379 Phosphoserine.
FT MOD_RES 384 384 Phosphothreonine.
FT MOD_RES 484 484 Phosphotyrosine.
FT MOD_RES 507 507 Phosphotyrosine.
FT MOD_RES 525 525 Phosphotyrosine; by autocatalysis.
FT MOD_RES 526 526 Phosphotyrosine.
FT MOD_RES 530 530 Phosphothreonine.
FT MOD_RES 546 546 Phosphotyrosine (By similarity).
FT MOD_RES 579 579 Phosphoserine.
FT MOD_RES 582 582 Phosphothreonine.
FT MOD_RES 629 629 Phosphotyrosine.
FT MOD_RES 630 630 Phosphotyrosine.
FT MOD_RES 631 631 Phosphotyrosine.
FT VAR_SEQ 283 305 Missing (in isoform Short).
FT /FTId=VSP_005010.
FT VARIANT 45 45 R -> H (in dbSNP:rs16906862).
FT /FTId=VAR_033838.
FT MUTAGEN 297 297 S->A: Abolishes YWHAG binding.
FT MUTAGEN 630 630 Y->F: Loss of interaction with BLNK.
FT CONFLICT 119 119 P -> A (in Ref. 5; CAA51970).
FT CONFLICT 250 250 G -> P (in Ref. 5; CAA51970).
FT HELIX 22 31
FT STRAND 38 43
FT STRAND 47 49
FT STRAND 51 57
FT STRAND 60 68
FT STRAND 74 76
FT STRAND 82 84
FT HELIX 85 92
FT STRAND 99 101
FT HELIX 119 136
FT HELIX 140 158
FT HELIX 163 165
FT STRAND 169 172
FT HELIX 175 183
FT STRAND 184 186
FT STRAND 187 189
FT STRAND 192 201
FT STRAND 203 209
FT STRAND 212 220
FT STRAND 221 224
FT STRAND 226 228
FT STRAND 229 231
FT STRAND 234 236
FT HELIX 237 244
FT STRAND 251 253
FT HELIX 342 344
FT HELIX 346 348
FT HELIX 351 353
FT STRAND 361 364
FT HELIX 367 369
FT STRAND 370 372
FT STRAND 376 379
FT STRAND 381 391
FT STRAND 393 403
FT HELIX 406 409
FT HELIX 412 425
FT STRAND 435 449
FT HELIX 456 462
FT HELIX 468 487
FT HELIX 497 499
FT STRAND 500 504
FT STRAND 507 510
FT HELIX 515 518
FT STRAND 524 527
FT HELIX 536 538
FT HELIX 541 546
FT STRAND 548 550
FT HELIX 551 566
FT TURN 567 569
FT TURN 572 575
FT HELIX 578 586
FT HELIX 599 608
FT TURN 613 615
FT HELIX 619 635
SQ SEQUENCE 635 AA; 72066 MW; EAA6BDE65881FC68 CRC64;
MASSGMADSA NHLPFFFGNI TREEAEDYLV QGGMSDGLYL LRQSRNYLGG FALSVAHGRK
AHHYTIEREL NGTYAIAGGR THASPADLCH YHSQESDGLV CLLKKPFNRP QGVQPKTGPF
EDLKENLIRE YVKQTWNLQG QALEQAIISQ KPQLEKLIAT TAHEKMPWFH GKISREESEQ
IVLIGSKTNG KFLIRARDNN GSYALCLLHE GKVLHYRIDK DKTGKLSIPE GKKFDTLWQL
VEHYSYKADG LLRVLTVPCQ KIGTQGNVNF GGRPQLPGSH PATWSAGGII SRIKSYSFPK
PGHRKSSPAQ GNRQESTVSF NPYEPELAPW AADKGPQREA LPMDTEVYES PYADPEEIRP
KEVYLDRKLL TLEDKELGSG NFGTVKKGYY QMKKVVKTVA VKILKNEAND PALKDELLAE
ANVMQQLDNP YIVRMIGICE AESWMLVMEM AELGPLNKYL QQNRHVKDKN IIELVHQVSM
GMKYLEESNF VHRDLAARNV LLVTQHYAKI SDFGLSKALR ADENYYKAQT HGKWPVKWYA
PECINYYKFS SKSDVWSFGV LMWEAFSYGQ KPYRGMKGSE VTAMLEKGER MGCPAGCPRE
MYDLMNLCWT YDVENRPGFA AVELRLRNYY YDVVN
//
