P48025 (KSYK_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified May 1, 2013. Version 133. History...
Names and origin
|Protein names||Recommended name:|
Tyrosine-protein kinase SYK
Spleen tyrosine kinase
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||629 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. Ref.7 Ref.8 Ref.10 Ref.12 Ref.14 Ref.15 Ref.16 Ref.18 Ref.19 Ref.22 Ref.23 Ref.24 Ref.25
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Autoinhibited. Intramolecular binding of the interdomains A and B (also called linker region) to parts of the catalytic domain keep the catalytic center in an inactive conformation. The phosphorylation of the interdomains or the binding of the SH2 domains with dually phosphorylated ITAM domains on transmembrane proteins disrupt those intramolecular interactions allowing the kinase domain to adopt an active conformation. The phosphorylation of SYK and of the ITAM domains which is responsible for SYK activation is essentially mediated by SRC subfamily kinases, like LYN, upon transmembrane receptors engagement. May also be negatively regulated by PTPN6 through dephosphorylation By similarity. Downstream signaling adapters and intermediates like BLNK or RHOH may mediate positive and/or negative feedback regulation. Negatively regulated by CBL and CBLB through ubiquitination and probable degradation. Phosphorylates SH3BP2 which in turn may regulate SYK through LYN By similarity. Ref.11 Ref.23
Interacts with LYN; phosphorylates SYK. Interacts with RHOH (phosphorylated); regulates mast cells activation. Interacts with NFAM1 (phosphorylated); probably involved in BCR signaling. Interacts with VAV1 (via SH2 domain); phosphorylates VAV1 upon BCR activation By similarity. Interacts with GAB2 (phosphorylated); probably involved in IgE Fc receptor signaling. Interacts (via its SH2 domains) with CD79A (via its phosphorylated ITAM domain); the interaction stimulates SYK autophosphorylation and activation. Interacts with FCRL3 By similarity. Interacts (via SH2 domains) with FCER1G (via ITAM domain); activates SYK and mediates neutrophils and macrophages integrin-mediated activation. Interacts with ITGB2 and FGR; involved in ITGB2 downstream signaling. Interacts with ITGB3; upon activation by ITGB3 promotes platelet adhesion By similarity. Interacts (via SH2 domains) with TYROBP (via ITAM domain); involved in neutrophils and macrophages integrin-mediated activation. Interacts with MSN and SELPLG; mediates the selectin-dependent activation of SYK by SELPLG By similarity. Interacts with BLNK (via SH2 domain). Interacts (via the second SH2 domain) with USP25 (via C-terminus); phosphorylates USP25 and regulates USP25 intracellular levels By similarity. Interacts (via SH2 domains) with CLEC1B (dimer) By similarity. Interacts with CLEC7A; participates in leukocyte activation in presence of fungal pathogens. Interacts (phosphorylated) with SLA; may regulate SYK through CBL recruitment By similarity. Interacts with YWHAG; attenuates BCR-induced membrane translocation and activation of SYK By similarity. Ref.5 Ref.8 Ref.13 Ref.15 Ref.17 Ref.18 Ref.21 Ref.23
The SH2 domains mediate the interaction of SYK with the phosphorylated ITAM domains of transmembrane proteins. Some proteins like CLEC1B have a partial ITAM domain (also called hemITAM) containing a single YxxL motif. The interaction with SYK requires CLEC1B homodimerization By similarity.
Autophosphorylated. Phosphorylated on tyrosine residues by LYN following receptors engagement. Phosphorylation on Tyr-317 creates a binding site for CBL, an adapter protein that serves as a negative regulator of BCR-stimulated calcium ion signaling. Phosphorylation at Tyr-342 creates a binding site for VAV1 By similarity. Phosphorylation on Tyr-342 and Tyr-346 enhances the phosphorylation and activation of phospholipase C-gamma and the early phase of calcium ion mobilization via a phosphoinositide 3-kinase-independent pathway By similarity. Phosphorylation on Ser-291 is very common, it peaks 5 minutes after BCR stimulation, and creates a binding site for YWHAG By similarity. Phosphorylation at Tyr-624 creates a binding site for BLNK By similarity. Dephosphorylated by PTPN6 By similarity. Ref.4 Ref.8 Ref.9
Ubiquitinated by CBLB after BCR activation; which promotes proteasomal degradation. Ref.11
Embryos display severe systemic hemorrhage and mice are not viable dying perinatally. While T-cells development is not affected, the development of B-cells is impaired most probably at the pro-B to pre-B transition and mice lack mature B-cells. Ref.1 Ref.6
Contains 1 protein kinase domain.
Contains 2 SH2 domains.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 629||629||Tyrosine-protein kinase SYK||PRO_0000088166|
|Domain||14 – 106||93||SH2 1|
|Domain||167 – 258||92||SH2 2|
|Domain||365 – 625||261||Protein kinase|
|Nucleotide binding||371 – 379||9||ATP By similarity|
|Region||107 – 166||60||Interdomain A|
|Region||259 – 364||106||Interdomain B|
|Active site||488||1||Proton acceptor By similarity|
|Binding site||396||1||ATP By similarity|
Amino acid modifications
|Modified residue||27||1||Phosphotyrosine By similarity|
|Modified residue||43||1||Phosphoserine By similarity|
|Modified residue||46||1||Phosphotyrosine By similarity|
|Modified residue||130||1||Phosphotyrosine By similarity|
|Modified residue||201||1||Phosphoserine By similarity|
|Modified residue||255||1||Phosphothreonine By similarity|
|Modified residue||289||1||Phosphoserine By similarity|
|Modified residue||290||1||Phosphotyrosine By similarity|
|Modified residue||291||1||Phosphoserine By similarity|
|Modified residue||310||1||Phosphoserine Ref.20|
|Modified residue||311||1||Phosphothreonine By similarity|
|Modified residue||313||1||Phosphoserine Ref.20|
|Modified residue||317||1||Phosphotyrosine; by LYN Ref.9 Ref.20|
|Modified residue||339||1||Phosphothreonine By similarity|
|Modified residue||342||1||Phosphotyrosine Ref.8 Ref.9 Ref.20|
|Modified residue||344||1||Phosphoserine By similarity|
|Modified residue||346||1||Phosphotyrosine Ref.9 Ref.20|
|Modified residue||358||1||Phosphotyrosine By similarity|
|Modified residue||373||1||Phosphoserine By similarity|
|Modified residue||378||1||Phosphothreonine By similarity|
|Modified residue||478||1||Phosphotyrosine By similarity|
|Modified residue||501||1||Phosphotyrosine By similarity|
|Modified residue||519||1||Phosphotyrosine; by autocatalysis Ref.8 Ref.20|
|Modified residue||520||1||Phosphotyrosine Ref.8 Ref.20|
|Modified residue||524||1||Phosphothreonine By similarity|
|Modified residue||540||1||Phosphotyrosine Ref.20|
|Modified residue||573||1||Phosphoserine By similarity|
|Modified residue||576||1||Phosphothreonine By similarity|
|Modified residue||623||1||Phosphotyrosine Ref.20|
|Modified residue||624||1||Phosphotyrosine Ref.20|
|Modified residue||625||1||Phosphotyrosine By similarity|
|Mutagenesis||41||1||R → A: Loss of interaction with FCER1G and TYROBP; when associated with A-194. Ref.18|
|Mutagenesis||194||1||R → A: Loss of interaction with FCER1G and TYROBP; when associated with A-41. Ref.18|
|Sequence conflict||326||1||Missing in CAA90034. Ref.2|
|Sequence conflict||446 – 447||2||EL → DV in CAA90034. Ref.2|
Helix Strand Turn
|Beta strand||346 – 348||3|
|||"Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk."|
Turner M., Mee P.J., Costello P.S., Williams O., Price A.A., Duddy L.P., Furlong M.T., Geahlen R.L., Tybulewicz V.L.
Nature 378:298-302(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], DISRUPTION PHENOTYPE.
|||"Molecular characterization of the murine syk protein tyrosine kinase cDNA, transcripts and protein."|
Flueck M., Zuercher G., Andres A., Ziemiecki A.
Biochem. Biophys. Res. Commun. 213:273-281(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||Richards J.D., Gold M.R., Hourihane S.L., Defranco A.L., Matsuuchi L.|
Submitted (SEP-1995) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling."|
Kurosaki T., Takata M., Yamanashi Y., Inazu T., Taniguchi T., Yamamoto T., Yamamura H.
J. Exp. Med. 179:1725-1729(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY LYN.
|||"Syk protein-tyrosine kinase is regulated by tyrosine-phosphorylated Ig alpha/Ig beta immunoreceptor tyrosine activation motif binding and autophosphorylation."|
Rowley R.B., Burkhardt A.L., Chao H.-G., Matsueda G.R., Bolen J.B.
J. Biol. Chem. 270:11590-11594(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CD79A.
|||"Syk tyrosine kinase required for mouse viability and B-cell development."|
Cheng A.M., Rowley B., Pao W., Hayday A., Bolen J.B., Pawson T.
Nature 378:303-306(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
|||"The Fc receptor gamma-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen."|
Poole A., Gibbins J.M., Turner M., van Vugt M.J., van de Winkel J.G., Saito T., Tybulewicz V.L., Watson S.P.
EMBO J. 16:2333-2341(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ACTIVATION OF PLATELETS BY COLLAGEN, FUNCTION IN PLCG2 PHOSPHORYLATION.
|||"Inhibition of beta 2 integrin receptor and Syk kinase signaling in monocytes by the Src family kinase Fgr."|
Vines C.M., Potter J.W., Xu Y., Geahlen R.L., Costello P.S., Tybulewicz V.L., Lowell C.A., Chang P.W., Gresham H.D., Willman C.L.
Immunity 15:507-519(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN INTEGRIN SIGNALING, PHOSPHORYLATION AT TYR-342; TYR-519 AND TYR-520, INTERACTION WITH ITGB2 AND FGR.
|||"Regulation of signaling in B cells through the phosphorylation of Syk on linker region tyrosines. A mechanism for negative signaling by the Lyn tyrosine kinase."|
Hong J.J., Yankee T.M., Harrison M.L., Geahlen R.L.
J. Biol. Chem. 277:31703-31714(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-317; TYR-342 AND TYR-346.
|||"Coordinate interactions of Csk, Src, and Syk kinases with [alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton."|
Obergfell A., Eto K., Mocsai A., Buensuceso C., Moores S.L., Brugge J.S., Lowell C.A., Shattil S.J.
J. Cell Biol. 157:265-275(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN INTEGRIN-MEDIATED PLATELET ADHESION.
|||"Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk."|
Sohn H.W., Gu H., Pierce S.K.
J. Exp. Med. 197:1511-1524(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION BY CBLB, ENZYME REGULATION.
|||"Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk."|
Abtahian F., Guerriero A., Sebzda E., Lu M.M., Zhou R., Mocsai A., Myers E.E., Huang B., Jackson D.G., Ferrari V.A., Tybulewicz V., Lowell C.A., Lepore J.J., Koretzky G.A., Kahn M.L.
Science 299:247-251(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN VASCULAR DEVELOPMENT.
|||"NFAM1, an immunoreceptor tyrosine-based activation motif-bearing molecule that regulates B cell development and signaling."|
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.
Proc. Natl. Acad. Sci. U.S.A. 101:8126-8131(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NFAM1.
|||"Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production."|
Underhill D.M., Rossnagle E., Lowell C.A., Simmons R.M.
Blood 106:2543-2550(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ROS PRODUCTION, FUNCTION IN RESPONSE TO FUNGAL PATHOGEN.
|||"Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins."|
Rogers N.C., Slack E.C., Edwards A.D., Nolte M.A., Schulz O., Schweighoffer E., Williams D.L., Gordon S., Tybulewicz V.L., Brown G.D., Reis e Sousa C.
Immunity 22:507-517(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN RESPONSE TO FUNGAL PATHOGEN, INTERACTION WITH CLEC7A, SUBCELLULAR LOCATION.
|||"A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2."|
Suzuki-Inoue K., Fuller G.L.J., Garcia A., Eble J.A., Poehlmann S., Inoue O., Gartner T.K., Hughan S.C., Pearce A.C., Laing G.D., Theakston R.D.G., Schweighoffer E., Zitzmann N., Morita T., Tybulewicz V.L.J., Ozaki Y., Watson S.P.
Blood 107:542-549(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ACTIVATION OF PLATELETS BY CLEC1B.
|||"Scaffolding adapter Grb2-associated binder 2 requires Syk to transmit signals from FcepsilonRI."|
Yu M., Lowell C.A., Neel B.G., Gu H.
J. Immunol. 176:2421-2429(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH GAB2.
|||"Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs."|
Mocsai A., Abram C.L., Jakus Z., Hu Y., Lanier L.L., Lowell C.A.
Nat. Immunol. 7:1326-1333(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN INTEGRIN-MEDIATED NEUTROPHIL ACTIVATION, INTERACTION WITH FCER1G AND TYROBP, MUTAGENESIS OF ARG-41 AND ARG-194.
|||"Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption."|
Zou W., Kitaura H., Reeve J., Long F., Tybulewicz V.L., Shattil S.J., Ginsberg M.H., Ross F.P., Teitelbaum S.L.
J. Cell Biol. 176:877-888(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN OSTEOCLASTIC BONE RESORPTION.
|||"Quantitative time-resolved phosphoproteomic analysis of mast cell signaling."|
Cao L., Yu K., Banh C., Nguyen V., Ritz A., Raphael B.J., Kawakami Y., Kawakami T., Salomon A.R.
J. Immunol. 179:5864-5876(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-310; SER-313; TYR-317; TYR-342; TYR-346; TYR-519; TYR-520; TYR-540; TYR-623 AND TYR-624, MASS SPECTROMETRY.
Tissue: Mast cell.
|||"The kinase Syk as an adaptor controlling sustained calcium signalling and B-cell development."|
Kulathu Y., Hobeika E., Turchinovich G., Reth M.
EMBO J. 27:1333-1344(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH BLNK.
|||"Neutrophil-specific deletion of Syk kinase results in reduced host defense to bacterial infection."|
Van Ziffle J.A., Lowell C.A.
Blood 114:4871-4882(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN RESPONSE TO BACTERIA.
|||"RhoH plays critical roles in Fc epsilon RI-dependent signal transduction in mast cells."|
Oda H., Fujimoto M., Patrick M.S., Chida D., Sato Y., Azuma Y., Aoki H., Abe T., Suzuki H., Shirai M.
J. Immunol. 182:957-962(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN MAST CELL ACTIVATION, INTERACTION WITH RHOH, ENZYME REGULATION.
|||"Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence."|
Gross O., Poeck H., Bscheider M., Dostert C., Hannesschlaeger N., Endres S., Hartmann G., Tardivel A., Schweighoffer E., Tybulewicz V., Mocsai A., Tschopp J., Ruland J.
Nature 459:433-436(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN RESPONSE TO FUNGAL PATHOGEN, FUNCTION IN INFLAMMASOME ACTIVATION, FUNCTION IN REGULATION OF TRANSCRIPTION.
|||"Identification of a dendritic cell receptor that couples sensing of necrosis to immunity."|
Sancho D., Joffre O.P., Keller A.M., Rogers N.C., Martinez D., Hernanz-Falcon P., Rosewell I., Reis e Sousa C.
Nature 458:899-903(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN IMMUNE SYSTEM STIMULATION BY CELL NECROSIS.
|+||Additional computationally mapped references.|
|U25685 mRNA. Translation: AAA87462.1.|
Z49877 mRNA. Translation: CAA90034.1.
U36776 mRNA. Translation: AAA79996.1.
|RefSeq||NP_001185906.1. NM_001198977.1. |
3D structure databases
|SMR||P48025. Positions 8-629. |
Protein-protein interaction databases
|IntAct||P48025. 6 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000055087; ENSMUSP00000060828; ENSMUSG00000021457. |
ENSMUST00000120135; ENSMUSP00000113852; ENSMUSG00000021457.
|MGI||MGI:99515. Syk. |
Enzyme and pathway databases
|BRENDA||18.104.22.168. 3474. |
|Reactome||REACT_89750. Hemostasis. |
Gene expression databases
|GermOnline||ENSMUSG00000021457. Mus musculus. |
Family and domain databases
|Gene3D||1.10.930.10. 1 hit. |
3.30.505.10. 2 hits.
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF07714. Pkinase_Tyr. 1 hit. |
PF00017. SH2. 2 hits.
|PIRSF||PIRSF000604. TyrPK_SYK. 1 hit. |
|PRINTS||PR00401. SH2DOMAIN. |
|SMART||SM00252. SH2. 2 hits. |
SM00219. TyrKc. 1 hit.
|SUPFAM||SSF56112. Kinase_like. 1 hit. |
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 2 hits.
|ChiTaRS||SYK. mouse. |
|Accession||Primary (citable) accession number: P48025|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
|Human and mouse protein kinases|
Human and mouse protein kinases: classification and index
Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
Index of Protein Data Bank (PDB) cross-references
Index of protein domains and families