Q00655 (KSYK_PIG) Reviewed, UniProtKB/Swiss-Prot
Last modified May 29, 2013. Version 119. History...
Names and origin
|Protein names||Recommended name:|
Tyrosine-protein kinase SYK
Spleen tyrosine kinase
|Organism||Sus scrofa (Pig) [Reference proteome]|
|Taxonomic identifier||9823 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Laurasiatheria › Cetartiodactyla › Suina › Suidae › Sus|
|Sequence length||628 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|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.3 Ref.4 Ref.5
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 By similarity. 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 By similarity. Negatively regulated by CBL and CBLB through ubiquitination and probable degradation By similarity. Phosphorylates SH3BP2 which in turn may regulate SYK through LYN. Ref.5 Ref.6
Interacts with LYN; phosphorylates SYK. Interacts with RHOH (phosphorylated); regulates mast cells activation By similarity. Interacts with NFAM1 (phosphorylated); probably involved in BCR signaling By similarity. Interacts with VAV1 (via SH2 domain); phosphorylates VAV1 upon BCR activation. Interacts with GAB2 (phosphorylated); probably involved in IgE Fc receptor signaling By similarity. Interacts (via its SH2 domains) with CD79A (via its phosphorylated ITAM domain); the interaction stimulates SYK autophosphorylation and activation By similarity. Interacts with FCRL3 By similarity. Interacts (via SH2 domains) with FCER1G (via ITAM domain); activates SYK and mediates neutrophils and macrophages integrin-mediated activation By similarity. Interacts with ITGB2 and FGR; involved in ITGB2 downstream signaling By similarity. 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 By similarity. Interacts with MSN and SELPLG; mediates the selectin-dependent activation of SYK by SELPLG By similarity. Interacts with BLNK (via SH2 domain) By similarity. 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 By similarity. 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.2 Ref.3
Spleen and with lesser amounts in thymus.
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-316 creates a binding site for CBL, an adapter protein that serves as a negative regulator of BCR-stimulated calcium ion signaling. Phosphorylation at Tyr-341 creates a binding site for VAV1 By similarity. Phosphorylation on Tyr-341 and Tyr-345 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-290 is very common, it peaks 5 minutes after BCR stimulation, and creates a binding site for YWHAG By similarity. Phosphorylation at Tyr-623 creates a binding site for BLNK By similarity. Dephosphorylated by PTPN6 By similarity. Ref.2 Ref.3
Shows high susceptibility to proteolysis.
Ubiquitinated by CBLB after BCR activation; which promotes proteasomal degradation By similarity.
Contains 1 protein kinase domain.
Contains 2 SH2 domains.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 628||628||72 kDa tyrosine-protein kinase SYK||PRO_0000024468|
|Chain||313 – 628||316||40 kDa tyrosine-protein kinase SYK||PRO_0000024469|
|Domain||10 – 102||93||SH2 1|
|Domain||163 – 253||91||SH2 2|
|Domain||364 – 624||261||Protein kinase|
|Nucleotide binding||370 – 378||9||ATP By similarity|
|Region||103 – 162||60||Interdomain A By similarity|
|Region||254 – 363||110||Interdomain B By similarity|
|Active site||487||1||Proton acceptor By similarity|
|Binding site||395||1||ATP By similarity|
Amino acid modifications
|Modified residue||23||1||Phosphotyrosine By similarity|
|Modified residue||39||1||Phosphoserine By similarity|
|Modified residue||42||1||Phosphotyrosine By similarity|
|Modified residue||126||1||Phosphotyrosine By similarity|
|Modified residue||196||1||Phosphoserine By similarity|
|Modified residue||250||1||Phosphothreonine By similarity|
|Modified residue||288||1||Phosphoserine By similarity|
|Modified residue||289||1||Phosphotyrosine By similarity|
|Modified residue||290||1||Phosphoserine By similarity|
|Modified residue||309||1||Phosphoserine By similarity|
|Modified residue||312||1||Phosphoserine By similarity|
|Modified residue||316||1||Phosphotyrosine; by LYN By similarity|
|Modified residue||338||1||Phosphothreonine By similarity|
|Modified residue||341||1||Phosphotyrosine Ref.3|
|Modified residue||343||1||Phosphoserine By similarity|
|Modified residue||345||1||Phosphotyrosine By similarity|
|Modified residue||357||1||Phosphotyrosine By similarity|
|Modified residue||372||1||Phosphoserine By similarity|
|Modified residue||377||1||Phosphothreonine By similarity|
|Modified residue||477||1||Phosphotyrosine By similarity|
|Modified residue||500||1||Phosphotyrosine By similarity|
|Modified residue||518||1||Phosphotyrosine; by autocatalysis By similarity|
|Modified residue||519||1||Phosphotyrosine By similarity|
|Modified residue||523||1||Phosphothreonine By similarity|
|Modified residue||539||1||Phosphotyrosine By similarity|
|Modified residue||572||1||Phosphoserine By similarity|
|Modified residue||622||1||Phosphotyrosine By similarity|
|Modified residue||623||1||Phosphotyrosine By similarity|
|Modified residue||624||1||Phosphotyrosine By similarity|
|Mutagenesis||341||1||Y → F: Alters interaction with VAV1. Ref.3|
|Mutagenesis||345||1||Y → F: Moderately alters interaction with VAV1. Ref.3|
|Mutagenesis||395||1||K → R: Loss of kinase activity. Ref.5|
|||"Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis."|
Taniguchi T., Kobayashi T., Kondo J., Takahashi K., Nakamura H., Suzuki J., Nagai K., Yamada T., Nakamura S., Yamamura H.
J. Biol. Chem. 266:15790-15796(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 313-333; 346-354 AND 369-379.
|||"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, INTERACTION WITH LYN, AUTOPHOSPHORYLATION.
|||"Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product."|
Deckert M., Tartare-Deckert S., Couture C., Mustelin T., Altman A.
Immunity 5:591-604(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN TRANSCRIPTION REGULATION, INTERACTION WITH VAV1, MUTAGENESIS OF TYR-341 AND TYR-345, PHOSPHORYLATION AT TYR-341.
|||"BLNK mediates Syk-dependent Btk activation."|
Baba Y., Hashimoto S., Matsushita M., Watanabe D., Kishimoto T., Kurosaki T., Tsukada S.
Proc. Natl. Acad. Sci. U.S.A. 98:2582-2586(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF BTK.
|||"Adaptor protein 3BP2 is a potential ligand of Src homology 2 and 3 domains of Lyn protein-tyrosine kinase."|
Maeno K., Sada K., Kyo S., Miah S.M., Kawauchi-Kamata K., Qu X., Shi Y., Yamamura H.
J. Biol. Chem. 278:24912-24920(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF SH3BP2, MUTAGENESIS OF LYS-395, ENZYME REGULATION.
|||"Interdomain A is crucial for ITAM-dependent and -independent regulation of Syk."|
Adachi T., Wienands J., Tsubata T., Kurosaki T.
Biochem. Biophys. Res. Commun. 364:111-117(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION.
|M73237 mRNA. Translation: AAA31112.1.|
|RefSeq||NP_001098422.1. NM_001104952.1. |
3D structure databases
|SMR||Q00655. Positions 4-256, 356-628. |
Protein-protein interaction databases
Protocols and materials databases
Genome annotation databases
Enzyme and pathway databases
|BRENDA||126.96.36.199. 6170. |
|Reactome||REACT_85674. Hemostasis. |
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.
|Accession||Primary (citable) accession number: Q00655|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families