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Q64725 (KSYK_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified June 11, 2014. Version 130. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Tyrosine-protein kinase SYK

EC=2.7.10.2
Alternative name(s):
Spleen tyrosine kinase
p72Syk
Gene names
Name:Syk
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length629 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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.2

Catalytic activity

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

Enzyme regulation

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. 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 By similarity. Phosphorylates SH3BP2 which in turn may regulate SYK through LYN By similarity.

Subunit structure

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. 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. 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. 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. Interacts with BLNK (via SH2 domain). Interacts (via the second SH2 domain) with USP25 (via C-terminus); phosphorylates USP25 and regulates USP25 intracellular levels. Interacts (via SH2 domains) with CLEC1B (dimer). Interacts with CLEC7A; participates in leukocyte activation in presence of fungal pathogens. Interacts (phosphorylated) with SLA; may regulate SYK through CBL recruitment. Interacts with YWHAG; attenuates BCR-induced membrane translocation and activation of SYK By similarity. Interacts (via SH2 domains) with GCSAM; the interaction increases after B-cell receptor stimulation, resulting in enhanced SYK autophosphorylation and activity By similarity.

Subcellular location

Cell membrane Probable. Cytoplasmcytosol Probable.

Domain

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.

Post-translational modification

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 By similarity. 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.3

Ubiquitinated by CBLB after BCR activation; which promotes proteasomal degradation By similarity.

Sequence similarities

Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily.

Contains 1 protein kinase domain.

Contains 2 SH2 domains.

Ontologies

Keywords
   Biological processAdaptive immunity
Angiogenesis
Immunity
Innate immunity
   Cellular componentCell membrane
Cytoplasm
Membrane
   Coding sequence diversityAlternative splicing
   DomainRepeat
SH2 domain
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Transferase
Tyrosine-protein kinase
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processB cell receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

adaptive immune response

Inferred from sequence or structural similarity. Source: UniProtKB

angiogenesis

Inferred from electronic annotation. Source: UniProtKB-KW

blood vessel morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to molecule of fungal origin

Inferred from sequence or structural similarity. Source: UniProtKB

defense response to bacterium

Inferred from sequence or structural similarity. Source: UniProtKB

innate immune response

Inferred from sequence or structural similarity. Source: UniProtKB

integrin-mediated signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

intracellular signal transduction

Inferred from electronic annotation. Source: InterPro

leukocyte activation involved in immune response

Inferred from sequence or structural similarity. Source: UniProtKB

leukocyte cell-cell adhesion

Inferred from sequence or structural similarity. Source: UniProtKB

lymph vessel development

Inferred from sequence or structural similarity. Source: UniProtKB

macrophage activation involved in immune response

Inferred from sequence or structural similarity. Source: UniProtKB

neutrophil activation involved in immune response

Inferred from sequence or structural similarity. Source: UniProtKB

neutrophil chemotaxis

Inferred from sequence or structural similarity. Source: UniProtKB

peptidyl-tyrosine phosphorylation

Inferred from sequence or structural similarity. Source: GOC

positive regulation of bone resorption

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of cell adhesion mediated by integrin

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of mast cell degranulation

Inferred from mutant phenotype PubMed 16861349. Source: RGD

protein autophosphorylation

Inferred from direct assay PubMed 16861349. Source: RGD

protein phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of ERK1 and ERK2 cascade

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of arachidonic acid secretion

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of immune response

Inferred from direct assay PubMed 12417718. Source: RGD

regulation of neutrophil degranulation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of phagocytosis

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of platelet activation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of platelet aggregation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of superoxide anion generation

Inferred from sequence or structural similarity. Source: UniProtKB

serotonin secretion by platelet

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

early phagosome

Inferred from sequence or structural similarity. Source: UniProtKB

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

non-membrane spanning protein tyrosine kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 18579528. Source: UniProtKB

protein domain specific binding

Inferred from mutant phenotype PubMed 16861349. Source: RGD

protein kinase activity

Inferred from direct assay PubMed 16861349. Source: RGD

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform SykB (identifier: Q64725-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform SykA (identifier: Q64725-2)

The sequence of this isoform differs from the canonical sequence as follows:
     277-299: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 629629Tyrosine-protein kinase SYK
PRO_0000088167

Regions

Domain14 – 10693SH2 1
Domain167 – 25892SH2 2
Domain365 – 625261Protein kinase
Nucleotide binding371 – 3799ATP By similarity
Region107 – 16660Interdomain A By similarity
Region259 – 364106Interdomain B By similarity

Sites

Active site4881Proton acceptor By similarity
Binding site3961ATP By similarity

Amino acid modifications

Modified residue271Phosphotyrosine By similarity
Modified residue431Phosphoserine By similarity
Modified residue461Phosphotyrosine By similarity
Modified residue1301Phosphotyrosine By similarity
Modified residue2011Phosphoserine By similarity
Modified residue2551Phosphothreonine By similarity
Modified residue2891Phosphoserine By similarity
Modified residue2901Phosphotyrosine By similarity
Modified residue2911Phosphoserine By similarity
Modified residue3101Phosphoserine By similarity
Modified residue3111Phosphothreonine By similarity
Modified residue3131Phosphoserine By similarity
Modified residue3171Phosphotyrosine; by LYN Ref.3
Modified residue3391Phosphothreonine By similarity
Modified residue3421Phosphotyrosine Ref.3
Modified residue3441Phosphoserine By similarity
Modified residue3461Phosphotyrosine Ref.3
Modified residue3581Phosphotyrosine By similarity
Modified residue3731Phosphoserine By similarity
Modified residue3781Phosphothreonine By similarity
Modified residue4781Phosphotyrosine By similarity
Modified residue5011Phosphotyrosine By similarity
Modified residue5191Phosphotyrosine; by autocatalysis By similarity
Modified residue5201Phosphotyrosine By similarity
Modified residue5241Phosphothreonine By similarity
Modified residue5401Phosphotyrosine By similarity
Modified residue5731Phosphoserine By similarity
Modified residue5761Phosphothreonine By similarity
Modified residue6231Phosphotyrosine By similarity
Modified residue6241Phosphotyrosine By similarity
Modified residue6251Phosphotyrosine By similarity

Natural variations

Alternative sequence277 – 29923Missing in isoform SykA.
VSP_005011

Sequences

Sequence LengthMass (Da)Tools
Isoform SykB [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 81169A643EC6A6FE

FASTA62971,529
        10         20         30         40         50         60 
MAGNAVDNAN HLTYFFGNIT REEAEDYLVQ GGMTDGLYLL RQSRNYLGGF ALSVAHNRKA 

        70         80         90        100        110        120 
HHYTIERELN GTYAISGGRA HASPADLCHY HSQEPEGLVC LLKKPFNRPP GVQPKTGPFE 

       130        140        150        160        170        180 
DLKENLIREY VKQTWNLQGQ ALEQAIISQK PQLEKLIATT AHEKMPWFHG NISRDESEQT 

       190        200        210        220        230        240 
VLIGSKTNGK FLIRARDNNG SFALCLLHEG KVLHYRIDRD KTGKLSIPEG KKFDTLWQLV 

       250        260        270        280        290        300 
EHYSYKPDGL LRVLTVPCQK IGVQMGHPGS SNAHPVTWSP GGIISRIKSY SFPKPGHKKP 

       310        320        330        340        350        360 
PPPQGSRPES TVSFNPYEPT GGAWGPDRGL QREALPMDTE VYESPYADPE EIRPKEVYLD 

       370        380        390        400        410        420 
RKLLTLEDNE LGSGNFGTVK KGYYQMKKVV KTVAVKILKN EANDPALKDE LLAEANVMQQ 

       430        440        450        460        470        480 
LDNPYIVRMI GICEAESWML VMEMAAWGPL NKYLQQNRHI KDKNIIELVH QVSMGMKYLE 

       490        500        510        520        530        540 
ESNFVHRDLA ARNVLLVTQH YAKISDFGLS KALRADENYY KAQTHGKWPV KWYAPECINY 

       550        560        570        580        590        600 
FKFSSKSDVW SFGVLMWEAF SYGQKPYRGM KGSEVTAMLE KGERMGCPPG CPREMYDLMF 

       610        620 
LCWTYDVENR PGFAAVELRL RNYYYDVVN 

« Hide

Isoform SykA [UniParc].

Checksum: 084007CC11CDFE0F
Show »

FASTA60668,975

References

[1]"Molecular cloning of rodent p72Syk. Evidence of alternative mRNA splicing."
Rowley R.B., Bolen J.B., Fargnoli J.
J. Biol. Chem. 270:12659-12664(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], ALTERNATIVE SPLICING (ISOFORMS SYKA AND SYKB).
[2]"SH2 domains mediate the sequential phosphorylation of HS1 protein by p72syk and Src-related protein tyrosine kinases."
Ruzzene M., Brunati A.M., Marin O., Donella-Deana A., Pinna L.A.
Biochemistry 35:5327-5332(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF HCLS1.
[3]"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 BY LYN, PHOSPHORYLATION AT TYR-342 AND TYR-346.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U21684 mRNA. Translation: AAA75167.1.
U21683 mRNA. Translation: AAA75166.1.
RefSeqNP_036890.1. NM_012758.1. [Q64725-1]
UniGeneRn.87407.

3D structure databases

ProteinModelPortalQ64725.
SMRQ64725. Positions 8-261, 357-629.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid247220. 2 interactions.
IntActQ64725. 1 interaction.

Chemistry

BindingDBQ64725.
ChEMBLCHEMBL4364.

PTM databases

PhosphoSiteQ64725.

Proteomic databases

PaxDbQ64725.
PRIDEQ64725.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID25155.
KEGGrno:25155.

Organism-specific databases

CTD6850.
RGD3796. Syk.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000113264.
HOVERGENHBG001540.
InParanoidQ64725.
KOK05855.
PhylomeDBQ64725.

Enzyme and pathway databases

BRENDA2.7.10.2. 5301.
ReactomeREACT_227097. Immune System.

Gene expression databases

GenevestigatorQ64725.

Family and domain databases

Gene3D1.10.930.10. 1 hit.
3.30.505.10. 2 hits.
InterProIPR011009. Kinase-like_dom.
IPR023420. Kinase_SYK/ZAP-70_inter-SH2.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR000980. SH2.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR012234. Tyr_kinase_non-rcpt_SYK/ZAP70.
[Graphical view]
PfamPF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 2 hits.
[Graphical view]
PIRSFPIRSF000604. TyrPK_SYK. 1 hit.
PRINTSPR00401. SH2DOMAIN.
PR00109. TYRKINASE.
SMARTSM00252. SH2. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF55550. SSF55550. 2 hits.
SSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

NextBio605611.
PROQ64725.

Entry information

Entry nameKSYK_RAT
AccessionPrimary (citable) accession number: Q64725
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: November 1, 1996
Last modified: June 11, 2014
This is version 130 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families