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Protein

Tyrosine-protein kinase SYK

Gene

SYK

Organism
Sus scrofa (Pig)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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. In addition to 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. Together with CEACAM20, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response (By similarity).By similarity3 Publications

Catalytic activityi

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

Enzyme regulationi

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.By similarity2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei395ATPPROSITE-ProRule annotation1
Active sitei487Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi370 – 378ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Adaptive immunity, Angiogenesis, Immunity, Innate immunity

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.2. 6170.

Names & Taxonomyi

Protein namesi
Recommended name:
Tyrosine-protein kinase SYK (EC:2.7.10.2)
Alternative name(s):
Spleen tyrosine kinase
Cleaved into the following 2 chains:
Gene namesi
Name:SYK
OrganismiSus scrofa (Pig)
Taxonomic identifieri9823 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaSuinaSuidaeSus
Proteomesi
  • UP000008227 Componenti: Unplaced

Subcellular locationi

72 kDa tyrosine-protein kinase SYK :
40 kDa tyrosine-protein kinase SYK :

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi341Y → F: Alters interaction with VAV1. 1 Publication1
Mutagenesisi345Y → F: Moderately alters interaction with VAV1. 1 Publication1
Mutagenesisi395K → R: Loss of kinase activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000244681 – 62872 kDa tyrosine-protein kinase SYKAdd BLAST628
ChainiPRO_0000024469313 – 62840 kDa tyrosine-protein kinase SYKAdd BLAST316

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei23PhosphotyrosineBy similarity1
Modified residuei39PhosphoserineBy similarity1
Modified residuei42PhosphotyrosineBy similarity1
Modified residuei126PhosphotyrosineBy similarity1
Modified residuei196PhosphoserineBy similarity1
Modified residuei250PhosphothreonineBy similarity1
Modified residuei288PhosphoserineBy similarity1
Modified residuei289PhosphotyrosineBy similarity1
Modified residuei290PhosphoserineBy similarity1
Modified residuei309PhosphoserineBy similarity1
Modified residuei312PhosphoserineBy similarity1
Modified residuei316Phosphotyrosine; by LYNBy similarity1
Modified residuei338PhosphothreonineBy similarity1
Modified residuei341Phosphotyrosine1 Publication1
Modified residuei343PhosphoserineBy similarity1
Modified residuei345PhosphotyrosineBy similarity1
Modified residuei357PhosphotyrosineBy similarity1
Modified residuei372PhosphoserineBy similarity1
Modified residuei377PhosphothreonineBy similarity1
Modified residuei477PhosphotyrosineBy similarity1
Modified residuei500PhosphotyrosineBy similarity1
Modified residuei518Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei519PhosphotyrosineBy similarity1
Modified residuei523PhosphothreonineBy similarity1
Modified residuei539PhosphotyrosineBy similarity1
Modified residuei572PhosphoserineBy similarity1
Modified residuei622PhosphotyrosineBy similarity1
Modified residuei623PhosphotyrosineBy similarity1
Modified residuei624PhosphotyrosineBy similarity1

Post-translational modificationi

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).By similarity
Shows high susceptibility to proteolysis.
Ubiquitinated by CBLB after BCR activation; which promotes proteasomal degradation.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ00655.
PRIDEiQ00655.

PTM databases

iPTMnetiQ00655.

Expressioni

Tissue specificityi

Spleen and with lesser amounts in thymus.

Interactioni

Subunit structurei

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). Interacts (via SH2 domains) with GCSAM; the interaction increases after B-cell receptor stimulation, resulting in enhanced SYK autophosphorylation and activity (By similarity).Interacts with TNS2; leading to the phosphorylation of SYK (By similarity). Interacts with FLNA (via filamin repeat 5); docks SYK to the plasma membrane (By similarity). Interacts CEACAM1; lipopolysaccharide activated neutrophils induce phosphorylation of SYK resulting in the formation of a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome (By similarity). Interacts (via SH2 domains) with CEACAM20 (phosphorylated form); the interaction further enhances CEACAM20 phosphorylation (By similarity).By similarity

GO - Molecular functioni

Protein-protein interaction databases

IntActiQ00655. 1 interactor.
MINTiMINT-6622752.

Structurei

3D structure databases

ProteinModelPortaliQ00655.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini10 – 102SH2 1PROSITE-ProRule annotationAdd BLAST93
Domaini163 – 253SH2 2PROSITE-ProRule annotationAdd BLAST91
Domaini364 – 624Protein kinasePROSITE-ProRule annotationAdd BLAST261

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni103 – 162Interdomain ABy similarityAdd BLAST60
Regioni254 – 363Interdomain BBy similarityAdd BLAST110

Domaini

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).By similarity

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 2 SH2 domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, SH2 domain

Phylogenomic databases

eggNOGiENOG410JR52. Eukaryota.
ENOG4111TV9. LUCA.
HOGENOMiHOG000113264.
HOVERGENiHBG001540.
InParanoidiQ00655.
KOiK05855.

Family and domain databases

Gene3Di1.10.930.10. 1 hit.
3.30.505.10. 2 hits.
InterProiIPR011009. 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]
PfamiPF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 2 hits.
[Graphical view]
PIRSFiPIRSF000604. TyrPK_SYK. 1 hit.
PRINTSiPR00401. SH2DOMAIN.
PR00109. TYRKINASE.
SMARTiSM00252. SH2. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF55550. SSF55550. 3 hits.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 2 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q00655-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MADSANHLPF FFGQITREEA EDYLVQGGMS DGLYLLRQSR NYLGGFALSV
60 70 80 90 100
AYDRKAHHYT IERELNGTYA ISGGRTHGSP AELCHYHSQE LDGLVCLLKN
110 120 130 140 150
PFNRPPGVQP KTGPFEDLKE NLIREYVKQT WNLQGQALEQ AIISQKPQLE
160 170 180 190 200
KLIATTAHEK MPWFHGKISR DESEQIVLIG SKTNGKFLIR ARDNGSYALG
210 220 230 240 250
LLHEGKVLHY RIDKDKTGKL SIPGGKNFDT LWQLVEHYSY KSDGLLRVLT
260 270 280 290 300
VPCQKIGGQT GNDSFRPQLP SAHPATWSAG GIISRIKSYS FPKPGHRKAS
310 320 330 340 350
SPQGNRPESL VSYNPYESDR GPWANEREAQ REALPMDTEV YESPYADPEE
360 370 380 390 400
IRPKEVYLDR KLLTLEDKEL GSGNFGTVKK GYYQMKKVVK TVAVKILKNE
410 420 430 440 450
ANDPALKDEL LAEANVMQQL DNPYIVRMIG ICEAESWMLV MEMAELGPLN
460 470 480 490 500
KYLQQNRHVK DKNIIELVHQ VSMGMKYLEE CNFVHRDLAA RNVLLVTQHY
510 520 530 540 550
AKISDFGLSK ALRADENYYK AQTHGKWPVK WYAPECINYY KFSSKSDVWS
560 570 580 590 600
FGVLMWEAFS YGQKPYRGMK GSEVSAMLEK GERMGCPPGC PREMYELMTL
610 620
CWTYDVENRP GFVAVELRLR NYYYDVVN
Length:628
Mass (Da):71,620
Last modified:April 1, 1993 - v1
Checksum:iD7C0CEF7EBBEBC1E
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M73237 mRNA. Translation: AAA31112.1.
PIRiA40802.
RefSeqiNP_001098422.1. NM_001104952.1.
UniGeneiSsc.55112.

Genome annotation databases

GeneIDi100125540.
KEGGissc:100125540.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M73237 mRNA. Translation: AAA31112.1.
PIRiA40802.
RefSeqiNP_001098422.1. NM_001104952.1.
UniGeneiSsc.55112.

3D structure databases

ProteinModelPortaliQ00655.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ00655. 1 interactor.
MINTiMINT-6622752.

PTM databases

iPTMnetiQ00655.

Proteomic databases

PaxDbiQ00655.
PRIDEiQ00655.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi100125540.
KEGGissc:100125540.

Organism-specific databases

CTDi6850.

Phylogenomic databases

eggNOGiENOG410JR52. Eukaryota.
ENOG4111TV9. LUCA.
HOGENOMiHOG000113264.
HOVERGENiHBG001540.
InParanoidiQ00655.
KOiK05855.

Enzyme and pathway databases

BRENDAi2.7.10.2. 6170.

Family and domain databases

Gene3Di1.10.930.10. 1 hit.
3.30.505.10. 2 hits.
InterProiIPR011009. 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]
PfamiPF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 2 hits.
[Graphical view]
PIRSFiPIRSF000604. TyrPK_SYK. 1 hit.
PRINTSiPR00401. SH2DOMAIN.
PR00109. TYRKINASE.
SMARTiSM00252. SH2. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF55550. SSF55550. 3 hits.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 2 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiKSYK_PIG
AccessioniPrimary (citable) accession number: Q00655
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: April 1, 1993
Last modified: November 30, 2016
This is version 139 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.