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Q64725

- KSYK_RAT

UniProt

Q64725 - KSYK_RAT

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Protein

Tyrosine-protein kinase SYK

Gene

Syk

Organism
Rattus norvegicus (Rat)
Status
Reviewed - 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.1 Publication

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. 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).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei396 – 3961ATPPROSITE-ProRule annotation
Active sitei488 – 4881Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi371 – 3799ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. non-membrane spanning protein tyrosine kinase activity Source: UniProtKB
  3. protein domain specific binding Source: RGD
  4. protein kinase activity Source: RGD

GO - Biological processi

  1. adaptive immune response Source: UniProtKB
  2. angiogenesis Source: UniProtKB-KW
  3. B cell receptor signaling pathway Source: UniProtKB
  4. blood vessel morphogenesis Source: UniProtKB
  5. cellular response to molecule of fungal origin Source: UniProtKB
  6. defense response to bacterium Source: UniProtKB
  7. innate immune response Source: UniProtKB
  8. integrin-mediated signaling pathway Source: UniProtKB
  9. intracellular signal transduction Source: InterPro
  10. leukocyte activation involved in immune response Source: UniProtKB
  11. leukocyte cell-cell adhesion Source: UniProtKB
  12. lymph vessel development Source: UniProtKB
  13. macrophage activation involved in immune response Source: UniProtKB
  14. neutrophil activation involved in immune response Source: UniProtKB
  15. neutrophil chemotaxis Source: UniProtKB
  16. peptidyl-tyrosine phosphorylation Source: GOC
  17. positive regulation of bone resorption Source: UniProtKB
  18. positive regulation of cell adhesion mediated by integrin Source: UniProtKB
  19. positive regulation of mast cell degranulation Source: RGD
  20. protein autophosphorylation Source: RGD
  21. protein phosphorylation Source: UniProtKB
  22. regulation of arachidonic acid secretion Source: UniProtKB
  23. regulation of ERK1 and ERK2 cascade Source: UniProtKB
  24. regulation of immune response Source: RGD
  25. regulation of neutrophil degranulation Source: UniProtKB
  26. regulation of phagocytosis Source: UniProtKB
  27. regulation of platelet activation Source: UniProtKB
  28. regulation of platelet aggregation Source: UniProtKB
  29. regulation of superoxide anion generation Source: UniProtKB
  30. serotonin secretion by platelet Source: UniProtKB
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. 5301.
ReactomeiREACT_198646. FCGR activation.
REACT_213009. Fc epsilon receptor (FCERI) signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Tyrosine-protein kinase SYK (EC:2.7.10.2)
Alternative name(s):
Spleen tyrosine kinase
p72Syk
Gene namesi
Name:Syk
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494: Unplaced

Organism-specific databases

RGDi3796. Syk.

Subcellular locationi

Cell membrane Curated. Cytoplasmcytosol Curated

GO - Cellular componenti

  1. cytosol Source: Reactome
  2. early phagosome Source: UniProtKB
  3. plasma membrane Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 629629Tyrosine-protein kinase SYKPRO_0000088167Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei27 – 271PhosphotyrosineBy similarity
Modified residuei43 – 431PhosphoserineBy similarity
Modified residuei46 – 461PhosphotyrosineBy similarity
Modified residuei130 – 1301PhosphotyrosineBy similarity
Modified residuei201 – 2011PhosphoserineBy similarity
Modified residuei255 – 2551PhosphothreonineBy similarity
Modified residuei289 – 2891PhosphoserineBy similarity
Modified residuei290 – 2901PhosphotyrosineBy similarity
Modified residuei291 – 2911PhosphoserineBy similarity
Modified residuei310 – 3101PhosphoserineBy similarity
Modified residuei311 – 3111PhosphothreonineBy similarity
Modified residuei313 – 3131PhosphoserineBy similarity
Modified residuei317 – 3171Phosphotyrosine; by LYN1 Publication
Modified residuei339 – 3391PhosphothreonineBy similarity
Modified residuei342 – 3421Phosphotyrosine1 Publication
Modified residuei344 – 3441PhosphoserineBy similarity
Modified residuei346 – 3461Phosphotyrosine1 Publication
Modified residuei358 – 3581PhosphotyrosineBy similarity
Modified residuei373 – 3731PhosphoserineBy similarity
Modified residuei378 – 3781PhosphothreonineBy similarity
Modified residuei478 – 4781PhosphotyrosineBy similarity
Modified residuei501 – 5011PhosphotyrosineBy similarity
Modified residuei519 – 5191Phosphotyrosine; by autocatalysisBy similarity
Modified residuei520 – 5201PhosphotyrosineBy similarity
Modified residuei524 – 5241PhosphothreonineBy similarity
Modified residuei540 – 5401PhosphotyrosineBy similarity
Modified residuei573 – 5731PhosphoserineBy similarity
Modified residuei576 – 5761PhosphothreonineBy similarity
Modified residuei623 – 6231PhosphotyrosineBy similarity
Modified residuei624 – 6241PhosphotyrosineBy similarity
Modified residuei625 – 6251PhosphotyrosineBy similarity

Post-translational modificationi

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

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ64725.
PRIDEiQ64725.

PTM databases

PhosphoSiteiQ64725.

Expressioni

Gene expression databases

GenevestigatoriQ64725.

Interactioni

Subunit structurei

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).By similarity

Protein-protein interaction databases

BioGridi247220. 2 interactions.
IntActiQ64725. 1 interaction.

Structurei

3D structure databases

ProteinModelPortaliQ64725.
SMRiQ64725. Positions 8-261, 357-629.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini14 – 10693SH2 1PROSITE-ProRule annotationAdd
BLAST
Domaini167 – 25892SH2 2PROSITE-ProRule annotationAdd
BLAST
Domaini365 – 625261Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni107 – 16660Interdomain ABy similarityAdd
BLAST
Regioni259 – 364106Interdomain BBy similarityAdd
BLAST

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

eggNOGiCOG0515.
HOGENOMiHOG000113264.
HOVERGENiHBG001540.
InParanoidiQ64725.
KOiK05855.
PhylomeDBiQ64725.

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. 2 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]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. Align

Isoform SykB (identifier: Q64725-1) [UniParc]FASTAAdd to Basket

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.

« Hide

        10         20         30         40         50
MAGNAVDNAN HLTYFFGNIT REEAEDYLVQ GGMTDGLYLL RQSRNYLGGF
60 70 80 90 100
ALSVAHNRKA HHYTIERELN GTYAISGGRA HASPADLCHY HSQEPEGLVC
110 120 130 140 150
LLKKPFNRPP GVQPKTGPFE DLKENLIREY VKQTWNLQGQ ALEQAIISQK
160 170 180 190 200
PQLEKLIATT AHEKMPWFHG NISRDESEQT VLIGSKTNGK FLIRARDNNG
210 220 230 240 250
SFALCLLHEG KVLHYRIDRD KTGKLSIPEG KKFDTLWQLV EHYSYKPDGL
260 270 280 290 300
LRVLTVPCQK IGVQMGHPGS SNAHPVTWSP GGIISRIKSY SFPKPGHKKP
310 320 330 340 350
PPPQGSRPES TVSFNPYEPT GGAWGPDRGL QREALPMDTE VYESPYADPE
360 370 380 390 400
EIRPKEVYLD RKLLTLEDNE LGSGNFGTVK KGYYQMKKVV KTVAVKILKN
410 420 430 440 450
EANDPALKDE LLAEANVMQQ LDNPYIVRMI GICEAESWML VMEMAAWGPL
460 470 480 490 500
NKYLQQNRHI KDKNIIELVH QVSMGMKYLE ESNFVHRDLA ARNVLLVTQH
510 520 530 540 550
YAKISDFGLS KALRADENYY KAQTHGKWPV KWYAPECINY FKFSSKSDVW
560 570 580 590 600
SFGVLMWEAF SYGQKPYRGM KGSEVTAMLE KGERMGCPPG CPREMYDLMF
610 620
LCWTYDVENR PGFAAVELRL RNYYYDVVN
Length:629
Mass (Da):71,529
Last modified:November 1, 1996 - v1
Checksum:i81169A643EC6A6FE
GO
Isoform SykA (identifier: Q64725-2) [UniParc]FASTAAdd to Basket

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

Show »
Length:606
Mass (Da):68,975
Checksum:i084007CC11CDFE0F
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei277 – 29923Missing in isoform SykA. CuratedVSP_005011Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U21684 mRNA. Translation: AAA75167.1.
U21683 mRNA. Translation: AAA75166.1.
RefSeqiNP_036890.1. NM_012758.1. [Q64725-1]
UniGeneiRn.87407.

Genome annotation databases

GeneIDi25155.
KEGGirno:25155.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U21684 mRNA. Translation: AAA75167.1 .
U21683 mRNA. Translation: AAA75166.1 .
RefSeqi NP_036890.1. NM_012758.1. [Q64725-1 ]
UniGenei Rn.87407.

3D structure databases

ProteinModelPortali Q64725.
SMRi Q64725. Positions 8-261, 357-629.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 247220. 2 interactions.
IntActi Q64725. 1 interaction.

Chemistry

BindingDBi Q64725.
ChEMBLi CHEMBL4364.

PTM databases

PhosphoSitei Q64725.

Proteomic databases

PaxDbi Q64725.
PRIDEi Q64725.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

GeneIDi 25155.
KEGGi rno:25155.

Organism-specific databases

CTDi 6850.
RGDi 3796. Syk.

Phylogenomic databases

eggNOGi COG0515.
HOGENOMi HOG000113264.
HOVERGENi HBG001540.
InParanoidi Q64725.
KOi K05855.
PhylomeDBi Q64725.

Enzyme and pathway databases

BRENDAi 2.7.10.2. 5301.
Reactomei REACT_198646. FCGR activation.
REACT_213009. Fc epsilon receptor (FCERI) signaling.

Miscellaneous databases

NextBioi 605611.
PROi Q64725.

Gene expression databases

Genevestigatori Q64725.

Family and domain databases

Gene3Di 1.10.930.10. 1 hit.
3.30.505.10. 2 hits.
InterProi IPR011009. 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 ]
Pfami PF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 2 hits.
[Graphical view ]
PIRSFi PIRSF000604. TyrPK_SYK. 1 hit.
PRINTSi PR00401. SH2DOMAIN.
PR00109. TYRKINASE.
SMARTi SM00252. SH2. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view ]
SUPFAMi SSF55550. SSF55550. 2 hits.
SSF56112. SSF56112. 1 hit.
PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 2 hits.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  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.

Entry informationi

Entry nameiKSYK_RAT
AccessioniPrimary (citable) accession number: Q64725
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: November 1, 1996
Last modified: October 29, 2014
This is version 133 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, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3