Tyrosine-protein kinase SYK - Sus scrofa (Pig)

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Q00655 (KSYK_PIG) Reviewed, UniProtKB/Swiss-Prot

Last modified May 29, 2013. Version 119. History...

Clusters with 100%, 90%, 50% identity |

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Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents Customize order

Names and origin

Protein names

Recommended name:
Tyrosine-protein kinase SYK
EC=2.7.10.2

Alternative name(s):
Spleen tyrosine kinase

Gene names

Name:

SYK

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

Protein attributes

Sequence length	628 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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.3 Ref.4 Ref.5
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 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
Subunit structure	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
Subcellular location	72 kDa tyrosine-protein kinase SYK: Cell membrane Probable. Cytoplasm › cytosol. Note: Mainly associated with membranes. 40 kDa tyrosine-protein kinase SYK: Cell membrane Probable. Cytoplasm › cytosol. Note: Equally distributed between membranes and cytosol.
Tissue specificity	Spleen and with lesser amounts in thymus.
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-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.
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 process	Adaptive immunity Angiogenesis Immunity Innate immunity
Cellular component	Cell membrane Cytoplasm Membrane
Domain	Repeat SH2 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	B 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 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 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 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 neutrophil degranulation Inferred from sequence or structural similarity. Source: UniProtKB regulation of phagocytosis 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_component	cytosol 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_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW non-membrane spanning protein tyrosine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 628

628

72 kDa tyrosine-protein kinase SYK

PRO_0000024468

Chain

313 – 628

316

40 kDa tyrosine-protein kinase SYK

PRO_0000024469

Regions

Domain

10 – 102

SH2 1

Domain

163 – 253

SH2 2

Domain

364 – 624

261

Protein kinase

Nucleotide binding

370 – 378

ATP By similarity

Region

103 – 162

Interdomain A By similarity

Region

254 – 363

110

Interdomain B By similarity

Sites

Active site

487

Proton acceptor By similarity

Binding site

395

ATP By similarity

Amino acid modifications

Modified residue

Phosphotyrosine By similarity

Modified residue

Phosphoserine By similarity

Modified residue

Phosphotyrosine By similarity

Modified residue

126

Phosphotyrosine By similarity

Modified residue

196

Phosphoserine By similarity

Modified residue

250

Phosphothreonine By similarity

Modified residue

288

Phosphoserine By similarity

Modified residue

289

Phosphotyrosine By similarity

Modified residue

290

Phosphoserine By similarity

Modified residue

309

Phosphoserine By similarity

Modified residue

312

Phosphoserine By similarity

Modified residue

316

Phosphotyrosine; by LYN By similarity

Modified residue

338

Phosphothreonine By similarity

Modified residue

341

Phosphotyrosine Ref.3

Modified residue

343

Phosphoserine By similarity

Modified residue

345

Phosphotyrosine By similarity

Modified residue

357

Phosphotyrosine By similarity

Modified residue

372

Phosphoserine By similarity

Modified residue

377

Phosphothreonine By similarity

Modified residue

477

Phosphotyrosine By similarity

Modified residue

500

Phosphotyrosine By similarity

Modified residue

518

Phosphotyrosine; by autocatalysis By similarity

Modified residue

519

Phosphotyrosine By similarity

Modified residue

523

Phosphothreonine By similarity

Modified residue

539

Phosphotyrosine By similarity

Modified residue

572

Phosphoserine By similarity

Modified residue

622

Phosphotyrosine By similarity

Modified residue

623

Phosphotyrosine By similarity

Modified residue

624

Phosphotyrosine By similarity

Experimental info

Mutagenesis

341

Y → F: Alters interaction with VAV1. Ref.3

Mutagenesis

345

Y → F: Moderately alters interaction with VAV1. Ref.3

Mutagenesis

395

K → R: Loss of kinase activity. Ref.5

Sequences

Sequence

Length

Mass (Da)

Tools

Q00655 [UniParc].

Last modified April 1, 1993. Version 1.
Checksum: D7C0CEF7EBBEBC1E
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FASTA

628

71,620

        10         20         30         40         50         60 
MADSANHLPF FFGQITREEA EDYLVQGGMS DGLYLLRQSR NYLGGFALSV AYDRKAHHYT 

        70         80         90        100        110        120 
IERELNGTYA ISGGRTHGSP AELCHYHSQE LDGLVCLLKN PFNRPPGVQP KTGPFEDLKE 

       130        140        150        160        170        180 
NLIREYVKQT WNLQGQALEQ AIISQKPQLE KLIATTAHEK MPWFHGKISR DESEQIVLIG 

       190        200        210        220        230        240 
SKTNGKFLIR ARDNGSYALG LLHEGKVLHY RIDKDKTGKL SIPGGKNFDT LWQLVEHYSY 

       250        260        270        280        290        300 
KSDGLLRVLT VPCQKIGGQT GNDSFRPQLP SAHPATWSAG GIISRIKSYS FPKPGHRKAS 

       310        320        330        340        350        360 
SPQGNRPESL VSYNPYESDR GPWANEREAQ REALPMDTEV YESPYADPEE IRPKEVYLDR 

       370        380        390        400        410        420 
KLLTLEDKEL GSGNFGTVKK GYYQMKKVVK TVAVKILKNE ANDPALKDEL LAEANVMQQL 

       430        440        450        460        470        480 
DNPYIVRMIG ICEAESWMLV MEMAELGPLN KYLQQNRHVK DKNIIELVHQ VSMGMKYLEE 

       490        500        510        520        530        540 
CNFVHRDLAA RNVLLVTQHY AKISDFGLSK ALRADENYYK AQTHGKWPVK WYAPECINYY 

       550        560        570        580        590        600 
KFSSKSDVWS FGVLMWEAFS YGQKPYRGMK GSEVSAMLEK GERMGCPPGC PREMYELMTL 

       610        620 
CWTYDVENRP GFVAVELRLR NYYYDVVN

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References

[1]	"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. Tissue: Spleen.
[2]	"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.
[3]	"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.
[4]	"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.
[5]	"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.
[6]	"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.

Cross-references

Sequence databases
EMBL GenBank DDBJ	M73237 mRNA. Translation: AAA31112.1.
PIR	A40802.
RefSeq	NP_001098422.1. NM_001104952.1.
UniGene	Ssc.55112.
3D structure databases
ProteinModelPortal	Q00655.
SMR	Q00655. Positions 4-256, 356-628.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-6622752.
STRING	9823.ENSSSCP00000010237.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	100125540.
KEGG	ssc:100125540.
Organism-specific databases
CTD	6850.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000113264.
HOVERGEN	HBG001540.
KO	K05855.
OrthoDB	EOG4WSW93.
Enzyme and pathway databases
BRENDA	2.7.10.2. 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. IPR023420. Kinase_SYK/ZAP-70_inter-SH2. IPR000719. Prot_kinase_cat_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]
Pfam	PF07714. Pkinase_Tyr. 1 hit. PF00017. SH2. 2 hits. [Graphical view]
PIRSF	PIRSF000604. TyrPK_SYK. 1 hit.
PRINTS	PR00401. SH2DOMAIN. PR00109. TYRKINASE.
SMART	SM00252. SH2. 2 hits. SM00219. TyrKc. 1 hit. [Graphical view]
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. [Graphical view]
ProtoNet	Search...

Entry information

Entry name

KSYK_PIG

Accession

Primary (citable) accession number: Q00655

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	April 1, 1993
Last modified:	May 29, 2013
This is version 119 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents

Preferred order of sections

Names and origin

Cleaved into the following 2 chains:

Protein attributes

General annotation (Comments)

Ontologies

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Experimental info

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Family and domain databases

Entry information

Relevant documents