| IED ID | IndEnz0002007522 |
| Enzyme Type ID | protease007522 |
| Protein Name |
Tyrosine-protein kinase SYK EC 2.7.10.2 Spleen tyrosine kinase p72-Syk |
| Gene Name | SYK |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MASSGMADSANHLPFFFGNITREEAEDYLVQGGMSDGLYLLRQSRNYLGGFALSVAHGRKAHHYTIERELNGTYAIAGGRTHASPADLCHYHSQESDGLVCLLKKPFNRPQGVQPKTGPFEDLKENLIREYVKQTWNLQGQALEQAIISQKPQLEKLIATTAHEKMPWFHGKISREESEQIVLIGSKTNGKFLIRARDNNGSYALCLLHEGKVLHYRIDKDKTGKLSIPEGKKFDTLWQLVEHYSYKADGLLRVLTVPCQKIGTQGNVNFGGRPQLPGSHPATWSAGGIISRIKSYSFPKPGHRKSSPAQGNRQESTVSFNPYEPELAPWAADKGPQREALPMDTEVYESPYADPEEIRPKEVYLDRKLLTLEDKELGSGNFGTVKKGYYQMKKVVKTVAVKILKNEANDPALKDELLAEANVMQQLDNPYIVRMIGICEAESWMLVMEMAELGPLNKYLQQNRHVKDKNIIELVHQVSMGMKYLEESNFVHRDLAARNVLLVTQHYAKISDFGLSKALRADENYYKAQTHGKWPVKWYAPECINYYKFSSKSDVWSFGVLMWEAFSYGQKPYRGMKGSEVTAMLEKGERMGCPAGCPREMYDLMNLCWTYDVENRPGFAAVELRLRNYYYDVVN |
| Enzyme Length | 635 |
| Uniprot Accession Number | P43405 |
| Absorption | |
| Active Site | ACT_SITE 494; /note="Proton acceptor"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-ProRule:PRU10028" |
| Activity Regulation | ACTIVITY 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. Phosphorylates SH3BP2 which in turn may regulate SYK through LYN (By similarity). {ECO:0000250}. |
| Binding Site | BINDING 402; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-[protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028}; |
| DNA Binding | |
| EC Number | 2.7.10.2 |
| Enzyme Function | 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. 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 (By similarity). Required for the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770). Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Involved in interleukin-3/IL3-mediated signaling pathway in basophils (By similarity). 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). {ECO:0000250|UniProtKB:P48025, ECO:0000269|PubMed:12387735, ECO:0000269|PubMed:12456653, ECO:0000269|PubMed:15123770, ECO:0000269|PubMed:15388330, ECO:0000269|PubMed:19909739, ECO:0000269|PubMed:8657103, ECO:0000269|PubMed:9535867}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 377..385; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Features | Active site (1); Alternative sequence (1); Beta strand (28); Binding site (1); Chain (1); Domain (3); Helix (24); Modified residue (31); Mutagenesis (2); Natural variant (1); Nucleotide binding (1); Region (2); Sequence conflict (2); Turn (2) |
| Keywords | 3D-structure;ATP-binding;Adaptive immunity;Alternative splicing;Angiogenesis;Cell membrane;Cytoplasm;Host-virus interaction;Immunity;Innate immunity;Kinase;Membrane;Nucleotide-binding;Phosphoprotein;Reference proteome;Repeat;SH2 domain;Transferase;Tyrosine-protein kinase;Ubl conjugation |
| Interact With | P05067; P22681; P20273; P11049; P07766; P00533; P04626; P21860; P30273; P36888; Q13480; P06239; P08581; P19174; Q9ULZ3; Q9NP31; P40763; Q96IP4; P54274; Q8TF42; Q9UHP3; P01023; Q06481-5; P05067; Q13867; P27824-2; Q86YQ8-2; Q9UGL9; O14576-2; P0DMV8; Q07954-2; P41271-2; P62136; P63000; P29353-7; Q9Y4K3; A0A024RC47 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}. Cytoplasm, cytosol {ECO:0000305}. |
| Modified Residue | MOD_RES 28; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132, ECO:0007744|PubMed:19690332"; MOD_RES 44; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 47; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 131; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 202; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 256; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 295; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 296; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 297; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 316; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 317; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 319; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 323; /note="Phosphotyrosine; by LYN"; /evidence="ECO:0000269|PubMed:21469132, ECO:0007744|PubMed:19369195"; MOD_RES 345; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 348; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 350; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 352; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 364; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 379; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 384; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 484; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 507; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 525; /note="Phosphotyrosine; by autocatalysis"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 526; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 530; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 546; /note="Phosphotyrosine"; /evidence="ECO:0000250|UniProtKB:P48025"; MOD_RES 579; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 582; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 629; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132"; MOD_RES 630; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:18369315, ECO:0000269|PubMed:21469132"; MOD_RES 631; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:21469132" |
| Post Translational Modification | PTM: Ubiquitinated by CBLB after BCR activation; which promotes proteasomal degradation. {ECO:0000250}.; PTM: Autophosphorylated. Phosphorylated on tyrosine residues by LYN following receptors engagement. Phosphorylation on Tyr-323 creates a binding site for CBL, an adapter protein that serves as a negative regulator of BCR-stimulated calcium ion signaling. Phosphorylation at Tyr-348 creates a binding site for VAV1. Phosphorylation on Tyr-348 and Tyr-352 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). Phosphorylated on tyrosine residues in response to IL15 (PubMed:15123770). Phosphorylation on Ser-297 is very common, it peaks 5 minutes after BCR stimulation, and creates a binding site for YWHAG. Phosphorylation at Tyr-630 creates a binding site for BLNK. Dephosphorylated by PTPN6. {ECO:0000250, ECO:0000269|PubMed:10458769, ECO:0000269|PubMed:15123770, ECO:0000269|PubMed:18369315, ECO:0000269|PubMed:21469132}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (2); X-ray crystallography (79) |
| Cross Reference PDB | 1A81; 1CSY; 1CSZ; 1XBA; 1XBB; 1XBC; 3BUW; 3EMG; 3FQE; 3FQH; 3FQS; 3SRV; 3TUB; 3TUC; 3TUD; 3VF8; 3VF9; 4DFL; 4DFN; 4F4P; 4FL1; 4FL2; 4FL3; 4FYN; 4FYO; 4FZ6; 4FZ7; 4GFG; 4I0R; 4I0S; 4I0T; 4PUZ; 4PV0; 4PX6; 4RSS; 4RX7; 4RX8; 4RX9; 4WNM; 4XG2; 4XG3; 4XG4; 4XG6; 4XG7; 4XG8; 4XG9; 4YJO; 4YJP; 4YJQ; 4YJR; 4YJS; 4YJT; 4YJU; 4YJV; 5C26; 5C27; 5CXH; 5CXZ; 5CY3; 5GHV; 5LMA; 5LMB; 5T68; 5TIU; 5TR6; 5TT7; 5Y5T; 5Y5U; 6HM6; 6HM7; 6SSB; 6VOV; 6ZC0; 6ZCP; 6ZCQ; 6ZCR; 6ZCS; 6ZCU; 6ZCX; 6ZCY; 7SA7; |
| Mapped Pubmed ID | 10026222; 10051622; 10072481; 10329697; 10498607; 10523831; 10556826; 10579907; 10643150; 10648173; 10825200; 10918585; 10931839; 10940905; 11071869; 11226282; 11262396; 11368773; 11380624; 11425868; 11441091; 11449366; 11481033; 11507089; 11606584; 11907067; 11909947; 11988077; 12009018; 12089510; 12133942; 12181444; 12209081; 12393431; 12417718; 12445683; 12468431; 12477728; 12573241; 12586631; 12660731; 12682251; 12711606; 12869549; 12885943; 12907655; 1374290; 1376928; 14512302; 14557262; 14646171; 14656219; 14656892; 14699155; 15010370; 15059510; 15059847; 15062056; 15069015; 15107455; 15143214; 15161916; 15163542; 15166239; 15184383; 15188513; 15337524; 15345594; 1550550; 15507431; 15509800; 15536084; 15556646; 15557085; 15583006; 15601820; 15670211; 15707999; 15744341; 15754322; 15795233; 15809313; 15845454; 15955106; 15956283; 1599430; 16033816; 16085052; 16174766; 16273093; 16289966; 16371508; 16449524; 16456001; 16474166; 16501050; 16546099; 16713566; 16754322; 16849466; 16849645; 16888096; 16921024; 16938345; 16964403; 17050534; 1705565; 17066093; 17070777; 17082600; 17110603; 17130299; 17145863; 17308335; 17346310; 17363902; 17506820; 17507237; 17675521; 17681949; 17693136; 17721511; 17721605; 17874182; 17879956; 17942891; 17993265; 18006696; 18022864; 18052078; 18068154; 18178826; 18189269; 18200499; 18206515; 18273061; 18362147; 18374639; 18401419; 18420802; 18485118; 18564921; 18590740; 18644434; 18691974; 18715866; 18715989; 1874735; 18776906; 18803050; 18938080; 18945214; 19092849; 19122653; 19136564; 19150851; 19151749; 19195024; 19206206; 19220318; 19236749; 19248119; 19296913; 19297020; 19372136; 19385048; 19409513; 19421152; 19435818; 19436043; 19453968; 19464057; 19477690; 19530990; 19535334; 19549911; 19553680; 19581935; 19587381; 19592646; 19700402; 19776763; 19783684; 19800574; 19829710; 19850008; 19893036; 19965664; 20013945; 20014315; 20068106; 2011584; 20133729; 20201079; 20236696; 20368800; 20379614; 20401456; 20439541; 20528870; 20563729; 20585042; 20668539; 20670933; 20705591; 20807769; 20956537; 21044950; 21047529; 21067271; 21086786; 21171946; 21255137; 21352196; 21378271; 21394647; 21468383; 21516116; 21552259; 21636860; 21642504; 21659545; 21693067; 21725048; 21730355; 21749309; 21807898; 21822214; 21876553; 21903390; 21908615; 21926965; 21953500; 21981270; 22000807; 22025527; 22031919; 22041900; 22219190; 22235999; 22267732; 22287277; 22321643; 22336204; 22354960; 22366891; 22425453; 22464456; 22489915; 22541243; 22577255; 22581261; 22585575; 22623428; 22624718; 22659134; 22669259; 22689578; 22693567; 22702505; 22707146; 22759374; 22837212; 22848421; 22864779; 22877633; 22880054; 22956578; 23039362; 23071339; 23087912; 23151054; 23154170; 23204309; 23223229; 23242981; 23264619; 23281368; 23293025; 23350847; 23396946; 23416715; 23424645; 23447535; 23609194; 23609447; 23764004; 23803069; 23803121; 23960082; 24013589; 24023253; 24076779; 24122028; 24189400; 24220695; 24275652; 24286216; 24326074; 24376268; 24376657; 24438103; 24477596; 24489640; 24520947; 24523870; 24525236; 24606918; 24700868; 24726806; 24728074; 24779514; 25092868; 25156507; 25160932; 25170122; 25241761; 25251945; 25257535; 25277753; 25287889; 25287946; 25331948; 25416956; 25432781; 25531330; 25543269; 25612940; 25633741; 25644261; 25748087; 25767114; 25814554; 25858425; 25896065; 25921550; 25922567; 25965880; 25974135; 26032420; 26096845; 26187144; 26202982; 26212014; 26251216; 26315286; 26320624; 26381330; 26384287; 26429917; 26492563; 26582197; 26584182; 26742467; 26756335; 26848618; 26884848; 26889814; 26910509; 26980390; 27034738; 27181361; 27258042; 27293079; 27297662; 27338330; 27356299; 27365531; 27381982; 27461624; 27461628; 27504936; 27510553; 27578246; 27614019; 27789138; 27839918; 27888629; 27994755; 28036404; 28054556; 28082678; 28088788; 28089901; 28105029; 28131718; 28202529; 28336564; 2841328; 28468967; 28512645; 28674449; 28736554; 28760774; 28767218; 28786489; 28827787; 28877763; 28919467; 28957395; 29052597; 29263215; 29272492; 29274344; 29401256; 29440271; 29497423; 29545260; 29890824; 30033874; 30091681; 30135222; 30203714; 30249354; 30251328; 30333224; 30460241; 30475060; 30609049; 30644389; 30721460; 30737623; 30744170; 30872780; 30923129; 31139177; 31175361; 31199889; 31367693; 31449558; 31519182; 31616406; 31707778; 31881809; 31901221; 31943762; 31947584; 31974654; 32005797; 32010124; 32292557; 32678160; 32768227; 32784334; 32977621; 32989091; 33159047; 33198789; 33255747; 33328565; 33422057; 33435587; 33488575; 33615197; 33623139; 33782605; 33839682; 33878293; 33979042; 34343834; 34601763; 3500860; 7487883; 7513017; 7517665; 7518558; 7521688; 7522622; 7528327; 7530449; 7537740; 7538118; 7565679; 7579336; 7592958; 7600304; 7623809; 7761456; 8071371; 8197119; 8226994; 8340414; 8547634; 8608222; 8617742; 8621719; 8627166; 8629002; 8630373; 8630736; 8647200; 8663278; 8702662; 8798676; 8809042; 8810294; 8862523; 8900180; 8910399; 8919032; 8947047; 8972730; 8977235; 8995358; 8995445; 9015216; 9042338; 9050880; 9151714; 9188445; 9199344; 9226159; 9259313; 9280292; 9314552; 9326643; 9341187; 9351824; 9396765; 9490415; 9490675; 9525940; 9590251; 9697839; 9705962; 9790917; 9824671; 9830044; 9862674; 9864141; 9864153; 9885206; 9890970; 9989983; |
| Motif | |
| Gene Encoded By | |
| Mass | 72,066 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:10596 |
| Cross Reference Brenda | 2.7.10.2;2.7.12.1; |