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{{For|the school abbreviated SYK|Helsingin Suomalainen Yhteiskoulu}}
{{Infobox_gene}}
'''Spleen tyrosine kinase''', also known as '''Syk''', is an [[enzyme]] which in humans is encoded by the ''SYK'' ''gene''.<ref name="entrez">{{cite web | title = Entrez Gene: SYK Spleen tyrosine kinase | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6850| accessdate = }}</ref><ref name="pmid1423621">{{cite journal | vauthors = Chan AC, Iwashima M, Turck CW, Weiss A | title = ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain | journal = Cell | volume = 71 | issue = 4 | pages = 649–62 | date = November 1992 | pmid = 1423621 | doi = 10.1016/0092-8674(92)90598-7 }}</ref><ref name="pmid8082894">{{cite journal | vauthors = Ku G, Malissen B, Mattei MG | title = Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans | journal = Immunogenetics | volume = 40 | issue = 4 | pages = 300–2 | year = 1994 | pmid = 8082894 | doi = 10.1007/BF00189976 }}</ref>


== Function ==


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SYK, along with [[Zap-70]], is a member of the Syk family of [[tyrosine kinase]]s. These non-receptor cytoplasmic tyrosine kinases share a characteristic dual [[SH2 domain]] separated by a linker domain.<ref name="Seda_2015">{{cite journal | vauthors = Seda V, Mraz M | title = B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells | journal = European Journal of Haematology | volume = 94 | issue = 3 | pages = 193–205 | date = March 2015 | pmid = 25080849 | doi = 10.1111/ejh.12427 }}</ref> However, activation of SYK relies less on phosporylation by Src family kinases than Zap-70.<ref>{{cite journal | vauthors = Fasbender F, Claus M, Wingert S, Sandusky M, Watzl C | title = Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes | journal = Frontiers in Immunology | volume = 8 | pages = 789 | date = 2017-07-07 | pmid = 28736554 | pmc = 5500614 | doi = 10.3389/fimmu.2017.00789 }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
While Syk and Zap-70 are primarily expressed in hematopoietic tissues, there is expression of Syk in a variety of tissues. Within [[B cell|B]]  and [[T cell]]s respectively, Syk and Zap-70 transmit signals from the B-Cell receptor and T-Cell receptor.<ref name="Seda_2015"/> Syk plays a similar role in transmitting signals from a variety of cell surface receptors including CD74, [[Fc Receptor]], and [[integrin]]s.
{{GNF_Protein_box
| image = PBB_Protein_SYK_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1a81.
  | PDB = {{PDB2|1a81}}, {{PDB2|1csy}}, {{PDB2|1csz}}, {{PDB2|1xba}}, {{PDB2|1xbb}}, {{PDB2|1xbc}}
| Name = Spleen tyrosine kinase
| HGNCid = 11491
| Symbol = SYK
| AltSymbols =;
| OMIM = 600085
| ECnumber = 
| Homologene = 2390
| MGIid = 99515
| GeneAtlas_image1 = PBB_GE_SYK_209269_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_SYK_207540_s_at_tn.png
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004715 |text = non-membrane spanning protein tyrosine kinase activity}} {{GNF_GO|id=GO:0004716 |text = receptor signaling protein tyrosine kinase activity}} {{GNF_GO|id=GO:0005178 |text = integrin binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0016740 |text = transferase activity}}
| Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0019815 |text = B cell receptor complex}} {{GNF_GO|id=GO:0042101 |text = T cell receptor complex}}
| Process = {{GNF_GO|id=GO:0001820 |text = serotonin secretion}} {{GNF_GO|id=GO:0006461 |text = protein complex assembly}} {{GNF_GO|id=GO:0007159 |text = leukocyte adhesion}} {{GNF_GO|id=GO:0007167 |text = enzyme linked receptor protein signaling pathway}} {{GNF_GO|id=GO:0007229 |text = integrin-mediated signaling pathway}} {{GNF_GO|id=GO:0007242 |text = intracellular signaling cascade}} {{GNF_GO|id=GO:0007257 |text = activation of JNK activity}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}} {{GNF_GO|id=GO:0009887 |text = organ morphogenesis}} {{GNF_GO|id=GO:0018108 |text = peptidyl-tyrosine phosphorylation}} {{GNF_GO|id=GO:0019370 |text = leukotriene biosynthetic process}} {{GNF_GO|id=GO:0030593 |text = neutrophil chemotaxis}} {{GNF_GO|id=GO:0043306 |text = positive regulation of mast cell degranulation}} {{GNF_GO|id=GO:0045401 |text = positive regulation of interleukin-3 biosynthetic process}} {{GNF_GO|id=GO:0045425 |text = positive regulation of granulocyte macrophage colony-stimulating factor biosynthetic process}} {{GNF_GO|id=GO:0045579 |text = positive regulation of B cell differentiation}} {{GNF_GO|id=GO:0045588 |text = positive regulation of gamma-delta T cell differentiation}} {{GNF_GO|id=GO:0046638 |text = positive regulation of alpha-beta T cell differentiation}} {{GNF_GO|id=GO:0046641 |text = positive regulation of alpha-beta T cell proliferation}} {{GNF_GO|id=GO:0046777 |text = protein amino acid autophosphorylation}} {{GNF_GO|id=GO:0050731 |text = positive regulation of peptidyl-tyrosine phosphorylation}} {{GNF_GO|id=GO:0050850 |text = positive regulation of calcium-mediated signaling}} {{GNF_GO|id=GO:0050853 |text = B cell receptor signaling pathway}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 6850
    | Hs_Ensembl = ENSG00000165025
    | Hs_RefseqProtein = NP_003168
    | Hs_RefseqmRNA = NM_003177
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 9
    | Hs_GenLoc_start = 92603890
    | Hs_GenLoc_end = 92700652
    | Hs_Uniprot = P43405
    | Mm_EntrezGene = 20963
    | Mm_Ensembl = ENSMUSG00000021457
    | Mm_RefseqmRNA = NM_011518
    | Mm_RefseqProtein = NP_035648
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 13
    | Mm_GenLoc_start = 52595933
    | Mm_GenLoc_end = 52661224
    | Mm_Uniprot = Q3UPF7
  }}
}}


'''Spleen [[tyrosine kinase]]''', also known as '''SYK''', is a human protein and gene.
=== Function during development ===
Mice that lack Syk completely (Syk<sup>−/−</sup>, Syk-knockout) die during embryonic development around midgestation. They show severe defects in the development of the lymphatic system. Normally, the lymphatic system and the blood system are strictly separated from each other. However, in Syk deficient mice the lymphatics and the blood vessels form abnormal shunts, leading to leakage of blood into the lymphatic system. The reason for this phenotype was identified by a genetic fate mapping approach, showing that Syk is expressed in myeloid cells which orchestrate the proper separation of lymphatics and blood system during embryogenesis and beyond. Thus, Syk is an essential regulator of the lymphatic system development in mice.<ref name="pmid20230750">{{cite journal | vauthors = Böhmer R, Neuhaus B, Bühren S, Zhang D, Stehling M, Böck B, Kiefer F | title = Regulation of developmental lymphangiogenesis by Syk(+) leukocytes | journal = Developmental Cell | volume = 18 | issue = 3 | pages = 437–49 | date = March 2010 | pmid = 20230750 | doi = 10.1016/j.devcel.2010.01.009 }}</ref>


SYK, along with [[Zap-70]], is a member of the Syk family of tyrosine kinases. These non-receptor cytoplasmic tyrosine kinases share a characteristic dual [[SH2 domain]] separated by a linker domain.
== Clinical significance ==


While Syk and Zap-70 are primarily expressed in hematopoietic tissues, there is expression of Syk in a variety of tissues. Within [[B cell|B]] and [[T cell]]s respectively, Syk and Zap-70 transmit signals from the B-Cell receptor and T-Cell receptor.  Syk plays a similar role in transmitting signals from a variety of cell surface receptors including CD74, [[Fc Receptor]], and [[integrin]]s.
Abnormal function of Syk has been implicated in several instances of hematopoeitic malignancies including translocations involving [[ITK (gene)|Itk]] and [[ETV6|Tel]].  Constitutive Syk activity can transform B cells.<ref name="Seda_2015"/> Several transforming viruses contain "[[Immunoreceptor tyrosine-based activation motif|Immunoreceptor Tyrosine Activation Motifs]]" (ITAMs) which lead to activation of Syk including [[Epstein-Barr virus|Epstein Barr virus]], [[bovine leukemia virus]], and [[mouse mammary tumor virus]].


Abnormal function of Syk has been implicated in several instances of hematopoeitic malignancies including translocations involving [[ITK (gene)|Itk]] and [[ETV6|Tel]].  Constitutive Syk activity can transform B cells.  Several transforming viruses contain "[[Immunoreceptor tyrosine-based activation motif|Immunoreceptor Tyrosine Activation Motifs]]" (ITAMs) which lead to activation of Syk including [[Epstein-Barr virus|Epstein Barr virus]], [[bovine leukemia virus]], and [[mouse mammary tumor virus]].
===SYK inhibition===
Given the central role of SYK in transmission of activating signals within B-cells, a suppression of this tyrosine kinase might aid in the treatment of B cell malignancies and [[autoimmune disease]]s.<ref name="Seda_2015" />


The role of Syk in epithelial malignancies is controversial. Several authors have suggested that abnormal Syk function facilitates transformation in [[Nasopharyngeal carcinoma]] and [[head and neck cancer]] while other authors have suggested a tumor supressor role in [[breast cancer|breast]] and [[gastric cancer]].
Syk inhibition has been proposed as a therapy for both [[lymphoma]] and [[chronic lymphocytic leukemia]].<ref name="Seda_2015"/> Syk inhibitors are in clinical development, including GS-9973 <ref name="Seda_2015"/> now named [[entospletinib]].<ref name="pmid27247756">{{cite journal | vauthors = Sharman J, Di Paolo J | title = Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib | journal = Therapeutic Advances in Hematology | volume = 7 | issue = 3 | pages = 157–70 | year = 2016 | pmid = 27247756 | pmc = 4872176 | doi = 10.1177/2040620716636542 }}</ref> Other inhibitors of [[B-cell receptor]] (BCR) signaling including [[ibrutinib]] (PCI-32765) which inhibits BTK,<ref name="pmid27641927">{{cite journal | vauthors = Roskoski R | title = Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms | journal = Pharmacological Research | volume = 113 | issue = Pt A | pages = 395–408 | year = 2016 | pmid = 27641927 | doi = 10.1016/j.phrs.2016.09.011 }}</ref> and [[idelalisib]] (PI3K inhibitor - CAL-101 / GS-1101) showed activity in the diseases as well.<ref name="pmid27252232">{{cite journal | vauthors = Cheah CY, Fowler NH | title = Idelalisib in the management of lymphoma | journal = Blood | volume = 128 | issue = 3 | pages = 331–6 | year = 2016 | pmid = 27252232 | doi = 10.1182/blood-2016-02-702761 }}</ref>


==Further reading==
The orally active SYK inhibitor [[fostamatinib]] (R788) in the treatment of [[rheumatoid arthritis]].<ref name="pmid24610702">{{cite journal | vauthors = Scott IC, Scott DL | title = Spleen tyrosine kinase inhibitors for rheumatoid arthritis: where are we now? | journal = Drugs | volume = 74 | issue = 4 | pages = 415–22 | year = 2014 | pmid = 24610702 | doi = 10.1007/s40265-014-0193-9 }}</ref>
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal | author=Turner M, Schweighoffer E, Colucci F, ''et al.'' |title=Tyrosine kinase SYK: essential functions for immunoreceptor signalling. |journal=Immunol. Today |volume=21 |issue= 3 |pages= 148-54 |year= 2000 |pmid= 10689303 |doi=  }}
*{{cite journal  | author=Fruman DA, Satterthwaite AB, Witte ON |title=Xid-like phenotypes: a B cell signalosome takes shape. |journal=Immunity |volume=13 |issue= 1 |pages= 1-3 |year= 2000 |pmid= 10933389 |doi=  }}
*{{cite journal  | author=Yanagi S, Inatome R, Takano T, Yamamura H |title=Syk expression and novel function in a wide variety of tissues. |journal=Biochem. Biophys. Res. Commun. |volume=288 |issue= 3 |pages= 495-8 |year= 2001 |pmid= 11676469 |doi= 10.1006/bbrc.2001.5788 }}
*{{cite journal  | author=Tohyama Y, Yamamura H |title=Complement-mediated phagocytosis--the role of Syk. |journal=IUBMB Life |volume=58 |issue= 5-6 |pages= 304-8 |year= 2006 |pmid= 16754322 |doi= 10.1080/15216540600746377 }}
*{{cite journal  | author=Schymeinsky J, Mócsai A, Walzog B |title=Neutrophil activation via beta2 integrins (CD11/CD18): molecular mechanisms and clinical implications. |journal=Thromb. Haemost. |volume=98 |issue= 2 |pages= 262-73 |year= 2007 |pmid= 17721605 |doi=  }}
}}
{{refend}}


==External links==
The Syk inhibitor [[nilvadipine]] has been shown to regulate amyloid-β production and [[Tau protein|Tau]] phosphorylation and hence has been proposed as a treatment for [[Alzheimer's Disease]]<ref>{{cite journal | vauthors = Paris D, Ait-Ghezala G, Bachmeier C, Laco G, Beaulieu-Abdelahad D, Lin Y, Jin C, Crawford F, Mullan M | title = The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation | journal = The Journal of Biological Chemistry | volume = 289 | issue = 49 | pages = 33927–44 | date = December 2014 | pmid = 25331948 | pmc = 4256331 | doi = 10.1074/jbc.M114.608091 }}</ref> and has entered phase III clinical trials.<ref>{{cite web | url = https://clinicaltrials.gov/ct2/show/NCT02017340 | title = A Phase III Trial of Nilvadipine to Treat Alzheimer's Disease | work = ClinicalTrials.gov | access-date=2017-04-02}}</ref>
 
===Epithelial malignancies===
The role of Syk in epithelial malignancies is controversial.  Several authors have suggested that abnormal Syk function facilitates transformation in [[Nasopharyngeal carcinoma]] and [[head and neck cancer]] while other authors have suggested a tumor suppressor role in [[breast cancer|breast]] and [[gastric cancer]].
 
Without Syk, the protein it makes, and genetic disruption in a panel of 55 genes thought also to be controlled by Syk, [[breast ductal carcinoma in situ]] (breast DCIS, which can become invasive), it is believed that the cancer has a markedly increased tendency to invade and metastasize.<ref name="pmid24523870">{{cite journal | vauthors = Blancato J, Graves A, Rashidi B, Moroni M, Tchobe L, Ozdemirli M, Kallakury B, Makambi KH, Marian C, Mueller SC | title = SYK allelic loss and the role of Syk-regulated genes in breast cancer survival | journal = PLoS One | volume = 9 | issue = 2 | pages = e87610 | year = 2014 | pmid = 24523870 | pmc = 3921124 | doi = 10.1371/journal.pone.0087610 }}</ref>
 
== Interactions ==
 
Syk has been shown to [[Protein-protein interaction|interact]] with:
 
* [[Cbl gene]]<ref name=pmid11331248/><ref name="pmid9857068">{{cite journal | vauthors = Lupher ML, Rao N, Lill NL, Andoniou CE, Miyake S, Clark EA, Druker B, Band H | title = Cbl-mediated negative regulation of the Syk tyrosine kinase. A critical role for Cbl phosphotyrosine-binding domain binding to Syk phosphotyrosine 323 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 52 | pages = 35273–81 | date = December 1998 | pmid = 9857068 | doi = 10.1074/jbc.273.52.35273 }}</ref><ref name="pmid12435267">{{cite journal | vauthors = Melander F, Andersson T, Dib K | title = Fgr but not Syk tyrosine kinase is a target for beta 2 integrin-induced c-Cbl-mediated ubiquitination in adherent human neutrophils | journal = The Biochemical Journal | volume = 370 | issue = Pt 2 | pages = 687–94 | date = March 2003 | pmid = 12435267 | pmc = 1223185 | doi = 10.1042/BJ20021201 }}</ref>
* [[CRKL]],<ref name="pmid11313252">{{cite journal | vauthors = Oda A, Ochs HD, Lasky LA, Spencer S, Ozaki K, Fujihara M, Handa M, Ikebuchi K, Ikeda H | title = CrkL is an adapter for Wiskott-Aldrich syndrome protein and Syk | journal = Blood | volume = 97 | issue = 9 | pages = 2633–9 | date = May 2001 | pmid = 11313252 | doi = 10.1182/blood.V97.9.2633 }}</ref>
* [[FCGR2A]],<ref name="pmid9268059">{{cite journal | vauthors = Ibarrola I, Vossebeld PJ, Homburg CH, Thelen M, Roos D, Verhoeven AJ | title = Influence of tyrosine phosphorylation on protein interaction with FcgammaRIIa | journal = Biochimica et Biophysica Acta | volume = 1357 | issue = 3 | pages = 348–58 | date = July 1997 | pmid = 9268059 | doi = 10.1016/S0167-4889(97)00034-7 }}</ref><ref name="pmid11141335">{{cite journal | vauthors = Kim MK, Pan XQ, Huang ZY, Hunter S, Hwang PH, Indik ZK, Schreiber AD | title = Fc gamma receptors differ in their structural requirements for interaction with the tyrosine kinase Syk in the initial steps of signaling for phagocytosis | journal = Clinical Immunology | volume = 98 | issue = 1 | pages = 125–32 | date = January 2001 | pmid = 11141335 | doi = 10.1006/clim.2000.4955 }}</ref>
* [[FYN]],<ref name="pmid9535867">{{cite journal | vauthors = Deckert M, Elly C, Altman A, Liu YC | title = Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases | journal = The Journal of Biological Chemistry | volume = 273 | issue = 15 | pages = 8867–74 | date = April 1998 | pmid = 9535867 | doi = 10.1074/jbc.273.15.8867 }}</ref><ref name="pmid9169439">{{cite journal | vauthors = Chung J, Gao AG, Frazier WA | title = Thrombspondin acts via integrin-associated protein to activate the platelet integrin alphaIIbbeta3 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 23 | pages = 14740–6 | date = June 1997 | pmid = 9169439 | doi = 10.1074/jbc.272.23.14740 }}</ref>
* [[Grb2]],<ref name=pmid10747947/><ref name="pmid11964172">{{cite journal | vauthors = Saci A, Liu WQ, Vidal M, Garbay C, Rendu F, Bachelot-Loza C | title = Differential effect of the inhibition of Grb2-SH3 interactions in platelet activation induced by thrombin and by Fc receptor engagement | journal = The Biochemical Journal | volume = 363 | issue = Pt 3 | pages = 717–25 | date = May 2002 | pmid = 11964172 | pmc = 1222524 | doi = 10.1042/0264-6021:3630717 }}</ref>
* [[Lck]],<ref name="pmid7539035">{{cite journal | vauthors = Thome M, Duplay P, Guttinger M, Acuto O | title = Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex | journal = The Journal of Experimental Medicine | volume = 181 | issue = 6 | pages = 1997–2006 | date = June 1995 | pmid = 7539035 | pmc = 2192070 | doi = 10.1084/jem.181.6.1997 }}</ref>
* [[LYN]],<ref name="pmid7831290">{{cite journal | vauthors = Sidorenko SP, Law CL, Chandran KA, Clark EA | title = Human spleen tyrosine kinase p72Syk associates with the Src-family kinase p53/56Lyn and a 120-kDa phosphoprotein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 2 | pages = 359–63 | date = January 1995 | pmid = 7831290 | pmc = 42739 | doi = 10.1073/pnas.92.2.359 }}</ref>
* [[PTK2]],<ref name="pmid9342235">{{cite journal | vauthors = Sada K, Minami Y, Yamamura H | title = Relocation of Syk protein-tyrosine kinase to the actin filament network and subsequent association with Fak | journal = European Journal of Biochemistry | volume = 248 | issue = 3 | pages = 827–33 | date = September 1997 | pmid = 9342235 | doi = 10.1111/j.1432-1033.1997.00827.x }}</ref>
* [[PTPN6]],<ref name="pmid10747947">{{cite journal | vauthors = Ganju RK, Brubaker SA, Chernock RD, Avraham S, Groopman JE | title = Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk | journal = The Journal of Biological Chemistry | volume = 275 | issue = 23 | pages = 17263–8 | date = June 2000 | pmid = 10747947 | doi = 10.1074/jbc.M000689200 }}</ref><ref name="pmid10072516">{{cite journal | vauthors = Dustin LB, Plas DR, Wong J, Hu YT, Soto C, Chan AC, Thomas ML | title = Expression of dominant-negative src-homology domain 2-containing protein tyrosine phosphatase-1 results in increased Syk tyrosine kinase activity and B cell activation | journal = Journal of Immunology | volume = 162 | issue = 5 | pages = 2717–24 | date = March 1999 | pmid = 10072516 | doi =  }}</ref> and
* [[VAV1]].<ref name="pmid11331248">{{cite journal | vauthors = Bertagnolo V, Marchisio M, Brugnoli F, Bavelloni A, Boccafogli L, Colamussi ML, Capitani S | title = Requirement of tyrosine-phosphorylated Vav for morphological differentiation of all-trans-retinoic acid-treated HL-60 cells | journal = Cell Growth & Differentiation | volume = 12 | issue = 4 | pages = 193–200 | date = April 2001 | pmid = 11331248 | doi =  }}</ref><ref name="pmid8986718">{{cite journal | vauthors = Deckert M, Tartare-Deckert S, Couture C, Mustelin T, Altman A | title = Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product | journal = Immunity | volume = 5 | issue = 6 | pages = 591–604 | date = December 1996 | pmid = 8986718 | doi = 10.1016/S1074-7613(00)80273-3 }}</ref><ref name="pmid8900182">{{cite journal | vauthors = Song JS, Gomez J, Stancato LF, Rivera J | title = Association of a p95 Vav-containing signaling complex with the FcepsilonRI gamma chain in the RBL-2H3 mast cell line. Evidence for a constitutive in vivo association of Vav with Grb2, Raf-1, and ERK2 in an active complex | journal = The Journal of Biological Chemistry | volume = 271 | issue = 43 | pages = 26962–70 | date = October 1996 | pmid = 8900182 | doi = 10.1074/jbc.271.43.26962 }}</ref>
{{Clear}}
 
== References ==
{{Reflist|35em}}
 
== Further reading ==
{{Refbegin|35em}}
* {{cite journal | vauthors = Turner M, Schweighoffer E, Colucci F, Di Santo JP, Tybulewicz VL | title = Tyrosine kinase SYK: essential functions for immunoreceptor signalling | journal = Immunology Today | volume = 21 | issue = 3 | pages = 148–54 | date = March 2000 | pmid = 10689303 | doi = 10.1016/S0167-5699(99)01574-1 }}
* {{cite journal | vauthors = Fruman DA, Satterthwaite AB, Witte ON | title = Xid-like phenotypes: a B cell signalosome takes shape | journal = Immunity | volume = 13 | issue = 1 | pages = 1–3 | date = July 2000 | pmid = 10933389 | doi = 10.1016/S1074-7613(00)00002-9 }}
* {{cite journal | vauthors = Yanagi S, Inatome R, Takano T, Yamamura H | title = Syk expression and novel function in a wide variety of tissues | journal = Biochemical and Biophysical Research Communications | volume = 288 | issue = 3 | pages = 495–8 | date = November 2001 | pmid = 11676469 | doi = 10.1006/bbrc.2001.5788 }}
* {{cite journal | vauthors = Tohyama Y, Yamamura H | title = Complement-mediated phagocytosis--the role of Syk | journal = IUBMB Life | volume = 58 | issue = 5-6 | pages = 304–8 | year = 2006 | pmid = 16754322 | doi = 10.1080/15216540600746377 }}
* {{cite journal | vauthors = Schymeinsky J, Mócsai A, Walzog B | title = Neutrophil activation via beta2 integrins (CD11/CD18): molecular mechanisms and clinical implications | journal = Thrombosis and Haemostasis | volume = 98 | issue = 2 | pages = 262–73 | date = August 2007 | pmid = 17721605 | doi = 10.1160/th07-02-0156 }}
{{Refend}}
 
== External links ==
* {{MeshName|Syk+kinase}}
* {{MeshName|Syk+kinase}}
{{protein-stub}}


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Revision as of 02:05, 25 October 2017

For the school abbreviated SYK, see Helsingin Suomalainen Yhteiskoulu.
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Spleen tyrosine kinase, also known as Syk, is an enzyme which in humans is encoded by the SYK gene.[1][2][3]

Function

SYK, along with Zap-70, is a member of the Syk family of tyrosine kinases. These non-receptor cytoplasmic tyrosine kinases share a characteristic dual SH2 domain separated by a linker domain.[4] However, activation of SYK relies less on phosporylation by Src family kinases than Zap-70.[5]

While Syk and Zap-70 are primarily expressed in hematopoietic tissues, there is expression of Syk in a variety of tissues. Within B and T cells respectively, Syk and Zap-70 transmit signals from the B-Cell receptor and T-Cell receptor.[4] Syk plays a similar role in transmitting signals from a variety of cell surface receptors including CD74, Fc Receptor, and integrins.

Function during development

Mice that lack Syk completely (Syk−/−, Syk-knockout) die during embryonic development around midgestation. They show severe defects in the development of the lymphatic system. Normally, the lymphatic system and the blood system are strictly separated from each other. However, in Syk deficient mice the lymphatics and the blood vessels form abnormal shunts, leading to leakage of blood into the lymphatic system. The reason for this phenotype was identified by a genetic fate mapping approach, showing that Syk is expressed in myeloid cells which orchestrate the proper separation of lymphatics and blood system during embryogenesis and beyond. Thus, Syk is an essential regulator of the lymphatic system development in mice.[6]

Clinical significance

Abnormal function of Syk has been implicated in several instances of hematopoeitic malignancies including translocations involving Itk and Tel. Constitutive Syk activity can transform B cells.[4] Several transforming viruses contain "Immunoreceptor Tyrosine Activation Motifs" (ITAMs) which lead to activation of Syk including Epstein Barr virus, bovine leukemia virus, and mouse mammary tumor virus.

SYK inhibition

Given the central role of SYK in transmission of activating signals within B-cells, a suppression of this tyrosine kinase might aid in the treatment of B cell malignancies and autoimmune diseases.[4]

Syk inhibition has been proposed as a therapy for both lymphoma and chronic lymphocytic leukemia.[4] Syk inhibitors are in clinical development, including GS-9973 [4] now named entospletinib.[7] Other inhibitors of B-cell receptor (BCR) signaling including ibrutinib (PCI-32765) which inhibits BTK,[8] and idelalisib (PI3K inhibitor - CAL-101 / GS-1101) showed activity in the diseases as well.[9]

The orally active SYK inhibitor fostamatinib (R788) in the treatment of rheumatoid arthritis.[10]

The Syk inhibitor nilvadipine has been shown to regulate amyloid-β production and Tau phosphorylation and hence has been proposed as a treatment for Alzheimer's Disease[11] and has entered phase III clinical trials.[12]

Epithelial malignancies

The role of Syk in epithelial malignancies is controversial. Several authors have suggested that abnormal Syk function facilitates transformation in Nasopharyngeal carcinoma and head and neck cancer while other authors have suggested a tumor suppressor role in breast and gastric cancer.

Without Syk, the protein it makes, and genetic disruption in a panel of 55 genes thought also to be controlled by Syk, breast ductal carcinoma in situ (breast DCIS, which can become invasive), it is believed that the cancer has a markedly increased tendency to invade and metastasize.[13]

Interactions

Syk has been shown to interact with:

References

  1. ↑ "Entrez Gene: SYK Spleen tyrosine kinase".
  2. ↑ Chan AC, Iwashima M, Turck CW, Weiss A (November 1992). "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain". Cell. 71 (4): 649–62. doi:10.1016/0092-8674(92)90598-7. PMID 1423621.
  3. ↑ Ku G, Malissen B, Mattei MG (1994). "Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans". Immunogenetics. 40 (4): 300–2. doi:10.1007/BF00189976. PMID 8082894.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Seda V, Mraz M (March 2015). "B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells". European Journal of Haematology. 94 (3): 193–205. doi:10.1111/ejh.12427. PMID 25080849.
  5. ↑ Fasbender F, Claus M, Wingert S, Sandusky M, Watzl C (2017-07-07). "Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes". Frontiers in Immunology. 8: 789. doi:10.3389/fimmu.2017.00789. PMC 5500614. PMID 28736554.
  6. ↑ Böhmer R, Neuhaus B, Bühren S, Zhang D, Stehling M, Böck B, Kiefer F (March 2010). "Regulation of developmental lymphangiogenesis by Syk(+) leukocytes". Developmental Cell. 18 (3): 437–49. doi:10.1016/j.devcel.2010.01.009. PMID 20230750.
  7. ↑ Sharman J, Di Paolo J (2016). "Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib". Therapeutic Advances in Hematology. 7 (3): 157–70. doi:10.1177/2040620716636542. PMC 4872176. PMID 27247756.
  8. ↑ Roskoski R (2016). "Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms". Pharmacological Research. 113 (Pt A): 395–408. doi:10.1016/j.phrs.2016.09.011. PMID 27641927.
  9. ↑ Cheah CY, Fowler NH (2016). "Idelalisib in the management of lymphoma". Blood. 128 (3): 331–6. doi:10.1182/blood-2016-02-702761. PMID 27252232.
  10. ↑ Scott IC, Scott DL (2014). "Spleen tyrosine kinase inhibitors for rheumatoid arthritis: where are we now?". Drugs. 74 (4): 415–22. doi:10.1007/s40265-014-0193-9. PMID 24610702.
  11. ↑ Paris D, Ait-Ghezala G, Bachmeier C, Laco G, Beaulieu-Abdelahad D, Lin Y, Jin C, Crawford F, Mullan M (December 2014). "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation". The Journal of Biological Chemistry. 289 (49): 33927–44. doi:10.1074/jbc.M114.608091. PMC 4256331. PMID 25331948.
  12. ↑ "A Phase III Trial of Nilvadipine to Treat Alzheimer's Disease". ClinicalTrials.gov. Retrieved 2017-04-02.
  13. ↑ Blancato J, Graves A, Rashidi B, Moroni M, Tchobe L, Ozdemirli M, Kallakury B, Makambi KH, Marian C, Mueller SC (2014). "SYK allelic loss and the role of Syk-regulated genes in breast cancer survival". PLoS One. 9 (2): e87610. doi:10.1371/journal.pone.0087610. PMC 3921124. PMID 24523870.
  14. ↑ 14.0 14.1 Bertagnolo V, Marchisio M, Brugnoli F, Bavelloni A, Boccafogli L, Colamussi ML, Capitani S (April 2001). "Requirement of tyrosine-phosphorylated Vav for morphological differentiation of all-trans-retinoic acid-treated HL-60 cells". Cell Growth & Differentiation. 12 (4): 193–200. PMID 11331248.
  15. ↑ Lupher ML, Rao N, Lill NL, Andoniou CE, Miyake S, Clark EA, Druker B, Band H (December 1998). "Cbl-mediated negative regulation of the Syk tyrosine kinase. A critical role for Cbl phosphotyrosine-binding domain binding to Syk phosphotyrosine 323". The Journal of Biological Chemistry. 273 (52): 35273–81. doi:10.1074/jbc.273.52.35273. PMID 9857068.
  16. ↑ Melander F, Andersson T, Dib K (March 2003). "Fgr but not Syk tyrosine kinase is a target for beta 2 integrin-induced c-Cbl-mediated ubiquitination in adherent human neutrophils". The Biochemical Journal. 370 (Pt 2): 687–94. doi:10.1042/BJ20021201. PMC 1223185. PMID 12435267.
  17. ↑ Oda A, Ochs HD, Lasky LA, Spencer S, Ozaki K, Fujihara M, Handa M, Ikebuchi K, Ikeda H (May 2001). "CrkL is an adapter for Wiskott-Aldrich syndrome protein and Syk". Blood. 97 (9): 2633–9. doi:10.1182/blood.V97.9.2633. PMID 11313252.
  18. ↑ Ibarrola I, Vossebeld PJ, Homburg CH, Thelen M, Roos D, Verhoeven AJ (July 1997). "Influence of tyrosine phosphorylation on protein interaction with FcgammaRIIa". Biochimica et Biophysica Acta. 1357 (3): 348–58. doi:10.1016/S0167-4889(97)00034-7. PMID 9268059.
  19. ↑ Kim MK, Pan XQ, Huang ZY, Hunter S, Hwang PH, Indik ZK, Schreiber AD (January 2001). "Fc gamma receptors differ in their structural requirements for interaction with the tyrosine kinase Syk in the initial steps of signaling for phagocytosis". Clinical Immunology. 98 (1): 125–32. doi:10.1006/clim.2000.4955. PMID 11141335.
  20. ↑ Deckert M, Elly C, Altman A, Liu YC (April 1998). "Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases". The Journal of Biological Chemistry. 273 (15): 8867–74. doi:10.1074/jbc.273.15.8867. PMID 9535867.
  21. ↑ Chung J, Gao AG, Frazier WA (June 1997). "Thrombspondin acts via integrin-associated protein to activate the platelet integrin alphaIIbbeta3". The Journal of Biological Chemistry. 272 (23): 14740–6. doi:10.1074/jbc.272.23.14740. PMID 9169439.
  22. ↑ 22.0 22.1 Ganju RK, Brubaker SA, Chernock RD, Avraham S, Groopman JE (June 2000). "Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk". The Journal of Biological Chemistry. 275 (23): 17263–8. doi:10.1074/jbc.M000689200. PMID 10747947.
  23. ↑ Saci A, Liu WQ, Vidal M, Garbay C, Rendu F, Bachelot-Loza C (May 2002). "Differential effect of the inhibition of Grb2-SH3 interactions in platelet activation induced by thrombin and by Fc receptor engagement". The Biochemical Journal. 363 (Pt 3): 717–25. doi:10.1042/0264-6021:3630717. PMC 1222524. PMID 11964172.
  24. ↑ Thome M, Duplay P, Guttinger M, Acuto O (June 1995). "Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex". The Journal of Experimental Medicine. 181 (6): 1997–2006. doi:10.1084/jem.181.6.1997. PMC 2192070. PMID 7539035.
  25. ↑ Sidorenko SP, Law CL, Chandran KA, Clark EA (January 1995). "Human spleen tyrosine kinase p72Syk associates with the Src-family kinase p53/56Lyn and a 120-kDa phosphoprotein". Proceedings of the National Academy of Sciences of the United States of America. 92 (2): 359–63. doi:10.1073/pnas.92.2.359. PMC 42739. PMID 7831290.
  26. ↑ Sada K, Minami Y, Yamamura H (September 1997). "Relocation of Syk protein-tyrosine kinase to the actin filament network and subsequent association with Fak". European Journal of Biochemistry. 248 (3): 827–33. doi:10.1111/j.1432-1033.1997.00827.x. PMID 9342235.
  27. ↑ Dustin LB, Plas DR, Wong J, Hu YT, Soto C, Chan AC, Thomas ML (March 1999). "Expression of dominant-negative src-homology domain 2-containing protein tyrosine phosphatase-1 results in increased Syk tyrosine kinase activity and B cell activation". Journal of Immunology. 162 (5): 2717–24. PMID 10072516.
  28. ↑ Deckert M, Tartare-Deckert S, Couture C, Mustelin T, Altman A (December 1996). "Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product". Immunity. 5 (6): 591–604. doi:10.1016/S1074-7613(00)80273-3. PMID 8986718.
  29. ↑ Song JS, Gomez J, Stancato LF, Rivera J (October 1996). "Association of a p95 Vav-containing signaling complex with the FcepsilonRI gamma chain in the RBL-2H3 mast cell line. Evidence for a constitutive in vivo association of Vav with Grb2, Raf-1, and ERK2 in an active complex". The Journal of Biological Chemistry. 271 (43): 26962–70. doi:10.1074/jbc.271.43.26962. PMID 8900182.

Further reading

  • Turner M, Schweighoffer E, Colucci F, Di Santo JP, Tybulewicz VL (March 2000). "Tyrosine kinase SYK: essential functions for immunoreceptor signalling". Immunology Today. 21 (3): 148–54. doi:10.1016/S0167-5699(99)01574-1. PMID 10689303.
  • Fruman DA, Satterthwaite AB, Witte ON (July 2000). "Xid-like phenotypes: a B cell signalosome takes shape". Immunity. 13 (1): 1–3. doi:10.1016/S1074-7613(00)00002-9. PMID 10933389.
  • Yanagi S, Inatome R, Takano T, Yamamura H (November 2001). "Syk expression and novel function in a wide variety of tissues". Biochemical and Biophysical Research Communications. 288 (3): 495–8. doi:10.1006/bbrc.2001.5788. PMID 11676469.
  • Tohyama Y, Yamamura H (2006). "Complement-mediated phagocytosis--the role of Syk". IUBMB Life. 58 (5–6): 304–8. doi:10.1080/15216540600746377. PMID 16754322.
  • Schymeinsky J, Mócsai A, Walzog B (August 2007). "Neutrophil activation via beta2 integrins (CD11/CD18): molecular mechanisms and clinical implications". Thrombosis and Haemostasis. 98 (2): 262–73. doi:10.1160/th07-02-0156. PMID 17721605.

External links

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