Tyrosine-protein kinase SYK explained

Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the SYK gene.[1] [2] [3]

Function

SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor tyrosine kinases share a characteristic dual SH2 domain separated by a linker domain. However, activation of SYK relies less on phosphorylation by Src family kinases than ZAP70.[4] SYK and ZAP70 share a common evolutionary origin and split from a common ancestor in the jawed vertebrates.[5]

While Syk and ZAP70 are primarily expressed in hematopoietic tissues, a variety of tissues express Syk. Within B and T cells, respectively, Syk and ZAP70 transmit signals from the B-cell receptor and T-cell receptor.[6] 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.[7]

Clinical significance

Abnormal function of Syk has been implicated in several instances of hematopoietic malignancies including translocations involving Itk and Tel. Constitutive Syk activity can transform B cells. 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.

Syk inhibition has been proposed as a therapy for both lymphoma and chronic lymphocytic leukemia. Syk inhibitors are in clinical development, including cerdulatinib and entospletinib.[8] Other inhibitors of B-cell receptor (BCR) signaling including ibrutinib (PCI-32765) which inhibits BTK,[9] and idelalisib (PI3K inhibitor - CAL-101 / GS-1101) showed activity in the diseases as well.[10]

The orally active SYK inhibitor fostamatinib (R788) in the treatment of immune thrombocytopenia.[11]

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[12] and has entered phase III clinical trials.[13]

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.[14]

Interactions

Syk has been shown to interact with:

Further reading

Notes and References

  1. Web site: Entrez Gene: SYK Spleen tyrosine kinase .
  2. Chan AC, Iwashima M, Turck CW, Weiss A . ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain . Cell . 71 . 4 . 649–62 . November 1992 . 1423621 . 10.1016/0092-8674(92)90598-7 . 54326428 .
  3. Ku G, Malissen B, Mattei MG . Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans . Immunogenetics . 40 . 4 . 300–2 . 1994 . 8082894 . 10.1007/BF00189976 . 33774157 .
  4. Fasbender F, Claus M, Wingert S, Sandusky M, Watzl C . Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes . Frontiers in Immunology . 8 . 789 . 2017-07-07 . 28736554 . 5500614 . 10.3389/fimmu.2017.00789 . free .
  5. Staal J, Driege Y, Haegman M, Borghi A, Hulpiau P, Lievens L, Gul IS, Sundararaman S, Gonçalves A, Dhondt I, Pinzón JH, Braeckman BP, Technau U, Saeys Y, van Roy F, Beyaert R . 6 . Ancient Origin of the CARD-Coiled Coil/Bcl10/MALT1-Like Paracaspase Signaling Complex Indicates Unknown Critical Functions . Frontiers in Immunology . 9 . 1136 . 2018 . 29881386 . 5978004 . 10.3389/fimmu.2018.01136 . free .
  6. Mócsai A, Ruland J, Tybulewicz VL . The SYK tyrosine kinase: a crucial player in diverse biological functions . Nature Reviews. Immunology . 10 . 6 . 387–402 . June 2010 . 20467426 . 10.1038/nri2765 . 4782221 .
  7. Böhmer R, Neuhaus B, Bühren S, Zhang D, Stehling M, Böck B, Kiefer F . Regulation of developmental lymphangiogenesis by Syk(+) leukocytes . Developmental Cell . 18 . 3 . 437–49 . March 2010 . 20230750 . 10.1016/j.devcel.2010.01.009 . free .
  8. Sharman J, Di Paolo J . Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib . Therapeutic Advances in Hematology . 7 . 3 . 157–70 . 2016 . 27247756 . 4872176 . 10.1177/2040620716636542 .
  9. Roskoski R . Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms . Pharmacological Research . 113 . Pt A . 395–408 . 2016 . 27641927 . 10.1016/j.phrs.2016.09.011 .
  10. Cheah CY, Fowler NH . Idelalisib in the management of lymphoma . Blood . 128 . 3 . 331–6 . 2016 . 27252232 . 10.1182/blood-2016-02-702761 . 5161010.
  11. Scott IC, Scott DL . Spleen tyrosine kinase inhibitors for rheumatoid arthritis: where are we now? . Drugs . 74 . 4 . 415–22 . 2014 . 24610702 . 10.1007/s40265-014-0193-9 . 24168330 .
  12. Paris D, Ait-Ghezala G, Bachmeier C, Laco G, Beaulieu-Abdelahad D, Lin Y, Jin C, Crawford F, Mullan M . The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation . The Journal of Biological Chemistry . 289 . 49 . 33927–44 . December 2014 . 25331948 . 4256331 . 10.1074/jbc.M114.608091 . free .
  13. A Phase III Trial of Nilvadipine to Treat Alzheimer's Disease . ClinicalTrials.gov . 3 March 2017 . 2017-04-02. Lawlor . Prof Brian .
  14. Blancato J, Graves A, Rashidi B, Moroni M, Tchobe L, Ozdemirli M, Kallakury B, Makambi KH, Marian C, Mueller SC . SYK allelic loss and the role of Syk-regulated genes in breast cancer survival . PLOS ONE . 9 . 2 . e87610 . 2014 . 24523870 . 3921124 . 10.1371/journal.pone.0087610 . 2014PLoSO...987610B . free .
  15. Lupher ML, Rao N, Lill NL, Andoniou CE, Miyake S, Clark EA, Druker B, Band H . 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 . December 1998 . 9857068 . 10.1074/jbc.273.52.35273 . free .
  16. Melander F, Andersson T, Dib K . 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 . March 2003 . 12435267 . 1223185 . 10.1042/BJ20021201 .
  17. Oda A, Ochs HD, Lasky LA, Spencer S, Ozaki K, Fujihara M, Handa M, Ikebuchi K, Ikeda H . CrkL is an adapter for Wiskott-Aldrich syndrome protein and Syk . Blood . 97 . 9 . 2633–9 . May 2001 . 11313252 . 10.1182/blood.V97.9.2633 . free .
  18. Ibarrola I, Vossebeld PJ, Homburg CH, Thelen M, Roos D, Verhoeven AJ . Influence of tyrosine phosphorylation on protein interaction with FcgammaRIIa . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1357 . 3 . 348–58 . July 1997 . 9268059 . 10.1016/S0167-4889(97)00034-7 . free .
  19. Kim MK, Pan XQ, Huang ZY, Hunter S, Hwang PH, Indik ZK, Schreiber AD . 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 . January 2001 . 11141335 . 10.1006/clim.2000.4955 .
  20. Deckert M, Elly C, Altman A, Liu YC . Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases . The Journal of Biological Chemistry . 273 . 15 . 8867–74 . April 1998 . 9535867 . 10.1074/jbc.273.15.8867 . free .
  21. Chung J, Gao AG, Frazier WA . Thrombspondin acts via integrin-associated protein to activate the platelet integrin alphaIIbbeta3 . The Journal of Biological Chemistry . 272 . 23 . 14740–6 . June 1997 . 9169439 . 10.1074/jbc.272.23.14740 . free .
  22. Saci A, Liu WQ, Vidal M, Garbay C, Rendu F, Bachelot-Loza C . 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 . May 2002 . 11964172 . 1222524 . 10.1042/0264-6021:3630717 .
  23. Thome M, Duplay P, Guttinger M, Acuto O . 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 . June 1995 . 7539035 . 2192070 . 10.1084/jem.181.6.1997 .
  24. Sidorenko SP, Law CL, Chandran KA, Clark EA . 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 . January 1995 . 7831290 . 42739 . 10.1073/pnas.92.2.359 . 1995PNAS...92..359S . free .
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  26. Ganju RK, Brubaker SA, Chernock RD, Avraham S, Groopman JE . Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk . The Journal of Biological Chemistry . 275 . 23 . 17263–8 . June 2000 . 10747947 . 10.1074/jbc.M000689200 . free .
  27. Dustin LB, Plas DR, Wong J, Hu YT, Soto C, Chan AC, Thomas ML . 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 . March 1999 . 10.4049/jimmunol.162.5.2717 . 10072516 . free .
  28. Bertagnolo V, Marchisio M, Brugnoli F, Bavelloni A, Boccafogli L, Colamussi ML, Capitani S . Requirement of tyrosine-phosphorylated Vav for morphological differentiation of all-trans-retinoic acid-treated HL-60 cells . Cell Growth & Differentiation . 12 . 4 . 193–200 . April 2001 . 11331248 .
  29. Deckert M, Tartare-Deckert S, Couture C, Mustelin T, Altman A . Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product . Immunity . 5 . 6 . 591–604 . December 1996 . 8986718 . 10.1016/S1074-7613(00)80273-3 . free .
  30. Song JS, Gomez J, Stancato LF, Rivera J . 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 . October 1996 . 8900182 . 10.1074/jbc.271.43.26962 . free .

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