Biology:Syk

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Generic protein structure example

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 phosphorylation 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". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6850. 
  2. ↑ "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain". Cell 71 (4): 649–62. November 1992. doi:10.1016/0092-8674(92)90598-7. PMID 1423621. 
  3. ↑ "Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans". Immunogenetics 40 (4): 300–2. 1994. doi:10.1007/BF00189976. PMID 8082894. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells". European Journal of Haematology 94 (3): 193–205. March 2015. doi:10.1111/ejh.12427. PMID 25080849. 
  5. ↑ "Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes". Frontiers in Immunology 8: 789. 2017-07-07. doi:10.3389/fimmu.2017.00789. PMID 28736554. 
  6. ↑ "Regulation of developmental lymphangiogenesis by Syk(+) leukocytes". Developmental Cell 18 (3): 437–49. March 2010. doi:10.1016/j.devcel.2010.01.009. PMID 20230750. 
  7. ↑ "Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib". Therapeutic Advances in Hematology 7 (3): 157–70. 2016. doi:10.1177/2040620716636542. PMID 27247756. 
  8. ↑ "Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms". Pharmacological Research 113 (Pt A): 395–408. 2016. doi:10.1016/j.phrs.2016.09.011. PMID 27641927. 
  9. ↑ "Idelalisib in the management of lymphoma". Blood 128 (3): 331–6. 2016. doi:10.1182/blood-2016-02-702761. PMID 27252232. 
  10. ↑ "Spleen tyrosine kinase inhibitors for rheumatoid arthritis: where are we now?". Drugs 74 (4): 415–22. 2014. doi:10.1007/s40265-014-0193-9. PMID 24610702. 
  11. ↑ "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation". The Journal of Biological Chemistry 289 (49): 33927–44. December 2014. doi:10.1074/jbc.M114.608091. PMID 25331948. 
  12. ↑ "A Phase III Trial of Nilvadipine to Treat Alzheimer's Disease". ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02017340. 
  13. ↑ "SYK allelic loss and the role of Syk-regulated genes in breast cancer survival". PLOS ONE 9 (2): e87610. 2014. doi:10.1371/journal.pone.0087610. PMID 24523870. 
  14. ↑ 14.0 14.1 "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. PMID 11331248. 
  15. ↑ "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. doi:10.1074/jbc.273.52.35273. PMID 9857068. 
  16. ↑ "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. doi:10.1042/BJ20021201. PMID 12435267. 
  17. ↑ "CrkL is an adapter for Wiskott-Aldrich syndrome protein and Syk". Blood 97 (9): 2633–9. May 2001. doi:10.1182/blood.V97.9.2633. PMID 11313252. 
  18. ↑ "Influence of tyrosine phosphorylation on protein interaction with FcgammaRIIa". Biochimica et Biophysica Acta 1357 (3): 348–58. July 1997. doi:10.1016/S0167-4889(97)00034-7. PMID 9268059. 
  19. ↑ "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. doi:10.1006/clim.2000.4955. PMID 11141335. 
  20. ↑ "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. doi:10.1074/jbc.273.15.8867. PMID 9535867. 
  21. ↑ "Thrombspondin acts via integrin-associated protein to activate the platelet integrin alphaIIbbeta3". The Journal of Biological Chemistry 272 (23): 14740–6. June 1997. doi:10.1074/jbc.272.23.14740. PMID 9169439. 
  22. ↑ 22.0 22.1 "Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk". The Journal of Biological Chemistry 275 (23): 17263–8. June 2000. doi:10.1074/jbc.M000689200. PMID 10747947. 
  23. ↑ "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. doi:10.1042/0264-6021:3630717. PMID 11964172. 
  24. ↑ "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. doi:10.1084/jem.181.6.1997. PMID 7539035. 
  25. ↑ "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. doi:10.1073/pnas.92.2.359. PMID 7831290. 
  26. ↑ "Relocation of Syk protein-tyrosine kinase to the actin filament network and subsequent association with Fak". European Journal of Biochemistry 248 (3): 827–33. September 1997. doi:10.1111/j.1432-1033.1997.00827.x. PMID 9342235. 
  27. ↑ "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. PMID 10072516. 
  28. ↑ "Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product". Immunity 5 (6): 591–604. December 1996. doi:10.1016/S1074-7613(00)80273-3. PMID 8986718. 
  29. ↑ "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. doi:10.1074/jbc.271.43.26962. PMID 8900182. 

Further reading

External links




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