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Gene Review

Syk  -  spleen tyrosine kinase

Mus musculus

Synonyms: Spleen tyrosine kinase, Sykb, Tyrosine-protein kinase SYK, ptk72
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Disease relevance of Syk


High impact information on Syk


Biological context of Syk

  • Macrophages derived from Syk-deficient (Syk-) mice were defective in phagocytosis of particles bound by FcgammaRs, as well as in many FcgammaR-induced signaling events, including tyrosine phosphorylation of a number of cellular substrates and activation of MAP kinases [12].
  • Thus, Src family kinases clearly have roles in two events leading to FcgammaR-mediated phagocytosis, one involving initiation of actin polymerization and the second involving activation of Syk and subsequent internalization [13].
  • The redistribution of Vav was mediated by its Src homology 2 (SH2) domain and required Syk activity [14].
  • Many FcgammaR-induced functional responses and signaling events were diminished or delayed in these macrophages, including immunoglobulin (Ig)G-coated erythrocyte phagocytosis, respiratory burst, actin cup formation, and activation of Syk, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinases 1 and 2 [13].
  • The G-CSF-R mutant lacks the immunoreceptor tyrosine-based activation motif (ITAM), putative binding site for Syk [15].

Anatomical context of Syk


Associations of Syk with chemical compounds

  • Signaling events necessary for these responses are likely initiated by the activation of Src-family and Syk-family tyrosine kinases after FcgammaR cross-linking [12].
  • Although piceatannol, a reportedly selective inhibitor of Syk, also prevented degranulation and activation of p38 MAPK, no fMLP-induced phosphorylation of Syk could be observed, raising doubts about the specificity of the inhibitor [20].
  • Molecular basis for a direct interaction between the Syk protein-tyrosine kinase and phosphoinositide 3-kinase [21].
  • After engagement of the B cell receptor for antigen, the Syk protein-tyrosine kinase becomes phosphorylated on multiple tyrosines, some of which serve as docking sites for downstream effectors with SH2 or other phosphotyrosine binding domains [21].
  • In contrast, Syk expression did not reconstitute anti-IgM-induced inositol phosphate production [22].
  • Piceatannol, an inhibitor of Syk tyrosine kinase, or infection of Syk small interference RNA blocked the recombinant CRP-induced RhoA activity and the phosphorylation of JNK and IRS-1 [23].

Physical interactions of Syk

  • In addition, upon G-CSF stimulation, Lyn coimmunoprecipitated with Syk [24].
  • To examine the proximal signaling processes mediated by the pre-TCR complex and the role of the TCR-zeta chain in these processes, we stimulated pre-TCR-expressing cells and analyzed the interactions of the TCR/CD3 invariant chains with the Syk/ZAP-70 family of protein tyrosine kinases [25].
  • Overexpression of truncation mutants of Cbl capable of binding Syk has the effect of blocking tyrosine phosphorylation of endogenous Cbl [26].
  • Attesting to the importance of the Dap12/Syk complex, Syk deficient macrophages do not undergo normal osteoclastogenesis [27].
  • The Src homology domain mediated binding of Syk to the phosphorylated immunoreceptor tyrosine-based motif (ITAM) of the receptor subunits results in a conformational change and activation [28].

Enzymatic interactions of Syk

  • Immunoprecipitation experiments revealed that gamma-tubulin from activated cells formed complexes with Fyn and Syk protein tyrosine kinases and several tyrosine phosphorylated proteins from both wild-type and Lyn(-/-) BMMCs [19].
  • With total spleen B cells, Btk was maximally phosphorylated at a lower concentration of anti-kappa than Syk [29].
  • Our data show that direct contact of NK cells with a panel of sensitive tumor targets leads to a rapid and transient tyrosine phosphorylation of Vav and to its association with tyrosine-phosphorylated Syk [30].

Regulatory relationships of Syk

  • We further detected that the non-Src tyrosine kinase Syk was activated during shape change in a manner dependent on Src-family kinaseactivation [31].
  • The present study provides genetic, biochemical, and pharmacological evidence that, on FcepsilonRI stimulation, Syk regulates Btk, and Btk selectively regulates the membrane translocation and enzymatic activity of PKCbetaI among the conventional PKC isoforms (alpha, betaI, and betaII) expressed in mast cells [32].
  • These results support a model in which Syk can initiate and directly activate the T cell's signaling machinery and position Cbl as a primary tyrosine kinase substrate in this pathway [33].
  • R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation [3].
  • Platelet Syk was scarcely activated in the FcR gamma(-/-) mice after myocardial ischemia and reperfusion, but significantly activated in the FcR gamma(+/+) mice [34].

Other interactions of Syk


Analytical, diagnostic and therapeutic context of Syk

  • Receptor ligation also leads to the tyrosine phosphorylation and catalytic activation of Syk, but the mechanism of association of this kinase with the antigen receptor remains to be established [39].
  • On the basis of immunoprecipitation and sequence analysis data, we propose that the human G-CSFR forms a three-component signaling complex with Lyn and Syk [24].
  • Because the Syk tyrosine kinase is activated during both phases of integrin signaling, we evaluated its role in alphaIIbbeta3 function in murine platelets rendered null for Syk by gene targeting and in human platelets incubated with piceatannol, a tyrosine kinase inhibitor reportedly selective for Syk [40].
  • In this paper we report our reanalysis of Syk expression in subpopulations of murine and human thymocytes by intracellular staining and flow cytometry using anti-Syk mAbs [41].
  • We demonstrate that the calcium-mobilizing action of a collagen-related peptide (CRP) is kinase-dependent, inhibited by the microinjection of the tandem SH2 domains of Syk and abolished in Syk-deficient mice [42].


  1. The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase. Mócsai, A., Humphrey, M.B., Van Ziffle, J.A., Hu, Y., Burghardt, A., Spusta, S.C., Majumdar, S., Lanier, L.L., Lowell, C.A., Nakamura, M.C. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  2. B cell antigen receptor desensitization: disruption of receptor coupling to tyrosine kinase activation. Vilen, B.J., Famiglietti, S.J., Carbone, A.M., Kay, B.K., Cambier, J.C. J. Immunol. (1997) [Pubmed]
  3. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. Braselmann, S., Taylor, V., Zhao, H., Wang, S., Sylvain, C., Baluom, M., Qu, K., Herlaar, E., Lau, A., Young, C., Wong, B.R., Lovell, S., Sun, T., Park, G., Argade, A., Jurcevic, S., Pine, P., Singh, R., Grossbard, E.B., Payan, D.G., Masuda, E.S. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  4. Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy. Hirahashi, J., Mekala, D., Van Ziffle, J., Xiao, L., Saffaripour, S., Wagner, D.D., Shapiro, S.D., Lowell, C., Mayadas, T.N. Immunity (2006) [Pubmed]
  5. Syk expression in endothelial cells and their morphologic defects in embryonic Syk-deficient mice. Yanagi, S., Inatome, R., Ding, J., Kitaguchi, H., Tybulewicz, V.L., Yamamura, H. Blood (2001) [Pubmed]
  6. Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. Zou, W., Kitaura, H., Reeve, J., Long, F., Tybulewicz, V.L., Shattil, S.J., Ginsberg, M.H., Ross, F.P., Teitelbaum, S.L. J. Cell Biol. (2007) [Pubmed]
  7. Initiation and processing of signals from the B cell antigen receptor. Reth, M., Wienands, J. Annu. Rev. Immunol. (1997) [Pubmed]
  8. Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76. Pivniouk, V., Tsitsikov, E., Swinton, P., Rathbun, G., Alt, F.W., Geha, R.S. Cell (1998) [Pubmed]
  9. T cell activation by clustered tyrosine kinases. Kolanus, W., Romeo, C., Seed, B. Cell (1993) [Pubmed]
  10. Vav3 regulates osteoclast function and bone mass. Faccio, R., Teitelbaum, S.L., Fujikawa, K., Chappel, J., Zallone, A., Tybulewicz, V.L., Ross, F.P., Swat, W. Nat. Med. (2005) [Pubmed]
  11. A chimeric human-cat fusion protein blocks cat-induced allergy. Zhu, D., Kepley, C.L., Zhang, K., Terada, T., Yamada, T., Saxon, A. Nat. Med. (2005) [Pubmed]
  12. A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages. Crowley, M.T., Costello, P.S., Fitzer-Attas, C.J., Turner, M., Meng, F., Lowell, C., Tybulewicz, V.L., DeFranco, A.L. J. Exp. Med. (1997) [Pubmed]
  13. Fcgamma receptor-mediated phagocytosis in macrophages lacking the Src family tyrosine kinases Hck, Fgr, and Lyn. Fitzer-Attas, C.J., Lowry, M., Crowley, M.T., Finn, A.J., Meng, F., DeFranco, A.L., Lowell, C.A. J. Exp. Med. (2000) [Pubmed]
  14. The Src homology 2 domain of Vav is required for its compartmentation to the plasma membrane and activation of c-Jun NH(2)-terminal kinase 1. Arudchandran, R., Brown, M.J., Peirce, M.J., Song, J.S., Zhang, J., Siraganian, R.P., Blank, U., Rivera, J. J. Exp. Med. (2000) [Pubmed]
  15. The carboxy-terminal region of the granulocyte colony-stimulating factor receptor transduces a phagocytic signal. Santini, V., Scappini, B., Indik, Z.K., Gozzini, A., Ferrini, P.R., Schreiber, A.D. Blood (2003) [Pubmed]
  16. Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk. Sohn, H.W., Gu, H., Pierce, S.K. J. Exp. Med. (2003) [Pubmed]
  17. Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes. van Oers, N.S., Killeen, N., Weiss, A. J. Exp. Med. (1996) [Pubmed]
  18. Coordinate interactions of Csk, Src, and Syk kinases with [alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton. Obergfell, A., Eto, K., Mocsai, A., Buensuceso, C., Moores, S.L., Brugge, J.S., Lowell, C.A., Shattil, S.J. J. Cell Biol. (2002) [Pubmed]
  19. Regulation of microtubule formation in activated mast cells by complexes of gamma-tubulin with Fyn and Syk kinases. Sulimenko, V., Dráberová, E., Sulimenko, T., Macurek, L., Richterová, V., Dráber, P., Dráber, P. J. Immunol. (2006) [Pubmed]
  20. Kinase pathways in chemoattractant-induced degranulation of neutrophils: the role of p38 mitogen-activated protein kinase activated by Src family kinases. Mócsai, A., Jakus, Z., Vántus, T., Berton, G., Lowell, C.A., Ligeti, E. J. Immunol. (2000) [Pubmed]
  21. Molecular basis for a direct interaction between the Syk protein-tyrosine kinase and phosphoinositide 3-kinase. Moon, K.D., Post, C.B., Durden, D.L., Zhou, Q., De, P., Harrison, M.L., Geahlen, R.L. J. Biol. Chem. (2005) [Pubmed]
  22. Reconstitution of B cell antigen receptor-induced signaling events in a nonlymphoid cell line by expressing the Syk protein-tyrosine kinase. Richards, J.D., Gold, M.R., Hourihane, S.L., DeFranco, A.L., Matsuuchi, L. J. Biol. Chem. (1996) [Pubmed]
  23. C-reactive protein suppresses insulin signaling in endothelial cells: role of spleen tyrosine kinase. Xu, J.W., Morita, I., Ikeda, K., Miki, T., Yamori, Y. Mol. Endocrinol. (2007) [Pubmed]
  24. Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases. Corey, S.J., Burkhardt, A.L., Bolen, J.B., Geahlen, R.L., Tkatch, L.S., Tweardy, D.J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  25. The pre-T cell receptor (TCR) complex is functionally coupled to the TCR-zeta subunit. van Oers, N.S., von Boehmer, H., Weiss, A. J. Exp. Med. (1995) [Pubmed]
  26. Characterization of Cbl tyrosine phosphorylation and a Cbl-Syk complex in RBL-2H3 cells. Ota, Y., Beitz, L.O., Scharenberg, A.M., Donovan, J.A., Kinet, J.P., Samelson, L.E. J. Exp. Med. (1996) [Pubmed]
  27. High dose M-CSF partially rescues the Dap12-/- osteoclast phenotype. Faccio, R., Zou, W., Colaianni, G., Teitelbaum, S.L., Ross, F.P. J. Cell. Biochem. (2003) [Pubmed]
  28. Protein tyrosine kinase Syk in mast cell signaling. Siraganian, R.P., Zhang, J., Suzuki, K., Sada, K. Mol. Immunol. (2002) [Pubmed]
  29. Antigen receptor proximal signaling in splenic B-2 cell subsets. Li, X., Martin, F., Oliver, A.M., Kearney, J.F., Carter, R.H. J. Immunol. (2001) [Pubmed]
  30. Role for the Rac1 exchange factor Vav in the signaling pathways leading to NK cell cytotoxicity. Galandrini, R., Palmieri, G., Piccoli, M., Frati, L., Santoni, A. J. Immunol. (1999) [Pubmed]
  31. Genetic and pharmacological analyses of involvement of Src-family, Syk and Btk tyrosine kinases in platelet shape change. Src-kinases mediate integrin alphaIIb beta3 inside-out signalling during shape change. Bauer, M., Maschberger, P., Quek, L., Briddon, S.J., Dash, D., Weiss, M., Watson, S.P., Siess, W. Thromb. Haemost. (2001) [Pubmed]
  32. Regulation of protein kinase CbetaI by two protein-tyrosine kinases, Btk and Syk. Kawakami, Y., Kitaura, J., Hartman, S.E., Lowell, C.A., Siraganian, R.P., Kawakami, T. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  33. Direct T cell activation by chimeric single chain Fv-Syk promotes Syk-Cbl association and Cbl phosphorylation. Fitzer-Attas, C.J., Schindler, D.G., Waks, T., Eshhar, Z. J. Biol. Chem. (1997) [Pubmed]
  34. Platelets activated by collagen through the immunoreceptor tyrosine-based activation motif in the Fc receptor gamma-chain play a pivotal role in the development of myocardial ischemia-reperfusion injury. Takaya, N., Katoh, Y., Iwabuchi, K., Hayashi, I., Konishi, H., Itoh, S., Okumura, K., Ra, C., Nagaoka, I., Daida, H. J. Mol. Cell. Cardiol. (2005) [Pubmed]
  35. Rapid ubiquitination of Syk following GPVI activation in platelets. Dangelmaier, C.A., Quinter, P.G., Jin, J., Tsygankov, A.Y., Kunapuli, S.P., Daniel, J.L. Blood (2005) [Pubmed]
  36. Lyn and Syk kinases are sequentially engaged in phagocytosis mediated by Fc gamma R. Strzelecka-Kiliszek, A., Kwiatkowska, K., Sobota, A. J. Immunol. (2002) [Pubmed]
  37. Redundancy in B Cell Developmental Pathways: c-Cbl Inactivation Rescues Early B Cell Development through a B Cell Linker Protein-Independent Pathway. Song, H., Zhang, J., Chiang, Y.J., Siraganian, R.P., Hodes, R.J. J. Immunol. (2007) [Pubmed]
  38. Scaffolding adapter Grb2-associated binder 2 requires Syk to transmit signals from FcepsilonRI. Yu, M., Lowell, C.A., Neel, B.G., Gu, H. J. Immunol. (2006) [Pubmed]
  39. The SH2 domains of Src family kinases associate with Syk. Aoki, Y., Kim, Y.T., Stillwell, R., Kim, T.J., Pillai, S. J. Biol. Chem. (1995) [Pubmed]
  40. Genetic and pharmacological analyses of Syk function in alphaIIbbeta3 signaling in platelets. Law, D.A., Nannizzi-Alaimo, L., Ministri, K., Hughes, P.E., Forsyth, J., Turner, M., Shattil, S.J., Ginsberg, M.H., Tybulewicz, V.L., Phillips, D.R. Blood (1999) [Pubmed]
  41. Pre-T cell receptor signals are responsible for the down-regulation of Syk protein tyrosine kinase expression. Chu, D.H., van Oers, N.S., Malissen, M., Harris, J., Elder, M., Weiss, A. J. Immunol. (1999) [Pubmed]
  42. Syk and Fyn are required by mouse megakaryocytes for the rise in intracellular calcium induced by a collagen-related peptide. Melford, S.K., Turner, M., Briddon, S.J., Tybulewicz, V.L., Watson, S.P. J. Biol. Chem. (1997) [Pubmed]
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