Spleen tyrosine kinase (Syk) is a cytoplasmic protein tyrosine kinase well known for its ability to couple immune cell receptors to intracellular signaling pathways that regulate cellular responses to extracellular antigens and antigen–immunoglobulin (Ig) complexes of particular importance to the initiation of inflammatory responses. Thus, Syk is an attractive target for therapeutic kinase inhibitors designed to ameliorate the symptoms and consequences of acute and chronic inflammation.
Syk is abundantly expressed in a wide range of haematopoietic cells such as B cells, mast cells, neutrophils, macrophages and platelets, as well as in various non-immune cells. Syk contains a C-terminal kinase domain and tandem N-terminal SH2 domains that bind phosphorylated ITAMs. These domains are separated by two distinct linker regions named Interdomain A (located between the N-SH2 and C-SH2 domains) and interdomain B (located between the C-SH2 and the kinase domain). The Interdomain A has a mainly structural role in providing a helical coiled-coil structure to the tandem SH2 domain, for the appropriate binding to phosphorylated ITAMs. Furthermore, it has been described to play a role in the inhibition of spontaneous activation of the kinase activity in the resting state. The Interdomain B contains autophosphorylation sites and has been shown to participate in the recruitment of downstream signalling molecules.
Syk was first implicated in platelet activation in 1992 by Ohta et al. who showed that Syk undergoes autophosphorylation in response to wheat-germ agglutinin. Later work by Fujii et al. showed that collagen could induce tyrosine phosphorylation of Syk and increase its kinase activity and was a result of direct collagen-induced signaling and not a function of feedback. Later work by Poole et al. demonstrated that platelets deficient in Syk have many deficits in Glycoprotein VI (GPVI) mediated platelet activation. It was shown that platelets devoid of Syk fail to aggregate, secrete stored granules, form arachidonic acid and exhibit no PLCγ2 phosphorylation in response to GPVI agonists. Syk's role in GPVI signaling is therefore undisputed and tight regulation of its activation and deactivation are of critical importance to ensure necessary platelet activation to prevent bleeding while preventing uncontrolled platelet activation that may lead to thrombosis.
Syk has been validated as a target for inhibition of B cell antigen receptor (BCR) and FcγR-mediated antigen presentation. Interruption of signaling at the level of Syk blocks immunoreceptor signaling prior to divergence of the signal transduction activation pathway, thus uncoupling immunoreceptor engagement from cellular activation. Notably, Syk inhibition leaves T cell function unaffected, since mature T cells do not utilize Syk in order to transduce activating signals downstream of the TCR, but rather the Syk family member ZAP70. Small molecule Syk inhibitor R406/788 (fostamatinib disodium; Rigel Pharmaceuticals, South San Francisco) is a potent multikinase inhibitor that demonstrated considerable selectivity for Syk. R406/788 was shown to block immune complex-mediated DC activation and antigen presentation in vitro and in vivo, abrogating sensitization by immune-complex-pulsed Dendritic cells (DCs) in an asthma model. Additionally, R406/788 inhibited activation of primary B cells isolated from human peripheral blood following BCR cross-linking.
R406/788 acts as a competitive inhibitor of ATP binding to the Syk kinase domain. R788 is a prodrug that, following oral administration, is readily converted into the active molecule R406. R788 is now in phase II clinical trials in Rheumatoid Arthritis (RA), Immune Thrombocytopenic Purpura (ITP) and B cell lymphoma, where activating signaling downstream of FcγR and/or the BCR have been shown to be important pathogenetic factors. Diffraction data obtained from the crystallographic analysis of human Syk protein kinase domain soaked with R406/788 are consistent with R406/788 competing with ATP for binding to the same pocket. Studies with IgE-crosslinked murine mast cells and BCR-stimulated Ramos B cells showed that R406/788 does not inhibit the activity of Src-family kinases, but inhibits signaling downstream of Syk (i.e.: activation of PLCγ, Akt, p38).
Reference:Lucrezia Colonna. Targeting Syk in Autoimmune Diabetes
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