| Structural highlights
Function
KSYK_HUMAN Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Spleen tyrosine kinase (SYK) is a cytosolic non-receptor protein tyrosine kinase that mediates key signal transduction pathways following the activation of immune cell receptors. SYK regulates cellular events induced by the B cell receptor and Fc receptors with high intrinsic activity. Furthermore, SYK has been regarded as an attractive target for the treatment of autoimmune diseases and cancers. Here, we report the crystal structures of SYK in complex with seven newly developed inhibitors (G206, G207, O178, O194, O259, O272, and O282) to provide structural insights into which substituents of the inhibitors and binding regions of SYK are essential for lead compound optimization. Our kinase inhibitors exhibited high inhibitory activities against SYK, with half-maximal inhibitory concentrations (IC50 ) of approximately 0.7-33 nM, but they showed dissimilar inhibitory activities against KDR, RET, JAK2, JAK3, and FLT3. Among the seven SYK inhibitors, O272 and O282 exhibited highly specific inhibitions against SYK, whereas O194 exhibited strong inhibition of both SYK and FLT3. Three inhibitors (G206, G207, and O178) more efficiently inhibited FLT3 while still substantially inhibiting SYK activity. The binding mode analysis suggested that a highly selective SYK inhibitor can be developed by optimizing the functional groups that facilitate direct interactions with Asn499. This article is protected by copyright. All rights reserved.
Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs.,Lee SJ, Choi JS, Han BG, Kim HS, Song HJ, Lee J, Nam S, Goh SH, Kim JH, Koh JS, Lee BI FEBS J. 2016 Aug 9. doi: 10.1111/febs.13831. PMID:27504936[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Law CL, Chandran KA, Sidorenko SP, Clark EA. Phospholipase C-gamma1 interacts with conserved phosphotyrosyl residues in the linker region of Syk and is a substrate for Syk. Mol Cell Biol. 1996 Apr;16(4):1305-15. PMID:8657103
- ↑ Deckert M, Elly C, Altman A, Liu YC. Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases. J Biol Chem. 1998 Apr 10;273(15):8867-74. PMID:9535867
- ↑ Chiu CW, Dalton M, Ishiai M, Kurosaki T, Chan AC. BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins. EMBO J. 2002 Dec 2;21(23):6461-72. PMID:12456653
- ↑ Urzainqui A, Serrador JM, Viedma F, Yanez-Mo M, Rodriguez A, Corbi AL, Alonso-Lebrero JL, Luque A, Deckert M, Vazquez J, Sanchez-Madrid F. ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1. Immunity. 2002 Oct;17(4):401-12. PMID:12387735
- ↑ Shim EK, Moon CS, Lee GY, Ha YJ, Chae SK, Lee JR. Association of the Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) with the p85 subunit of phosphoinositide 3-kinase. FEBS Lett. 2004 Sep 24;575(1-3):35-40. PMID:15388330 doi:10.1016/j.febslet.2004.07.090
- ↑ Cholay M, Reverdy C, Benarous R, Colland F, Daviet L. Functional interaction between the ubiquitin-specific protease 25 and the SYK tyrosine kinase. Exp Cell Res. 2010 Feb 15;316(4):667-75. doi: 10.1016/j.yexcr.2009.10.023. Epub, 2009 Nov 10. PMID:19909739 doi:10.1016/j.yexcr.2009.10.023
- ↑ Lee SJ, Choi JS, Han BG, Kim HS, Song HJ, Lee J, Nam S, Goh SH, Kim JH, Koh JS, Lee BI. Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs. FEBS J. 2016 Aug 9. doi: 10.1111/febs.13831. PMID:27504936 doi:http://dx.doi.org/10.1111/febs.13831
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