| Structural highlights
Function
[VAV_HUMAN] Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation. [KSYK_MOUSE] 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] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
Activated Syk, an essential tyrosine kinase in B cell signaling, interacts with Vav guanine nucleotide exchange factors and regulates Vav activity through tyrosine phosphorylation. The Vav SH2 domain binds Syk linker B by an unusual recognition of two closely spaced Syk tyrosines: Y342 and Y346. The binding affinity is highest when both Y342 and Y346 are phosphorylated. An investigation in B cells of the dependence of Vav phosphorylation and NFAT activation on phosphorylation of Y342 and Y346 finds that cellular response levels match the relative binding affinities of the Vav1 SH2 domain for singly and doubly phosphorylated linker B peptides. This key result suggests that the uncommon recognition determinant of these two closely spaced tyrosines is a limiting factor in signaling. Interestingly, differences in affinities for binding singly and doubly phosphorylated peptides are reflected in the on rate, not the off rate. Such a control mechanism would be highly effective for regulating binding among competing Syk binding partners. The nuclear magnetic resonance (NMR) structure of Vav1 SH2 in complex with a doubly phosphorylated linker B peptide reveals diverse conformations associated with the unusual SH2 recognition of two phosphotyrosines. NMR relaxation indicates compensatory changes in loop fluctuations upon binding, with implications for nonphosphotyrosine interactions of Vav1 SH2.
Two closely spaced tyrosines regulate NFAT signaling in B cells via Syk association with Vav.,Chen CH, Martin VA, Gorenstein NM, Geahlen RL, Post CB Mol Cell Biol. 2011 Jul;31(14):2984-96. Epub 2011 May 23. PMID:21606197[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Poole A, Gibbins JM, Turner M, van Vugt MJ, van de Winkel JG, Saito T, Tybulewicz VL, Watson SP. The Fc receptor gamma-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen. EMBO J. 1997 May 1;16(9):2333-41. PMID:9171347 doi:10.1093/emboj/16.9.2333
- ↑ Vines CM, Potter JW, Xu Y, Geahlen RL, Costello PS, Tybulewicz VL, Lowell CA, Chang PW, Gresham HD, Willman CL. Inhibition of beta 2 integrin receptor and Syk kinase signaling in monocytes by the Src family kinase Fgr. Immunity. 2001 Oct;15(4):507-19. PMID:11672534
- ↑ Obergfell A, Eto K, Mocsai A, Buensuceso C, Moores SL, Brugge JS, Lowell CA, Shattil SJ. Coordinate interactions of Csk, Src, and Syk kinases with [alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton. J Cell Biol. 2002 Apr 15;157(2):265-75. Epub 2002 Apr 8. PMID:11940607 doi:10.1083/jcb.200112113
- ↑ Abtahian F, Guerriero A, Sebzda E, Lu MM, Zhou R, Mocsai A, Myers EE, Huang B, Jackson DG, Ferrari VA, Tybulewicz V, Lowell CA, Lepore JJ, Koretzky GA, Kahn ML. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science. 2003 Jan 10;299(5604):247-51. PMID:12522250 doi:10.1126/science.1079477
- ↑ Underhill DM, Rossnagle E, Lowell CA, Simmons RM. Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood. 2005 Oct 1;106(7):2543-50. Epub 2005 Jun 14. PMID:15956283 doi:10.1182/blood-2005-03-1239
- ↑ Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, Williams DL, Gordon S, Tybulewicz VL, Brown GD, Reis e Sousa C. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005 Apr;22(4):507-17. PMID:15845454 doi:S1074-7613(05)00095-6
- ↑ Suzuki-Inoue K, Fuller GL, Garcia A, Eble JA, Pohlmann S, Inoue O, Gartner TK, Hughan SC, Pearce AC, Laing GD, Theakston RD, Schweighoffer E, Zitzmann N, Morita T, Tybulewicz VL, Ozaki Y, Watson SP. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood. 2006 Jan 15;107(2):542-9. Epub 2005 Sep 20. PMID:16174766 doi:2005-05-1994
- ↑ Mocsai A, Abram CL, Jakus Z, Hu Y, Lanier LL, Lowell CA. Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat Immunol. 2006 Dec;7(12):1326-33. Epub 2006 Nov 5. PMID:17086186 doi:10.1038/ni1407
- ↑ Zou W, Kitaura H, Reeve J, Long F, Tybulewicz VL, Shattil SJ, Ginsberg MH, Ross FP, Teitelbaum SL. Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J Cell Biol. 2007 Mar 12;176(6):877-88. PMID:17353363 doi:10.1083/jcb.200611083
- ↑ Van Ziffle JA, Lowell CA. Neutrophil-specific deletion of Syk kinase results in reduced host defense to bacterial infection. Blood. 2009 Nov 26;114(23):4871-82. doi: 10.1182/blood-2009-05-220806. Epub 2009 , Oct 1. PMID:19797524 doi:10.1182/blood-2009-05-220806
- ↑ Oda H, Fujimoto M, Patrick MS, Chida D, Sato Y, Azuma Y, Aoki H, Abe T, Suzuki H, Shirai M. RhoH plays critical roles in Fc epsilon RI-dependent signal transduction in mast cells. J Immunol. 2009 Jan 15;182(2):957-62. PMID:19124738
- ↑ Gross O, Poeck H, Bscheider M, Dostert C, Hannesschlager N, Endres S, Hartmann G, Tardivel A, Schweighoffer E, Tybulewicz V, Mocsai A, Tschopp J, Ruland J. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. 2009 May 21;459(7245):433-6. doi: 10.1038/nature07965. Epub 2009 Apr 1. PMID:19339971 doi:10.1038/nature07965
- ↑ Sancho D, Joffre OP, Keller AM, Rogers NC, Martinez D, Hernanz-Falcon P, Rosewell I, Reis e Sousa C. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature. 2009 Apr 16;458(7240):899-903. doi: 10.1038/nature07750. PMID:19219027 doi:10.1038/nature07750
- ↑ Chen CH, Martin VA, Gorenstein NM, Geahlen RL, Post CB. Two closely spaced tyrosines regulate NFAT signaling in B cells via Syk association with Vav. Mol Cell Biol. 2011 Jul;31(14):2984-96. Epub 2011 May 23. PMID:21606197 doi:10.1128/MCB.05043-11
|
