| 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
The association of Syk, a central tyrosine kinase in B cell signaling, with Vav SH2 domain is controlled by phosphorylation of two closely spaced tyrosines in Syk linker B: Y342 and Y346. Previous studies established both singly phosphorylated and doubly phosphorylated forms play a role in signaling. The structure of the doubly phosphorylated form identified a new recognition of phosphotyrosine whereby two phosphotyrosines bind simultaneously to the Vav SH2 domain, one in the canonical pTyr pocket and one in the specificity pocket on the opposite side of the central betasheet. It is unknown if the specificity pocket can bind phosphotyrosine independent of phosphotyrosine binding the pTyr pocket. To address this gap in knowledge, we determined the structure of the complex between Vav1 SH2 and a peptide (SykLBYpY) modeling the singly phosphorylatedY346 form of Syk with unphosphorylated Y342. The NMR data conclusively establish that recognition of phosphotyrosine is swapped between the two pockets; phosphorylated pY346 binds the specificity pocket of Vav1 SH2, and unphosphorylated Y342 occupies what is normally the pTyr binding pocket. Nearly identical changes in chemical shifts occurred upon binding all three forms of singly and doubly phosphorylated peptides; however somewhat smaller shift perturbations for SykLBYpY from residues in regions of high internal mobility suggest that internal motions are coupled to binding affinity. The differential recognition that includes this swapped binding of phosphotyrosine to the specificity pocket of Vav SH2 increases the repertoire of possible phosphotyrosine binding by SH2 domains in regulating proteinprotein interactions in cellular signaling.
Differential recognition of Syk-binding sites by each of the two phosphotyrosine-binding pockets of the Vav SH2 domain.,Chen CH, Piraner D, Gorenstein NM, Geahlen RL, Post CB Biopolymers. 2013 Aug 17. doi: 10.1002/bip.22371. PMID:23955592[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, Piraner D, Gorenstein NM, Geahlen RL, Post CB. Differential recognition of Syk-binding sites by each of the two phosphotyrosine-binding pockets of the Vav SH2 domain. Biopolymers. 2013 Aug 17. doi: 10.1002/bip.22371. PMID:23955592 doi:10.1002/bip.22371
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