SYK (spleen tyrosine kinase)

Alias_names	spleen tyrosine kinase
Other alias	P72-Syk
	Tyrosine-Protein Kinase SYK
	EC 2.7.10.2
	EC 2.7.10
HGNC (Hugo)	SYK
LocusID (NCBI)	6850
Atlas_Id	394
Location	9q22.2  [Link to chromosome band 9q22]
Location_base_pair	Starts at 90801680 and ends at 90898560 bp from pter ( according to hg19-Feb_2009)  [Mapping SYK.png]
	Figure 1. Mapping of SYK gene on chromosome 9q22.2 (from GeneCards Syk gene).

Description	SYK is a 72 kDa non-receptor type protein tyrosine kinase (PTK) that contains two SRC homology 2 (SH2) domains, interdomains A and B, and a C-terminal kinase domain (Fig. 2). SYK was initially shown to be expressed in lymphocytes and associated with the IgM and IgD receptor complexes in B cells (Taniguchi 1991; Hutchcroft 1992). The requirement for Src-PTKs associated with the B cell receptor (BCR) for phosphorylation of SYK was investigated early, and was shown to enhance the activity of SYK (Kurosaki 1994). The PTK ZAP70 was cloned in T lymphocytes and shown to be homologous to SYK (Chan 1992). An alternatively spliced form of SYK also exists, missing 23 amino acids from interdomain A (Sada 2001). The topology of the N-terminal part of SYK is similar to its counterpart ZAP70 as revealed by the crystal structure (Narula 1995; Hatada 1995). In 1998, Fütterer et al presented the crystal structure of the tandem SH2 domain of SYK complexed with a dually phosphorylated ITAM peptide (Fütterer 1998). The tandem SH2 domains selectively bind to diphosphorylated immunoreceptor tyrosine based activating motifs (ITAM) of the cytoplasmic region of the BCR (Sada 2001). The crystal structure of a full-length version of ZAP70 has given a greater understanding of the activation process for both SYK and Zap-70 (Deindl 2007). Atwell et al determined the structure of the unphosphorylated form of the SYK kinase catalytic domain (SYK-KD) in order to understand the molecular mechanism responsible for its enzymatic activity (Atwell 2004). The SYK kinase domain has a subdomain structure composed of a largely β-sheet N-terminal lobe, a largely α–helical C-terminal lobe, with the active site being sandwiched between the two lobes. The N-terminal lobe consists of a five-stranded β -sheet plus a single α –helix. The larger C-terminal lobe is predominantly α –helical with three short β -strands: one at the hinge region and two between the activation loop and the main body of the C-lobe. From the structure of the SYK kinase domain it was deduced that the SYK catalytic activity does not require activation loop phosphorylation. SYK have multiple sites of phosphorylation which both regulate activity and serve as docking motifs for other proteins (Sada 2001). Phosphorylation sites include Tyr-348 and Tyr-352 within the SH2-linker region (Brdicka 2005), Tyr-525 and Tyr-526 within the activation loop of the kinase domain (Zhang 2000), Tyr-630 in the C terminus of SYK, and others (Kulathu 2008; Tsang 2008; and reviewed by Sada 2001). In B cells, the phosphorylation of two tyrosines within the ITAM leads to the physical recruitment of SYK to the site of the clustered receptor in an interaction mediated by its tandem pair of SH2 domains (reviewed in Geahlen 2009). Shortly following BCR engagement, SYK that has been recruited to the receptor becomes phosphorylated on multiple tyrosines through both autophosphorylation and phosphorylation by Lyn.
	Figure 2. Schematic structure of spleen tyrosine kinase (SYK) protein (adopted from Pamuk et al 2010). The protein includes two tandem SH2 domains and a tyrosine kinase domain. Between the two SH2 domains is interdomain A while interdomain B is located between the tyrosine kinase domain and C-terminal domain. ITAM, immunoreceptor tyrosine-based activation motif; SH2, Src homology 2.
Expression	SYK expression in hematopoietic cells has been extensively determined by studying SYK as an effector of BCR signalling. Turner and co-workers found that after BCR activation, SYK-dependent signaling pathways regulate the clonal expansion, differentiation, or apoptosis of B cells (Turner 2000). Most of the cells of the hematopoietic system express SYK, but the PTK is also expressed at lower levels in some epithelial cells, fibroblasts, hepatocytes, vascular smooth muscle cells, endothelial cells and neuronal cells where it mediates various responses including adipogenesis, cell division, tumor suppression, ERK activation and neuronal differentiation (Turner 2000; Yanagi 2001; Zhou 2006; Tohyama 2009; Geahlen 2009; Mócsai 2010; Krisenko 2015). In hepatocytes, after the use of the SYK-selective inhibitor piceatannol, it was indicated that SYK is necessary for mitogen activated protein kinase (MAPK) activation by G-protein coupled receptors in this cell type (Tsuchida 2000). Additionally, SYK expression has also been observed in normal human breast tissue, benign lesions and low-tumourigenic breast cancer cell lines (Coopman 2000).
Localisation	SYK is an intracellular PTK, known to function at the plasma membrane, where the receptors to which it is recruited are located (Zhou 2006). In lymphoid and epithelial cells, SYK has been found to reside in both the nucleus and cytoplasm (Ma 2001; Wang 2003; Wang 2004). The expression and localization of SYK in the nucleus of breast cancer cells have been correlated with the repression of invasive tumor growth (Wang 2003).
Function	The SYK protein is known to have an important role in adaptive immune receptor signalling with recent reports indicating its mediation of other diverse biological functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development (Mócsai 2010). The protein is also involved in coupling activated immunoreceptors to downstream signaling events that mediate diverse cellular responses, including proliferation, differentiation, and phagocytosis. SYK plays a critical role in the transition of pro-B cells into pre-B cells (Turner 1995). SYK is greatly involved in signal transduction initiated by the classic immunoreceptors, including BCRs, Fc receptors, and the activating natural killer receptors (Tohyama 2009; Berton 2005; Crowley 1997). SYK is associated mainly with ITAM dependent pathways and affects early development and activation of various cells including B cells, mast cell degranulation, neutrophil and macrophage phagocytosis, as well as platelet activation (Zhou 2006; Tohyama 2009; Mócsai 2010). SYK-mediated phosphorylation of various adaptor proteins leads to the activation of downstream pathways that execute phagocytosis. SYK is important in complement-mediated phagocytosis resulting from the binding of C3bi-coated particles to complement receptor 3 (Tohyama 2009; Tohyama 2006). SYK is known to play a major role in the development of signal transduction events initiated after high-affinity IgE receptor (FCER1A) aggregation (Wong 2004; Matsubara 2006), mast cell activation, degranulation, and cytokine production (Matsubara 2006; Masuda 2008). It is anticipated that SYK activation coupled with platelet activation and aggregation may assist in lymphatic vessel development and their separation from blood vessels (Mócsai 2010, Turner 1995). SYK is claimed to have a role in osteoclast differentiation and osteoclast function (Tohyama 2009, Mócsai 2010). SYK has been found to have a major role in pre T-cell receptor (TCR) signalling. This is known to occur during the transition from the double negative 3 (DN3) to the DN4 stage of early thymocyte development (Palacios 2007). In vivo studies have shown that SYK is required for firm leukocyte adhesion to inflamed endothelium (Frommhold 2007) and development of vasculopathy reaction (Hirahashi 2006). The innate immune system uses pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and activate immune responses. SYK has been found to be a key component of these pathways and increased evidence points to the involvement of SYK-coupled PRRs in innate recognition of bacteria, with CLEC7A, CLEC6A and CLEC4E all implicated in sensing of mycobacterial PAMPs (Geijtenbeek 2009). SYK is presumably also involved in signalling PRR-mediated recognition of certain viruses. The role of ZAP70 in B cells have been investigated, but is poorly understood possibly due to the functional redundancy between SYK and ZAP70 (Fallah-Arani 2008). Toyabe et al displayed the ability of a T cell subpopulation to express high levels of SYK and partially compensate for loss of T-cell functions in patients with deficiency of ZAP70 (Toyabe 2001).
Homology	Both ZAP-70 and SYK are dependent upon a Src-family protein tyrosine kinase for association with the phosphorylated zeta-chain. Thus, the differential expression of these kinases suggests the possibility of different roles for ZAP70 and SYK in TCR signaling and thymic development (Palacios 2007). Activation of PTKs is an important mechanism in the transduction of signals from multi-subunit immunoreceptors, including the B and T cell receptors for antigen and the widely distributed receptors for the Fc portion of immunoglobulins (Paolini 2001). ZAP70 is expressed in T cells, natural killer cells and thymocytes, whereas SYK is present in all hematopoietic cells. Both ZAP70 and SYK are reported to be activated after TCR stimulation. Nonetheless, ZAP70 activation is known to require presence of Lck or another associated Src family PTK, while SYK is independent of Lck to undergo phosphorylation (Chan 1994, Couture 1994, Kolanus 1993). Regardless of its presence in all thymocyte subsets, SYK expression is downregulated three- to fourfold in peripheral T cells and, contrary to ZAP70, SYK expression is 12- to 15-fold higher in peripheral B cells compared to peripheral T cells (Chan 1994). Another study showed functional homology in antigen receptor signaling by demonstrating that expression of ZAP70 in SYK-B cells reconstitutes BCR function (Kong 1995). Another feature that distinguish ZAP70 from SYK is its greater dependency on Src kinases for activation and its ability to phosphorylate and promote the auto-activation of the downstream MAPK p38 (reviewed in Au-Yeung 2009).

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