Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

SYK

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101869

Synonyms

Historical Background

Catalytic activity corresponding to the SYK kinase was first detected in extracts from bovine thymus based on the phosphorylation on tyrosine of a synthetic peptide substrate. Purification of this activity by conventional column chromatographic approaches led to the isolation of an enzyme with a molecular mass of 40 kDa that was originally referred to as p40 (Zioncheck et al. 1986). Shortly thereafter, the same catalytic fragment was identified and purified from porcine spleen and given the name CPTK40 (Kobayashi et al. 1990). The fact that these two kinases were actually catalytic fragments was recognized when antibodies generated against p40 revealed a larger precursor of 72 kDa, the proteolytic cleavage of which yielded the activated 40 kDa fragment (Zioncheck et al. 1988). The full-length protein was originally referred to as PTK72. Similarly, the screening of a porcine cDNA library with probes based on the N-terminal sequence of CPTK40 identified a cDNA that coded for a 72 kDa enzyme, which was given the name SYK for spleen tyrosine kinase (Taniguchi et al. 1991). Cloning of the murine Syk gene and the preparation of antibodies against the conserved C-terminus confirmed the identity of the two kinases.

Early tissue distribution studies determined that SYK was present predominantly in cells of the immune system (Zioncheck et al. 1988; Taniguchi et al. 1991). In the spleen, SYK was present at highest levels in B cells, suggesting a role for the enzyme within the adaptive immune system. B cells respond to foreign antigens that they bind through polymorphic cell surface immunoglobulins formed during development by the rearrangement of genes coding for heavy and light chains. These are trafficked to the plasma membrane through an association with CD79a (Igα) and CD79b (Igβ) subunits. None of the components of the B cell antigen receptor (BCR) complex possess intrinsic catalytic activity, yet early studies indicated that receptor cross-linking resulted in increases in the phosphorylation of cellular proteins on tyrosine, including a prominent protein of 70–80 kDa (Gold et al. 1990; Campbell and Sefton 1990). This protein was subsequently shown to be PTK72/SYK. SYK was shown to be activated in response to BCR engagement and to physically associate with the clustered antigen receptor complex (Hutchcroft et al. 1991, 1992). Roles for SYK in signaling in the immune system are not restricted to B cells, and demonstrations of the association of SYK with other immune cell receptors including those for IgE, IgG, and G-CSF were soon reported. As detailed below, SYK couples an array of receptors to downstream signaling pathways important for the functions of a wide variety of hematopoietic and even nonhematopoietic cells.

Structure and Activation

SYK contains at the N-terminus a pair of Src homology-2 (SH2) domains that are separated by linker insert region A. The tandem SH2 domains are connected by linker insert region B to the C-terminal catalytic domain (for reviews, see Geahlen 2009; Mócsai et al. 2010) (Fig. 1). One alternatively spliced isoform of SYK, known as SykB or Syk(S), lacks 23 amino acids from the linker B region. The SYK family of kinases contains one additional member, ZAP70 (zeta-chain-associated protein of 70 kDa), that is best characterized as a critical regulator of signaling from the T cell antigen receptor. In its unbound form, the activity of SYK is restricted by hydrophobic interactions between residues within linkers A and B and residues on the backside of the C-terminal lobe of the kinase domain (Grädler et al. 2013). Conformational changes resulting from the simultaneous ligation of both SH2 domains or from the phosphorylation of linker B tyrosines lead to activation of the kinase.
SYK, Fig. 1

Domain structure and major sites of phosphorylation. The SYK molecule comprises a tandem pair of SH2 domains connected by linker A separated by linker B from the catalytic or kinase domain. Major sites of tyrosine phosphorylation are indicated using the murine SYK numbering system. SH2 Src homology 2

It is the tandem set of SH2 domains that allows the physical and functional interaction of SYK with immune recognition receptors (Fig. 2). SH2 domains are phosphotyrosine-binding motifs that mediate protein-protein interactions. Most, but not all, receptors whose engagement is coupled to the activation of SYK contain, or are associated with proteins that contain, cytoplasmic sequences known as immunoreceptor tyrosine-based activation motifs or ITAMs (Geahlen 2009; Mócsai et al. 2010). ITAMs have a consensus sequence of YXXL/IX(6–12)YXXL/I (Reth 1989). In the BCR complex, for example, CD79A and CD79B contain an ITAM with a sequence of YEGLNLDDCSMYEDI and YEGLDIDQTATYEDI, respectively. When the tyrosine within each YXXL/I cassette becomes phosphorylated, it serves as a docking site for one of the two SYK SH2 domains. Binding occurs in a head-to-tail orientation with the more N-terminal pYXXL/I cassette engaging the C-terminal SYK SH2 domain, while the second cassette is bound by the N-terminal SH2 domain. Signaling through receptors begins with their aggregation at the cell surface. ITAM phosphorylation is typically initiated by a kinase of the SRC family, which in B cells is predominantly LYN. The phosphorylation of both ITAM tyrosines allows for a high-affinity interaction between SYK and the receptor complex whereby both SH2 domains are engaged simultaneously. The resulting conformational change associated with SYK-ITAM binding results in the activation of the kinase, which is then rapidly phosphorylated on multiple tyrosines by a combination of autophosphorylation catalyzed by neighboring SYK molecules within the clustered receptor complex and by phosphorylation catalyzed in trans by SRC family kinases. These covalent modifications occur on tyrosines located within linker A, which modulates SYK-receptor interactions by a long-range conformation uncoupling of the tandem SH2 domain structure (Zhang et al. 2008); within linker B, which maintains SYK in an active conformation and mediates interactions with both positive (e.g., PLC-γ, PI3K, and VAV1) and negative (e.g., CBL family E3 ligases) effectors of BCR signaling; within the activation loop of the catalytic domain, a useful maker of kinase activation; and within the extreme C-terminus, which mediates interactions with the B cell linker protein (BLNK/SLP-65) (Fig. 1). Once activated, SYK phosphorylates a variety of protein substrates whose phosphorylation sites are typically characterized by tyrosines surrounded by numerous acidic residues. SYK couples the BCR to multiple intracellular signaling pathways including the PLC-γ/NFAT, PI3K/AKT/mTOR, RAS/MEK/ERK, PRKCB/IKK/NF-κB, and VAV1/RAC pathways (Fig. 3). Knockout studies at both the cellular and organism levels clearly demonstrate a requirement of SYK for nearly all intracellular signaling events mediated by BCR engagement (Turner et al. 1995; Takata et al. 1994).
SYK, Fig. 2

Recruitment of SYK to the B cell antigen receptor. Receptor engagement leads to the phosphorylation of pairs of tyrosines in ITAMs located in the cytoplasmic tails of CD79A and CD79B. ITAM phosphorylation is initiated by LYN, a SRC family tyrosine kinase. Each ITAM phosphotyrosine serves as a docking site for one of the two SYK SH2 domains, leading to activation of the kinase and to its phosphorylation on multiple tyrosines. BCR B cell receptor for antigen, LYN Lck/Yes-related protein tyrosine kinase, ITAM immunoreceptor tyrosine-based activation motif, P phosphotyrosine

SYK, Fig. 3

Common signaling pathways activated downstream of BCR engagement. Studies from SYK knockout cells indicate an essential role for SYK in transducing signals from the BCR to multiple intracellular signal transduction pathways

SYK and Immune Recognition Receptors

With the exception of mature T cells, SYK is abundantly expressed in most hematopoietic cells including thymocytes, mast cells, basophils, platelets, monocytes, macrophages, neutrophils, dendritic cells, microglial cells, erythrocytes, and NK cells. SYK is activated by and forms a functional association with a variety of receptors in these immune cells, many of which participate in the recognition of antigens or immunoglobulin-antigen complexes and most of these receptors contain ITAMs (Mócsai et al. 2010). Included among these is the high-affinity receptor for IgE, which is found on mast cells, basophils, and activated eosinophils (Hutchcroft et al. 1992; Siraganian et al. 2002). An ITAM exists on both the β- and γ-chains of the FcεRI complex and becomes phosphorylated by LYN following receptor clustering by antigens binding to receptor-associated IgE. The resulting release of inflammatory mediators of both the early and late phases of type I hypersensitivity reactions is clearly dependent on the presence and activity of SYK. Consequently, mast cells lacking SYK fail to degranulate in response to the clustering of FcεRI receptors (Costello et al. 1996). The ITAM-mediated activation of SYK also is required for signaling through the IgG receptors FcγRI, FcγRIIA, and FcγRIIIA in neutrophils and macrophages, which mediate such events as the phagocytosis of IgG-opsonized foreign particles (e.g., microbes) and the generation of the oxidative burst that kills ingested pathogens. Many additional receptors coupled to the activation of SYK also signal through an association with a small ITAM-containing subunit, either TYROBP (DAP12) or FCER1G (FcRγ). These include the IgA receptor FcαRI; the platelet collagen receptor GPVI; multiple NK cell-activating receptors; integrins; SIRP-β, PILR-β, Siglec-14, Siglec-15, and Siglec-16; PSGL-1; the lectin receptors CLEC4E, CLEC5A, and CLC6A; TNFRSF11A/RANK; and several TREM family receptors. These multiple interactions reflect the diverse roles for SYK within the innate and adaptive immune systems underlying its functions in such processes as neutrophil rolling and adherence, platelet activation, osteoclast activation, and the recognition of foreign microbes bearing pathogen-associated molecular patterns. A subset of C-type lectin receptors (CLEC7A (Dectin-1), CLEC2, and CLEC9A) are interesting exceptions to the ITAM requirement as they contain only a hemi-ITAM (i.e., a single YXXL/I motif). This unusual signaling modality requires the receptor to function as a dimer in which each separate subunit engages one of the two SYK SH2 domains, a model consistent with the requirement that both SYK SH2 domains be functional (Hughes et al. 2010).

SYK and Cancer

During development, B cells rearrange immunoglobulin genes to generate both a pre-B cell receptor in which products of the rearranged heavy chain genes associate with surrogate light chains and, later, a mature receptor containing the products of genes coding for both heavy and light chains. The expression of functional BCR complexes is required for cell survival during development, and this pro-survival function is dependent on SYK (Turner et al. 1995). An ability of SYK to promote cell survival has been co-opted by a number of cancer cells, not only those derived from B cells but also those of other hematopoietic lineages and, interestingly, some cells of nonhematopoietic origins (for review, see Krisenko and Geahlen 2015).

In tumors of B cell origin, tonic signaling from the BCR is thought to result in a constitutively active kinase that supports cancer cell survival such that the inhibition or knockdown of SYK leads to cell death. Examples in which this has been documented include B cell chronic lymphocytic leukemia (B-CLL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Even in hematopoietic cells lacking a BCR, SYK can exhibit a positive effect on cancer cell survival. For example, B cell acute lymphocytic leukemia (B-ALL) cells derived from pro-B cells lacking BCR expression also are sensitive to growth arrest by inhibitors of SYK. Many acute myeloid leukemia (AML) cells are dependent on SYK for survival; and in these cells SYK is activated downstream of β3-integrins. While mature T cells typically lack SYK, most all peripheral T cell lymphomas (PTCLs) express the kinase and in these cells it constitutively active.

Interestingly, SYK also is associated with many tumors derived from nonhematopoietic cells. SYK was initially characterized as a tumor suppressor due to its presence in normal breast epithelial cells and nonaggressive breast cancer cell lines, but its absence from highly invasive cells (Coopman et al. 2000). The reexpression of SYK in highly malignant cells reduces their motility, promotes adhesion, and attenuates the formation of distant metastases. A similar differential expression of SYK in well versus poorly differentiated cancer cells has been reported for carcinomas derived from a number of tissue types including the skin, bladder, colon, stomach, pancreas, and liver. The ability of SYK to promote cell adhesion and inhibit motility likely underlies its absence from many highly invasive cancer cells. In contrast, SYK has been reported as a promoter of tumorigenesis in several cancer cells including K-RAS “addicted” lung and pancreatic carcinoma (Singh et al. 2009), retinoblastoma (Zhang et al. 2012), ovarian carcinoma (Prinos et al. 2011), and small cell lung cancer (Udyavar et al. 2013).

These different assignations of tumor suppressive versus tumor-promoting activities to a single kinase are likely a consequence of its differential regulation of processes important in cells at different stages of tumorigenesis. In cases where SYK is a tumor promoter, its actions are typically ascribed to its ability to promote cell survival. A number of mechanisms have been proposed for this activity including the activation of pro-survival pathways, many mediated downstream of either activated AKT or NFκB, that lead either to the stabilization or enhanced expression of antiapoptotic proteins such as MCL-1, BCL-XL, BCL1A1, or XIAP or the repression of proapoptotic proteins such as HRK. It is noteworthy that, in many carcinomas, SYK is found preferentially in cells of epithelial morphology, but is absent from more aggressive cells of mesenchymal phenotype (Fig. 4). In fact, the mRNA for SYK is downregulated during TGF-β-induced epithelial-mesenchymal transition (EMT) in human mammary epithelial cells (Taubea et al. 2010). There is evidence that SYK itself can modulate this EMT process as inhibition or silencing of the kinase induces aspects of EMT in some breast and pancreatic carcinomas, and the ectopic expression of SYK can modulate the expression of genes required for invasive cell growth (Sung et al. 2009; Singh et al. 2009). The enhanced expression of SYK by a cancer cell can also represent a mechanism by which the cells establish resistance to antitumor agents as demonstrated by the elevated expression of the kinase in ovarian carcinoma cells that have developed resistance to paclitaxel (Yu et al. 2015). In fact, the overexpression of SYK itself in ovarian cancer cells can induce paclitaxel resistance. Proposed mechanisms by which SYK promotes cell survival include regulation of microtubule stability, stabilization of mRNA for antiapoptotic proteins, and clearance of ribonucleoprotein complexes from cells through autophagy.
SYK, Fig. 4

SYK and epithelial-derived tumors. SYK is found frequently in carcinomas with an epithelial phenotype, but is frequently absent from cells that have undergone an epithelial-mesenchymal transition (EMT)

SYK as a Drug Target

The involvement of SYK-associated receptors with types I, II, and III hypersensitivity reactions mediated by immunoglobulin receptors has naturally generated considerable interest in SYK as a drug target for the treatment of inflammatory diseases (for review, see Geahlen 2014). As a consequence, a wide variety of small molecule inhibitors have been developed to target the kinase, most of which are competitive with ATP for binding within the catalytic cleft. On a more limited basis, other therapeutic approaches, including the delivery of antisense oligonucleotides or siRNAs, have been investigated as mechanisms to downregulate kinase expression. For a select number of diseases, small molecule inhibitors have entered or are currently in clinical trials. These include allergic asthma, allergic rhinitis, rheumatoid arthritis, thrombocytopenic purpura, autoimmune hemolytic anemia, IgA nephropathy, chronic graft-versus-host disease, systemic lupus erythematosus, Alzheimer’s disease, and malaria. Other indications of particular interest for which animal models have been explored include heparin-induced thrombocytopenia, type I diabetes, atherosclerosis, arterial thrombosis, and ischemia-reperfusion injury. The association of SYK with cell transformation and tumor cell survival has created considerable interest in the use of small molecule inhibitors as antitumor agents. Clinical trials of SYK inhibitors already have shown positive responses in patients with B cell malignancies including B-CLL, DLBCL, FL, and MCL (Friedberg et al. 2010) and have been proposed for the treatment of retinoblastoma and drug-resistant ovarian cancer (Zhang et al. 2012; Yu et al. 2015).

Summary

SYK is expressed at highest levels in cells of the hematopoietic system, and it is within these cells that the kinase plays its most important roles as a mediator of signals, most typically from receptors that contain ITAMs. These motifs are characterized by a pair of tyrosines whose phosphorylation allows for the recruitment of SYK to the receptor resulting in its stimulation and the subsequent activation of downstream pathways that determine the outcome of receptor engagement. SYK is required for some of the most critical functions of the immune system: the recognition of foreign antigens, infected cells, and invading pathogens. While roles for SYK in mediating signaling from ITAM-bearing receptors in the immune system have been explored extensively, less is known regarding roles and mechanisms for SYK and its participation in signaling pathways downstream of receptors that lack ITAMs. We also have much to learn regarding the molecular mechanisms by which SYK can function as both a tumor promoter and tumor suppressor at different stages of tumorigenesis. More extensive clinical trials will be needed to realize the promise of SYK as a therapeutic target for the treatment of cancer and inflammatory diseases.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Medicinal Chemistry and Molecular PharmacologyPurdue UniversityWest LafayetteUSA