Abstract
Syk, a non-receptor tyrosine kinase, is an important component of immunoreceptor signaling in hematopoietic cells. It has been implicated in key regulatory pathways including phosphoinositide 3-kinase and phospholipase Cgamma (PLCgamma) activation in B cells and integrin signaling in platelets and bronchial epithelial cells. Recently, potential roles in cancer have been reported. In breast cancers, reduced Syk expression was associated with invasion, and its overexpression in cell lines was shown to inhibit cell motility. In contrast, Syk has been shown to mediate chemomigration in nasopharyngeal carcinoma cells. Its role in squamous cell carcinomas of the head and neck (SCCHN) has not yet been investigated. Syk mRNA and protein expression was detected in 6 of 10 SCCHN cell lines. When Syk was transfected into Syk-negative cells (SIHN-011A), chemomigration was enhanced in vitro and this was associated with activation of PLCgamma1. Conversely, abrogation of Syk activity by pharmacologic inhibition or small interfering RNA in HN6 cells with high levels of endogenous expression inhibited migration, haptotaxis, and engagement with matrix proteins; this was accompanied by decreased levels of phosphorylated AKT. Similar effects were seen in Syk-positive CAL 27 cells but not in Syk-negative SIHN-011A cells. Immunoprecipitation suggested co-association of Syk with epidermal growth factor receptor and GRB-2. Syk expression in SCCHN patient tissues was examined by semiquantitative real-time PCR (n = 45) and immunohistochemistry (n = 38) in two independent cohorts. Higher levels of Syk expression were observed in tumors and lymph node metastases relative to normal tissues. High Syk expression significantly correlated with worse survival and may be of prognostic value in SCCHN due to its potential role in cell migration and invasion.
Highlights
Syk is a member of the Syk/ZAP family of non–receptor tyrosine kinases whose two isoforms consist of two tandem NH2-terminal SH2 domains and a COOH-terminal kinase domain.Note: Supplementary data for this article are available at Cancer Research Online.Syk is abundant in B lymphocytes and expressed at lower levels in immature T cells, mast cells, and platelets
Syk interacts with the immunoreceptor tyrosine-based activation motifs of immunoglobulin a, T-cell receptor ~, CD3q, and FcqRI, coupling immune receptors to multiple downstream signaling events including activation of phospholipase Cg (PLCg), mobilization of calcium from intracellular stores, and activation of Ras/extracellular signal–regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), and nuclear factornB pathways [9, 10]
Syk expression was determined in a panel of 10 SCCHN cell lines by reverse transcription-PCR (RT-PCR; Fig. 1B) and Western blotting (Fig. 1C)
Summary
Syk is a member of the Syk/ZAP family of non–receptor tyrosine kinases whose two isoforms consist of two tandem NH2-terminal SH2 domains and a COOH-terminal kinase domain (ref. 1; Fig. 1A).Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).Syk is abundant in B lymphocytes and expressed at lower levels in immature T cells, mast cells, and platelets. Syk has been detected in fibroblasts [2, 3], epithelial cells [4], and breast tissues [5]. In endothelial cells, it plays a key role in proliferation, migration, and developmental angiogenesis/lymphangiogenesis [6,7,8]. Syk interacts with the immunoreceptor tyrosine-based activation motifs of immunoglobulin a, T-cell receptor ~, CD3q, and FcqRI, coupling immune receptors to multiple downstream signaling events including activation of phospholipase Cg (PLCg), mobilization of calcium from intracellular stores, and activation of Ras/extracellular signal–regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), and nuclear factornB pathways [9, 10]
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