The Syk Kinase Promotes Mammary Epithelial Integrity and Inhibits Breast Cancer Invasion by Stabilizing the E-Cadherin/Catenin Complex

Abstract

While first discovered in immunoreceptor signaling, the Syk protein kinase behaves as a tumor and metastasis suppressor in epithelial cells. Its reduced expression in breast and other carcinomas is correlated with decreased survival and increased metastasis risk, but its action mechanism remains largely unknown. Using phosphoproteomics we found that Syk phosphorylated E-cadherin and α-, β-, and p120-catenins on multiple tyrosine residues that concentrate at intercellular junctions. Increased Syk expression and activation enhanced E-cadherin/catenin phosphorylation, promoting their association and complex stability. In human breast cancer cells, Syk stimulated intercellular aggregation, E-cadherin recruitment and retention at adherens junctions, and promoted epithelial integrity, whereas it inhibited cell migration and invasion. Opposite effects were obtained with Syk knockdown or non-phosphorylatable mutant E-cadherin expression. Mechanistically, Syk stimulated the interaction of the E-cadherin/catenin complex with zonula occludens proteins and the actin cytoskeleton. Conditional Syk knockout in the lactating mouse mammary gland perturbed alveologenesis and disrupted E-cadherin localization at adherens junctions, corroborating the observations in cells. Hence, Syk is involved in the maintenance of the epithelial integrity of the mammary gland via the phosphorylation and stabilization of the E-cadherin/catenin adherens junction complex, thereby inhibiting cell migration and malignant tumor invasion.

Comparison of SYK Signaling Networks Reveals the Potential Molecular Determinants of Its Tumor-Promoting and Suppressing Functions

“…There is almost no information on SYK and mRNA, except for its role in stabilization of the mRNA encoding the BCL-XL protein, thereby protecting cells from apoptosis induced by oxidative or genotoxic stress [ 57 ]. Adherens and tight junctions seem to be specific SYK targets in MCF7 cells, which confirms observations by us and other groups on the regulation of the E-cadherin/catenin pathway by SYK [ 17 , 56 , 58 , 59 ]. Furthermore, our observations indicate a possible link between loss of SYK expression during breast tumor progression, loss of intercellular adhesion, and loss of control of mammary epithelial cell proliferation via the Hippo signaling pathway.…”

“…Indeed, SYK relocates to the actin filament network and subsequently associates with focal adhesion kinase (FAK) [ 55 ]. We demonstrated that SYK regulates cortactin and ezrin, both involved in actin-mediated cell adhesion and motility [ 20 ], and that SYK stimulates the interaction/stability of the E-cadherin/catenin complex [ 56 ]. The mRNA transport and surveillance pathways also were also particularly enriched in SYK targets in breast cancer cells.…”

Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

“…Thus, modulation of EMT can also be of importance in treatment of non-cancerous diseases [125][126][127]. It has been shown that E-cadherin downregulation may be associated with the development of a number of cancers such as breast cancer [128], lung cancer [129], skin cancer [130], and GC [131]. This can be related to the EMT mechanism.…”

CIRP Promotes the Progression of Non-small Cell Lung Cancer Through Activation of Wnt/β-catenin Signaling via CTNNB1

“…As the core factor in the canonical Wnt/βcatenin pathway, CTNNB1 can combine E-cadherin to form a cadherin/catenin complex and maintain cell-cell adhesion (36). When the Wnt signaling pathway is activated, CTNNB1 accumulation will occur in the nucleoplasm of tumor cells, leading to the loss of epithelial structural integrity and increased tumor invasion and metastasis (37,38). In addition, CTNNB1 can act as a signal transduction molecule and its activation signi cantly stimulates the production of VEGF, up-regulates the expression of MMPs to enhance the degradation of extracellular matrix (ECM), and thus promotes tumor cell growth, invasion and metastasis (39).…”