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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.
Highlights
E-cadherin/catenin-based adherens junctions (AJ) are an essential feature of epithelial cell layers. AJ remain stable to fulfil their adhesive role, they exhibit plasticity [1,2,3] allowing cells to adapt to the changing environment [4]
Using quantitative phosphoproteomics and in vitro kinase assays with recombinant proteins, we previously reported that E-Cdh and α-Ctn are direct substrates of the spleen tyrosine kinase (Syk) kinase [32]
We identified the Syk-mediated phosphorylation of β-Ctn at Y142, a residue known to be phosphorylated by the Fer and Fyn kinases that is involved in regulating its interaction with α-Ctn [37]. β-Ctn phosphorylation at Y142 has recently been observed at centrosomes where it may regulate centrosomal cohesion [38]
Summary
E-cadherin/catenin-based adherens junctions (AJ) are an essential feature of epithelial cell layers. AJ remain stable to fulfil their adhesive role, they exhibit plasticity [1,2,3] allowing cells to adapt to the changing environment [4]. E-Cdh loss, mutation, or defective regulation leads to epithelial-mesenchymal transition (EMT), tumor cell invasion, and metastasis formation [5]. E-Cdh highly conserved intracellular tail associates with different cytoplasmic proteins, α-, β-, and p120-catenin (Ctn) [6], and is involved in the interaction with the actin/myosin network [7,8]. E-Cdh/Ctn association, functionality, and dynamics are regulated through various mechanisms.
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