Role of Syk in the regulation of breast cancer cell-cell and cell -matrix interactions

Xiaoying Zhang, Purdue University

Abstract

Syk, a non-receptor tyrosine kinase, has been characterized recently as a tumor supressor in breast cancer whose expression is inversely correlated with malignancy. However the molecular mechanism by which Syk functions as a tumor suppressor is far from well defined. The interactions of a cell with neighboring cells and with the extracellular matrix (ECM) largely define the ability of tumor cells to become increasingly more malignant and to metastasize. This study attempts to elucidate in more detail the specific ways in which Syk regulates cell-cell and cell-ECM adhesions. ^ Here I report that active Syk promotes cell-cell adhesions while inhibiting cell motility. Syk was found to partially localize at cell-cell contacts in breast epithelial cells. Moreover, Syk recruits the adhesion proteins cortactin and vinculin to cell-cell contacts, where Syk physically interacts with cortactin. Furthermore, Syk can directly phosphorylate cortactin and enhance cortactin's phosphorylation in cells. Syk helps maintain breast tissue integrity by increasing cell-cell adhesions. ^ The expression of Syk also inhibits cell motility. Vinculin is recruited from focal adhesions to adherens junctions when Syk is expressed in cells. However, Syk also inhibits the motility of cells lacking E-cadherin. In cell spreading on fibronectin, Syk partially relocalizes to the cell edge and colocalizes with F-actin. Upon engagement of integrins with antibodies or fibronectin, Syk is activated and induces additional protein phosphorylation. These data suggest that Syk participates in an integrin-stimulated signaling pathway to regulate cell motility. Furthermore, tyrosine 342 and the ability of Syk to traffic into the nucleus were found to be required for the signaling and for suppression of cell motility. The expression of Syk modifies the structure of the microtubule network, affecting cell spreading, cell size, the stability of microtubules to depolymerization and the rate of microtubule repolymerization. Syk co-localizes and associates with γ-tubulin in centrosomes. Interestingly Syk increases the expression of γ-tubulin. These data suggest that Syk modulates cell-cell adhesions and suppresses cell motility by participating in an integrin-stimulated signaling pathway coupled to changes in the microtubule network.^

Degree

Ph.D.

Advisors

Robert L. Geahlen, Purdue University.

Subject Area

Biology, Molecular

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