SYNDECAN-4 SIGNALING MODULATES FAK PHOSPHORYLATION

Massachusetts General Hospital, Boston MA

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Abstract

Cell adhesion to extracellular matrix (ECM) proteins influences cell shape, survival, growth, differentiation and proliferation. Fibroblasts adherent to the ECM protein fibronectin will attach, spread and form focal adhesion and actin stress fibers. Focal adhesions are multi-protein complexes composed of adhesion receptors (integrins and syndecan-4), cytoplasmic structural proteins (talin, vinculin and tensin) and signaling molecules (src, FAK and PKC). The process of adhesion formation is dependent on two types of transmembrane receptors: integrins and syndecan-4. Cell adhesion is also imperative for effective cell migration. Cells expressing increased levels of syndecan-4 exhibit a decreased rate of migration suggesting that syndecan-4 may negatively regulate cell motility. One mechanism by which syndecan-4 may regulate focal adhesions, and thereby inhibit migration, is through regulation of focal adhesion associated proteins. This proposal hypothesizes that ligation of syndecan-4 leads to the activation of a signaling pathway that regulates the phosphorylation of key components of the focal adhesion complex. Specifically it is proposed to determine at what point, in the emerging syndecan-4 signaling pathway, focal adhesion associated protein regulation takes lace utilizing fibronectin null cells (to control for fibronectin synthesis) and to examine what part of the syndecan-4 molecule is necessary for eliciting the regulatory signal using syndecan-4 null fibroblasts transfected with various recombinant constructs of syndecan-4. Unregulated cell migration is a basic component to the metastasis of abnormal cells. Elucidation of syndecan-4's role in modulating the activity of focal adhesion associated proteins will significantly contribute to our understanding of tumor cell migration.