The interaction between the carboxy terminus of transmembrane receptors with the conserved PDZ binding module of adaptor proteins has emerged as a major mechanism of organizing signal-transduction protein complexes. The syndecan family of transmembrane proteoglycans belongs to this large group of PDZ- binding cell surface receptors. Until recently, the generally held concept of proteoglycan functions was centered on their heparan sulfate chains as the active component involved in binding of growth factors and of extracellular matrix proteins. This view is undergoing a revision, however, as a consequence of newly emerging findings, which suggest that the highly conserved cytoplasmic tails of the syndecan family of transmembrane proteoglycans also participate in the transduction of outside-in signals. While all the syndecans possess a PDZ-binding carboxy- terminus, the widely expressed syndecan-4 contains a unique phosphatidylinositol 4,5-bisphosphate binding domain in its cytoplasmic tail, and facilitates the activation of protein kinase C alpha. Recent findings from our laboratory indicate that the interaction between the cytoplasmic tail of syndecan-4 and PDZ domain-containing protein(s) is essential for the cellular response to basic fibroblast growth factor, as demonstrated by the impairment of migration, of proliferation, and of vascular network formation by endothelial cells upon the disruption of this interaction. The objective of this proposal is to elucidate the nature of the signaling mechanism through the PDZ-syndecan-4 interaction, employing the recently identified syndecan-4 PDZ partner synectin as a prototype. This interaction is part of a novel FGF signaling pathway, and forms a new paradigm for the regulation of signal transduction. We will focus on (1) characterizing the binding mechanism between syndecan-4 and synectin, (2) identifying additional synectin binding partners other than syndecan-4, in order to determine further downstream members of the syndecan-4-mediated signaling pathway, and (3) characterize the functions of synectin in general, and the endothelial cell-specific ones in particular, by a synectin gene knockout mouse model.
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