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Role of SDF-1/CXCR4 signaling in regulation of PKA activity during cell migration He, Daniel


Cell migration plays an important role in development and the immune system, and the signaling pathways governing this process are regulated in a spatial and temporal manner. One important signaling molecule is cAMP-dependent Protein Kinase (PKA), which has been shown to be a key regulator of migration. In migrating cells, PKA activity exists in a gradient that is highest at the leading edge, where it phosphorylates proteins that promote migration. Although the functions of PKA in migration have been identified, upstream regulators of PKA-mediated cell migration have yet to be defined. A candidate for regulation of PKA during migration is the chemokine receptor CXCR4, which has been shown to induce cell migration and signal through PKA-phosphorylatable proteins upon ligation with stromal derived factor-1 (SDF-1). I have created a novel CXCR4 deficient Jurkat cell line, JC4, and show that Jurkat cell migration towards SDF-1 is CXCR4-dependent. As well, we show through biochemical studies that the SDF-1/CXCR4 signaling pathway is an upstream regulator of PKA activation in CHO-CXCR4 cells, J774 macrophages, and Jurkat T-cells. Furthermore, the SDF-1/CXCR4 signaling pathway is an upstream regulator of PKA activation in migrating cells. This is supported by the observation that there is a CXCR4-dependent increase in PKA-phosphorylated substrates at the periphery of J774 macrophages and protrusions of Jurkat T-cells upon SDF-1 stimulation. Furthermore, SDF-1/CXCR4 signaling establishes a PKA activity gradient in migrating Jurkat cells that is highest at the leading edge. These studies define a regulatory role for the SDF-1/CXCR4 signaling pathway in promoting PKA-mediated cell migration.

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