Cell invasion during wound repair, development, angiogenesis and cancer depends on cell recognition of the provisional extracellular matrix (ECM) consisting of proteins such as fibronectin, fibrinogen, osteopontin, thrombospondin and vitronectin. An understanding of the common mechanism(s) regulating cell migration during tumor angiogenesis and metastasis may lead to the development of new approaches to stop these disease processes. We have found that activation of Protein Kinase A (PKA) disrupts endothelial cell and tumor cell migration. Cell permeable cAMP, over expressed PKA catalytic subunit or the hormone PTHrP activate PKA and thereby suppress cell migration. Additionally, blockade of integrin signal transduction and inhibition of the Galpha i linked integrin-associated protein, CD47, activate PKA and suppress cell migration without inhibiting cell attachment to the provisional ECM. Once activated, PKA promotes excessive activation of Rho and suppression of Rac GTPase activities, which in turn influences the actin dynamics associated with the migratory phenotype. In fact, activation of PKA blocks endothelial invasion into the provisional ECM and thereby disrupts angiogenesis in vivo. Therefore, PKA is a critical regulator of invasive cell behavior during tissue remodeling. In this proposal we will test the hypothesis that PKA activation plays a major role in the negative regulation of endothelial cell and tumor cell migration in vitro and in vivo. We will first evaluate the mechanisms by which PKA becomes activated by hormones and by blockade of integrin ligation. We will then determine the mechanism(s) by which PKA modulates small GTPase activity to inhibit migration. Finally, we will evaluate the role of PKA in regulating cell migration during angiogenesis and tumor cell metastasis in vivo. These studies will lead to advances in our understanding of the mechanisms regulating angiogenesis and metastasis and may lead to the development of new approaches for the treatment of cancer.
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