Cellular Responses to Vitronectin Binding Integrins

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION: (provided by applicant) Integrins and growth factor receptors function in a cooperative manner to regulate cellular behavior. During the previous funding cycle, the homologous vitronectin binding integrins, avB3 and avB5 were found to regulate distinct pathways of angiogenesis and differentially influence the invasive and metastatic properties of tumor cells. While both integrins promote cell attachment to vitronectin, cells expressing avB5 required growth factor stimulation in order to migrate on this substrate or metastasize in vivo. Specifically, avB5-, but not avB3- dependent downstream signaling, and cell migration were found to depend on Src kinases activated by growth factor/cytokine receptors. In this proposal, we will test the hypothesis that growth factor activation of Src is required for assembly of an avB5/focal adhesion kinase (FAK) signaling complex. We will then determine how this signal generating complex is formed and how it influences biological parameters regulated by integrin avB5, including cell migration in vitro and tumor cell invasion and metastasis in vivo. While avB5 influences the malignant behavior of carcinoma cells, recent studies have documented a role for this integrin complex, as well as Src kinase, in endothelial cell responsiveness to vascular endothelial growth factor (VEGF). For example, VEGF-mediated angiogenesis could be blocked in mice or chick embryos with avB5 antagonists, or by general inhibition of Src family kinase activity. However, mice lacking a single Src family kinase, or mice deficient in avf35, showed an apparently normal VEGF-mediated angiogenic response, yet displayed a complete loss of VEGF-dependent vascular permeability (VP). Therefore, avB5 and Src deficient mice and endothelial cells from these animals will be used as a models to evaluate the molecular basis of VEGF-mediated VP, and to determine the role that Src and integrin avB5 play in this process. We will test the hypothesis that the Src-dependent avB5/FAK complex assembly not only promotes signals necessary for cell migration, but is also important in regulating VEGF-mediated endothelial cell barrier function. Finally, we will determine how VEGF-mediated VP influences the host microenvironment and contributes to the malignant behavior of tumors.