My goal ultimately is to establish an independent program of research in gastrointestinal signal transduction focusing on early tumor invasion, and developing and testing novel interventional strategies using xenograft tumor models and transgenic animal models. I also hope to develop more useful, tractable, 3-D culture model systems recapitulating tumor architecture in vitro and ultimately to assay more closely how and why tumors invade, and the relationship of surrounding, non-dysplastic cells on this invasion. Although tumor invasion is multifaceted, I have chosen to focus my studies on a central signal-integrating molecule, FAK, focal adhesion kinase in this process. This proposal is designed in three phases: 1. Stress activation of FAK -- We will extend our studies on hyperosmotic stress-stimulation of FAK in fibroblasts to epithelial and cancer cells. This involves characterization of a novel FAK signaling pathway. Given the distinct cytoskeletal organization within these distinct cell types a detailed study of the role of Rho-family GTPases and their actin regulatory effectors on FAK signaling will be done. 2. We will define FAK domains required for epithelial adherens junction down regulation -- In this specific aim we will use this in vitro model to characterize which functional FAK domains are required for v-Src-mediated and EGF/HGF-stimulated E-cadherin phosphorylation, internalization and degradation, and adherens junction down-regulation. 3. We will establish which FAK domains are required and which are sufficient for tumor cell invasion and metastasis in vivo and in 3-dimensional (3-D) culture systems. Here we will directly test, using a xenograft tumor model in nude mice, whether FAK activation by various stimuli or mutations is sufficient, and which FAK domains are required, for human gastric and colorectal tumor invasion in vivo. Using the FAK molecule as a focal point, this proposal is designed to refine my signal transduction training and to extend my technical expertise to epithelial cell biology and cell-cell junction regulation, advanced cell imaging (in live cells) and to in vivo tumor invasion and metastasis. This K08 award will permit me to establish an independent publishing track record which is so critical to obtaining a future R01.
| Lunn, J Adrian; Jacamo, Rodrigo; Rozengurt, Enrique (2007) Preferential phosphorylation of focal adhesion kinase tyrosine 861 is critical for mediating an anti-apoptotic response to hyperosmotic stress. J Biol Chem 282:10370-9 |
| Lunn, J Adrian; Rozengurt, Enrique (2004) Hyperosmotic stress induces rapid focal adhesion kinase phosphorylation at tyrosines 397 and 577. Role of Src family kinases and Rho family GTPases. J Biol Chem 279:45266-78 |
