Anchorage-independent growth, evasion of contact or cell density-dependent inhibition of growth. Enhanced migration and invasion activities are among the most important properties of in vitro transformed cells. They correlate closely with the characteristics of cancer cells in vivo. The molecular signaling pathways involved in regulating these properties of transformed cells have been investigated by using avian sarcoma virus UR2, which encodes a truncated receptor tyrosine kinase called Ros, and its loss-of-function mutants, as well as a newly discovered Ros down stream effector called Vav3. The results indicate that PI3 kinase and the RhoGTPase signaling pathways play an important role in Ros- and Vav-induced anchorage-independent growth, escape from contact inhibition and enhancment of motility and invasion. The objective of this proposal is to further dissect and identify the down stream signaling pathways of P13 kinase and the RhoGTPases which are important in regulating anchorage-independent growth, evasion of contact inhibition, and motility and invasion of fibroblasts and epithelial cells. In addition, novel genes and pathways important for these transforming properties will be explored.
The specific aims are: 1. To elucidate molecular signaling important for anchorage independent growth of cells. 2. To elucidate molecular signaling regulating cell motility and invasion. 3. To explore novel genes and proteins involved in regulating cell motility and invasion. 4. To elucidate the molecular basis for evasion of contact inhibition of growth. Inducible Ros and Vav oncogenes along with various constitutively activated and dominant negative mutants of P13 kinase and Rho GTPases signaling molecules will be used to dissect signaling pathways in transformed fibroblasts and epithelial cells. Microarray and proteomic analysis will be used in the in vitro cell system and animal models to identify novel genes involved in evasion of contact inhibition and metastatic invasion.
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