Cell-substratum adhesion is mediated by integrins, a family of transmembrane, heterodimeric, extracellular matrix receptors that are concentrated at focal adhesions. Integin engagement influences a variety of signaling pathways and regulates cell behaviors including motility, proliferation, and survival. Disturbance of normal integrin function is associated with a variety of pathologic conditions including cancer. In the first segment of my seminar, I provide a broad overview of the cancer problem for a lay audience. Advances in our understanding of cancer as a genetic disease are discussed. The influence of cell adhesion on control of cell growth is reviewed.
In the second segment, I describe the identification of the focal adhesion protein, zyxin, by my lab. Recent work revealed that zyxin is down-regulated upon expression of the Ewing sarcoma oncoprotein, EWS-FLI. Loss of zyxin expression results in enhanced cell motility and is also associated with failed apoptotic signaling. Evidence that zyxin shuttles between focal adhesions and the nucleus is presented. The impact of reduced zyxin expression on tumor progression is discussed.
In the third segment of my seminar, I address a new frontier in cell biology, that is how cells respond to mechanical information. Cells and tissues are exposed to physical forces in vivo and excessive mechanical stress leads to a variety of pathological consequences. I describe a system for exposing cells to controlled mechanical stress and discuss the stretch response. We have discovered that the focal adhesion protein, zyxin, is exquisitely sensitive to mechanical stimulation and is required for the ability of cells to reinforce the actin cytoskeleton when challenged by exposure to cyclic stretch.