I. Adhesion, Signaling and Cancer
II. Discovery and Characterization of a Focal Adhesion Protein Implicated in Tumor Progression
III. Focal Adhesions as Stress Sensors
Part I: Adhesion, Signaling and Cancer
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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.
Mary Beckerle is Professor of Biology and Oncological Sciences at the University of Utah. Dr. Beckerle serves as the Executive Director of Huntsman Cancer Institute and holds the Ralph E. and Willia T. Main Presidential Endowed Chair.
She obtained her undergraduate training at Wells College and earned a PhD in Molecular, Cellular, and Developmental Biology at the University of Colorado at Boulder where she provided the initial evidence for a cytoplasmic dynein in microtubule-based intracellular transport. While a post-doctoral fellow at the University of North Carolina at Chapel Hill, Beckerle demonstrated the presence of a protease at cell-substratum adhesion sites, providing some of the earliest evidence that focal adhesions are dynamic, regulatory structures.
She subsequently identified zinc finger proteins, such as zyxin, as focal adhesion constituents and demonstrated shuttling of focal adhesion proteins to the nucleus. In recent work, Beckerle’s research team has elucidated novel pathways for the control of cell motility and has defined the mechanism by which cells reinforce their actin cytoskeltons in response to mechanical stress. Dr. Beckerle’s honors include receipt of a Guggenheim Fellowship, the American Cancer Society Sword of Hope Award, and the Utah Governor’s Medal for Science and Technology. In 2006, Beckerle served as President of the American Society for Cell Biology.
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Weinberg. R. 2006. The Biology of Cancer. Garland Science, New York.
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Katsumi, A., Orr, A.W, Tzima, E., and M.A. Schwartz (2004). Integrins in mechanotransduction. J. Biol. Chem. 279: 12001-12004.
Hynes, R.O. (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110: 673-687.
Yoshigi, M., L.H. Hoffman, C.C. Jensen, H.J. Yost, and M.C. Beckerle (2005) Mechanical force mobilizes zyxin from focal adhesions to actin filaments and regulates cytoskeletal reinforcement. J Cell Biol 171(2):209-15.
Hoffman, L.M., C.C. Jensen, S. Kloeker, C.-L.A. Wang, M. Yoshigi, and M.C. Beckerle (2006) Genetic ablation of zyxin causes Mena/VASP mislocalization, increased motility, and deficits in actin remodeling. J Cell Biol 172:771-82.
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