Cell migration is a basic biological process that is essential for all life. In order to migrate, a cell must coordinate the extension of membranes (protrusion) and their adhesion to the underlying matrix. Mechanisms for regulating both membrane protrusion and cell adhesion have been extensively studied. However, it is still is not known how these discrete steps are integrated. This lack of information prevents a current and comprehensive model for cell migration to be developed. Vinculin is an actin binding protein that is recruited to cell adhesions; it establishes linkages between cell adhesions and the actin networks that provide the driving force for membrane protrusion. Vinculin forms two types of actin assemblies that can mediate this linkage. These include branched actin networks and bundled actin filaments. The function of these diverse actin assemblies and how they are integrated to regulate cell migration is not known. This lack of information represents a major gap in our knowledge with respect to how cell migration is controlled at the cellular and organismal levels. This research will determine how the bundling and branching activities of vinculin are integrated to produce cell movements. At the completion of this project, novel mechanisms for coupling protrusion and adhesion will be identified and information for how these events are integrated will be attained.
The intellectual merit of this work will be the development of a contemporary model for cell migration. Such a model will advance the field as it will serve as a foundation for testing how new molecules affect cell migration and will ultimately promote migration research by lowering barriers for entry into the field. Intellectual merit for these studies also derives from the innovative combination of biophysical, biochemical and imaging approaches that will provide unprecedented integrative and quantitative insight into the mechanism of the biology.
This project will have broad impacts because it will have far reaching implications for a number of groups. Firstly, it will influence scientists across disciplines since cell migration is essential for numerous biological processes. Secondly, the work includes outreach to high school girls. The intent of this workshop is to alter the preconceived notions that high young women have about scientists and scientific careers, to facilitate their entry into scientific careers, and to enlist them as scientific ambassadors to disseminate information to the community. This feat will be accomplished by providing the high school students with the opportunity to execute some aspects of the research and by exposing a program at the University of Iowa that provides opportunities for high school students to conduct research in a laboratory. Thirdly, the project will also support a partnership between the PI's laboratory and a biochemistry professor from a rural liberal arts college that does not offer post-graduate programs. The liberal arts professor will aid in the execution of the research and learn how to make quantitative measurements of migrating cells. Finally, this project will continue to support the pre-doctoral training of graduate and undergraduate students in the PIs laboratory.
The goal of the work in this project was to better understand how cells adhere and coordinate their cytoskeletons so that a more accurate model emerges for how cells move. In the course of these studies, we made two major scientific breakthroughs. First, we found that there is a critical tyrosine residue in vinculin, a cell-cell and cell-matrix adhesion protein that governs its function at each site. Secondly we identified the molecular mechanism for how vinculin binds actin and the outcome of preventing this event. This work is important because it allows for a more complete understanding and a revision of textbook definition for how cells migrate. Another major outcome of this work is that it has supported the training and development of a talented group of young people into various scientific discplines. Many of the undergraduates supported by this award are currently enrolled in graduate programs in the basic sciences and the graduate students are pursuing post-doctoral studies also in the sciences. This proposal also allowed numerous high school girls to be exposed to cutting edge research at the University of Iowa and supported the development of a liberal arts science professor in the scientific discipline of cell migration.