Cell Adhesion, Migration, and Response to Mechanical Stimulation
Cells respond to their environment by migrating towards or away from signals, adhering to their surroundings, proliferating or dying, and reinforcing their skeletal structure to withstand mechanical stresses. These signals and responses are highly regulated in normal cells, but certain controls may be lost in transformed cells, such as metastatic cancer cells. We are investigating how cells receive information, process it, and respond appropriately. Since many proteins are involved in these activities, we are determining how particular proteins contribute to the responses. One protein of interest, zyxin, is an actin cytoskeletal regulator, binds many other proteins and probably functions as a scaffolding protein to bring proteins together at the appropriate time and place. Zyxin is sensitive to the mechanical environment and adjusts its subcellular distribution in response to mechanical input. We are currently pursuing studies to characterize the role of zyxin and its many binding partners in cell adhesion, migration, cytoskeletal reinforcement and response to mechanical stimulation.
Selected References:Zyxin: zinc fingers at sites of cell adhesion (1997) Bioessays
Tumor Progression and Metastasis
Ewing sarcoma is a pediatric bone tumor that is highly metastatic and resistant to therapy. The Beckerle Lab is working collaboratively with other research labs at the Huntsman Cancer Institute to determine the underlying mechanism of Ewing sarcoma pathogenesis with the hope that better understanding could lead to new treatment possibilities.
In Ewing sarcoma cells, the oncogenic transcription factor EWS/FLI activates and represses many genes. Using a knockdown/rescue approach to study the impact of EWS/FLI on cells, we identified dramatic EWS/FLI-dependent consequences in cell adhesion, migration and the actin cytoskeleton. Investigation of the molecular mechanisms behind these changes and development of pre-clinical models to evaluate Ewing sarcoma tumorigenesis and metastasis are underway, with the goal of improving options for therapeutic intervention.
Integrins (cell surface receptors that play a major role in communication between the intracellular and extracellular environments) affect cellular processes such as adhesion, migration proliferation, and survival. Integrins are critically important in developmental events, tissue maintenance, immune surveillance, and wound healing. Integrins also play key roles in diseases such as cancer, in which the interaction of tumor cells with their environment has far-reaching implications in tumor invasion and metastasis.
Upon binding of extracellular matrix (ECM), integrins cluster and recruit large signaling complexes to their cytoplasmic face that lead to alterations in both the actin cytoskeleton and gene expression. In turn, intracellular components can modulate the bining of integrins to the ECM. Scaffolding proteins, which mediate physical interactions with multiple protein partners, play an important role in signal integration by bringing together signaling molecules in a spatially and temporally regulated manner. We are currently working toward a molecular understanding of how binding of these partners contributes to integrin function, both in development and disease.