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Thomas Egelhoff , Ph.D.Interim ChairmanDepartment of Cell Biology |
Area of General Research Interest:
Mechanisms regulating cytoskeletal function during cell migration and cytokinesis; nonmuscle myosin II cell biology and biochemistry; cancer cell migration; keratinocyte motility and wound healing.
Current Programs:
Investigators:
Research Description
We study the mechanics and regulation of the cytoskeleton during force-requiring processes such as chemotaxis and cytokinesis. Chemotactic cell migration plays a central role in a wide variety of processes, ranging from metastatic behavior of cancer cells, to monocyte and neutrophil homing during infections, to keratinocyte migration during wound healing. Cytokinesis, the cytoskeleton-driven division of a cell into two daughter cells following mitosis, is also of fundamental importance during development and in pathological settings such as cancer.
Actin and conventional myosin (myosin II) are abundant and critical components of the force generating cytoskeleton in nonmuscle cells, yet the mechanisms regulating the localized assembly and activation of the actomyosin contractile system is not well understood. We use a multifaceted approach to understanding the roles and regulation of myosin II during cell adhesion, migration, and cytokinesis. Approaches emphasize live cell confocal microscopic analysis of GFP-fusion protein dynamics in conjunction with siRNA and genetic manipulation, biochemical studies on regulators of myosin II assembly, and molecular approaches such as cloning of genes implicated in regulation of myosin assembly and dynamics during chemotactic migration. Current studies focus on: (1) Human cancer cells. We are using cell imaging, biochemistry, protein structure function approaches, and siRNA methods to establish the roles and regulation of myosin contractile function in chemotactic cancer cell migration. (2) Mechanisms regulating cytoskeletal activation during wound responses in skin cells. Both in vivo and in culture, human keratinocytes respond to wound stimuli with a dramatic stimulation of cell migration. Our studies focus on deciphering the mechanisms that activate this cytoskeleton-based motility response. (3) We also use the simple amoeba Dictyostelium discoideum to address fundamental mechanisms regulating chemotaxis, cell motility, and the actomyosin cytoskeleton function during cell division. As in our cancer cell studies, we make extensive use of GFP-fusion proteins and live cell imaging, but we also utilize a wide array of genetic tools and mutagenesis methods that are not possible in mammalian systems, facilitating identification and verification of the roles of new players regulating cytoskeletal function.
Key References:
Myosin II Isoform Switching Mediates Invasiveness following TGFβ-induced Epithelial-Mesenchymal Transition. Beach, J.R., George S. Hussey, G.S., Miller, T.E., Chaudhury,A., Patel, P., Monslow,J., Zheng,Q., Keri, R.A., Reizes, O., Bresnick, A.R., Howe, P.H., Egelhoff, T.T. PNAS. IN PRESS, 2011.
Role of B regulatory subunits of PP2A in myosin II assembly control in Dictyostelium discoideum. Vandana Rai and Thomas T. Egelhoff. Eukaryotic Cell, 10:604-610, 2011.
A proteomic study of myosin II motor proteins during tumor cell migration. Venkaiah Betapudi, Giridharan Gokulrangan, Mark R. Chance, and Thomas T. Egelhoff. Journal of Molecular Biology, 407:673-686, 2011
A microfluidic imaging chamber for the direct observation of chemotactic transmigration. Breckenridge, M.T., Egelhoff, T.T., and Baskaran, H. Biomedical Microdevicies, 12:543-53. 2010.
Novel regulation and dynamics of myosin-II activation during epidermal wound responses. Betapudi, V, Rai, V., Beach, J., and Egelhoff, T.T. Experimental Cell Research, 316:980-991. 2010.
Insights into the roles of non-muscle myosin IIA in human keratinocyte migration. Sarkar, S., Egelhoff, T.T., and Baskaran, H. Cellular and Molecular Bioengineering, 4:486–494. 2009.
Roles of an Unconventional Protein Kinase and Myosin II in Amoeba Osmotic Shock Responses. Venkaiah Betapudi and Thomas T. Egelhoff. Traffic. 10:1773-84, 2009.
Myosin II Recruitment during Cytokinesis Independent of Centralspindlin-mediated Phosphorylation. Beach, J., and Egelhoff, T.T., Journal of Biological Chemistry. 284:27377-83. 2009.
Multiple Regulatory Steps Control Mammalian Nonmuscle Myosin II Assembly in Live Cells. Breckenridge, M., Dulyaninova N.G., and Egelhoff, T.T. Mol Biol Cell, 20:338-47. 2009.