The molecular basis of cellular motility and cytokinesis

Thomas Pollard , Ph.D.

Thomas D. Pollard , M.D.

Sterling Professor of Molecular, Cellular & Developmental Biology
Professor of Cell Biology
and Professor of Molecular Biophysics and Biochemistry
Dean of the Graduate School of Arts and Sciences

Room: KBT 548
Phone: 23565/23194

Web site:
Department of Cell Biology:

B.A. Pomona College 1964; M.D. Harvard Medical School 1968

We study the molecular basis of cellular motility and cytokinesis. Actin-based movements are essential for cell division, shaping organs during embryonic development, defense against microorganisms and wiring the nervous system. Movement of cells out of primary tumors is the chief cause of mortality in cancer. We use fission yeast for much of this work because they use the same molecular mechanisms at humans, but are much more amenable to experimentation using molecular genetics. We find it advantageous to combine biochemical, biophysical, cellular and genetic experiments with mathematical modeling to test hypotheses about molecular mechanisms and biological functions. We divide our effort between two main projects:

1. Actin filament dynamics: We aim to understand how assembly of actin filaments pushes the leading edge of motile cells and vesicles formed by endocytosis. We discovered that Arp2/3 complex is both the initiator of actin filament assembly and the central integrator of inputs from signaling pathways. Cell surface receptors activate WASp/Scar proteins, which stimulate Arp2/3 complex to nucleate new actin filaments as branches on the sides of pre-existing filaments. WASp brings together an actin monomer and Arp2/3 complex on the side of a filament to initiate a branch. Arp2/3 complex is incorporated into the network and new filaments are capped rapidly, so activated Arp2/3 complex must be supplied continuously to keep the network growing.

We study this pathway using biophysical methods including x-ray crystallography and transient state kinetics of purified proteins in parallel with real time quantitative measurements of proteins in live fission yeast cells. Computer simulations of mathematical models allow us to combine molecular and cellular data to test our hypotheses.

2. Cytokinesis: Cytokinesis remains one of the most mysterious of vital biological processes. Fission yeast is the ideal organism to learn how cells control the assembly of an equatorial contractile ring composed of actin filaments and myosin-II and trigger its constriction once chromosomes have separated. We study the key cytokinesis proteins. The formin protein Cdc12p nucleates actin filaments for the contractile ring and remains attached to their fast growing ends, so it can also anchor the filaments to the membrane. Myosin-II is the motor protein that applies tension to the actin filaments. Our time-lapse movies of live cells expressing fluorescent fusion proteins revealed the temporal and spatial pathway for contractile ring assembly. Numerical simulations show that a simple mechanism involving random searches by growing actin filaments, capture of these filaments and pulling by myosin-II and frequent release of these attachments accounts for contractile ring assembly. Mathematical modeling has also directed our attention to many unanswered questions to be explored at the cellular and molecular levels.

Selected Publications

Wu JQ, Pollard TD (2005). Counting cytokinesis proteins globally and locally in fission yeast. Science 310:310-314.

Kovar DR, Harris ES, Mahaffy R, Higgs HN, Pollard TD (2006) Control of the assembly of ATP- and ADP-actin by formins and profilin. Cell 124:423-435.

Vavylonis, D., Wu, J.-Q., Hao, S., O'Shaughnessy, B. and Pollard, T.D. (2008) Assembly mechanism of the contractile ring for cytokinesis by fission yeast. Science 319:97-100.

Nolen, B.J., Tomasevic, N., Russell, A., Pierce, D., Jia, Z., McCormick, C.D., Hartman, J., Sakowicz, R. and Pollard, T.D. (2009) Characterization of two classes of small molecule inhibitors of Arp2/3 complex. Nature 460:1031-1034.




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