Modeling mechanisms in cytokinesis, cell polarization and motility

Lehigh University, Bethlehem PA

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Abstract

Project Summary/Abstract The ability of cells to divide, establish a polarization direction, and move by crawling requires the coordinated interactions of the cytoskeleton with membranes as well as with the signaling system organizing on membranes. A major challenge for the development of predictive mathematical and computational models of these mechanisms of subcellular organization is accounting of how highly specific interactions at the molecular level lead to the emergent collective behavior. We address this complexity by employing computational and mathematical modeling methods linking molecular to cellular scales, in close collaboration with experimentalists working on model systems that reveal important cell biological functions and are amenable to quantitative approaches. We have three areas of current focus. (1) Understanding the molecular mechanisms and biophysical principles governing the nanoscale assembly of fission yeast nodes, which orchestrate cell cycle progression and cytokinesis. A multiscale approach, combining computational modeling techniques with experiments by collaborators will investigate the interactions among node proteins and the membrane, focusing on Cdc15, Mid1, and Cdr2. Key questions regarding node assembly, phosphorylation regulation, and nuclear shuttling will be addressed. (2) Modeling of membrane hydrodynamics and mechanics during fission yeast cytokinesis and its coupling to the spatial distribution of exocytosis and endocytosis. Coarse-grained fluid simulations will be tested against experiments with vesicle traffic mutants. We will investigate flow-induced transport of membrane proteins and its implications for the membrane and cytoskeleton. (3) Understanding force generation by dendritic networks in the presence of myosin I, the significance of severed oligomers in cellular actin transport, and the interaction for the actin cytoskeleton with focal adhesions and the extracellular matrix. Mathematical models will be developed at the level of individual actin filaments, oligomers, and talin linkers. Overall, the research integrates computer simulations, experimental observations, and collaborative expertise to deepen our understanding of actin and membrane dynamics and its implications for cellular behavior.