Class II (conventional) myosins are actin-dependent motors that are uniquely able to polymerize into bipolar filaments, which makes them capable of driving cell contraction. Nonmuscle myosin II (NMII) is ubiquitously expressed in animal cells, where it executes numerous mechanical tasks including cell adhesion and migration, as well as overall organization of the contractile cytoskeleton in the cell. In contrast to large and stable bipolar filaments formed by muscle-specific myosin II paralogs, NMII filaments are small and highly dynamic. By constantly cycling between polymeric and monomeric states, NMII can accommodate changing cellular needs and help the cell to choose an appropriate mode of migration. We recently discovered two new aspects of NMII dynamics: (1) copolymerization of NMII paralogs into hybrid bipolar filaments and (2) functional significance of activated, but unpolymerized NMII monomers that were previously considered to be only transient intermediates of NMII activation. Our goal is to determine physiological significance of these new aspects of NMII dynamics. Specifically, we will test our hypotheses that (1) copolymerization of NMII paralogs is a key mechanism to establish polarized organization of the contractile system in cells and thus promote directional cell migration and that (2) activated NMII monomers regulate dynamics of cell-matrix adhesions. A key element of both models is regulation of NMII at the heavy chain level, which modulates composition of hybrid bipolar filaments and generates activated NMII monomers. We address the following specific aims: (1) Roles of NMII copolymerization for contractile system organization and cell migration; (2) Roles of heavy chain- dependent mechanisms of NMII turnover for cytoskeleton polarization and cell migration; and (3) Roles of activated NMII monomers in dynamics of cell-matrix adhesions.
The results will contribute to understanding of the molecular mechanisms by which cells adapt their motility modes to changes in their environments. This knowledge can help to design drugs, treatments and diagnostic tools to fight human diseases deriving from aberrations in cell motility, such as cancer, immunological disorders and neurodegenerative diseases.
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