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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095977-07
Application #
9701215
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Xu, Jianhua
Project Start
2013-07-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Efimova, Nadia; Svitkina, Tatyana M (2018) Branched actin networks push against each other at adherens junctions to maintain cell-cell adhesion. J Cell Biol 217:1827-1845
Shutova, Maria S; Svitkina, Tatyana M (2018) Mammalian nonmuscle myosin II comes in three flavors. Biochem Biophys Res Commun 506:394-402
Svitkina, Tatyana M (2018) Ultrastructure of the actin cytoskeleton. Curr Opin Cell Biol 54:1-8
Svitkina, Tatyana (2018) The Actin Cytoskeleton and Actin-Based Motility. Cold Spring Harb Perspect Biol 10:
Stefani, Caroline; Gonzalez-Rodriguez, David; Senju, Yosuke et al. (2017) Ezrin enhances line tension along transcellular tunnel edges via NMIIa driven actomyosin cable formation. Nat Commun 8:15839
Efimova, Nadia; Korobova, Farida; Stankewich, Michael C et al. (2017) ?III Spectrin Is Necessary for Formation of the Constricted Neck of Dendritic Spines and Regulation of Synaptic Activity in Neurons. J Neurosci 37:6442-6459
Shutova, Maria S; Asokan, Sreeja B; Talwar, Shefali et al. (2017) Self-sorting of nonmuscle myosins IIA and IIB polarizes the cytoskeleton and modulates cell motility. J Cell Biol 216:2877-2889
Marchenko, Olena O; Das, Sulagna; Yu, Ji et al. (2017) A minimal actomyosin-based model predicts the dynamics of filopodia on neuronal dendrites. Mol Biol Cell 28:1021-1033
Svitkina, Tatyana M (2017) Platinum replica electron microscopy: Imaging the cytoskeleton globally and locally. Int J Biochem Cell Biol 86:37-41
Ong, K; Svitkina, T; Bi, E (2016) Visualization of in vivo septin ultrastructures by platinum replica electron microscopy. Methods Cell Biol 136:73-97

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