Cells assemble functionally diverse actin cytoskeleton networks with distinct architectures and dynamics to drive fundamental processes such as polarization, endocytosis, motility and division. The specific characteristics of different actin filament networks (actin filament density, organization and dynamics) are determined through the coordination action of specific sets of actin binding proteins (ABPs) with complementary binding properties. Most investigations primarily focus on individual F-actin networks. However, this provides limited overall understanding of F-actin network organization and function because cells typically assemble and use multiple F-actin networks simultaneously within the same cytoplasm. Consequently, F-actin networks must self-organize from a common pool of shared actin monomers and overlapping sets of ABPs. We have predicted that there are important interactions (cross talk) between networks that are critical for their form and function. Our long-term goal is to discover the direct and indirect interactions between self-organized F-actin networks, which are critical for establishing their unique identities and functions within a common cytoplasm, and to determine the underlying molecular mechanistic principles that govern these interactions. We are investigating two major actin cytoskeleton self-organization questions. The first is to determine the mechanisms by which the size and density of F-actin networks are regulated by competition for a limiting amount of actin monomers (Aim I). Although unassembled G-actin was not thought to be limiting, we systematically showed that competition for G-actin helps control the size and density of competitive F-actin networks in fission yeast, and that the actin monomer protein profilin plays a major role in regulating competition for limiting G-actin. Our goal is to determine the underlying mechanism by which profilin and other ABPs contribute to the proper distribution of G-actin between functionally diverse actin cytoskeleton networks. The second is to determine how diverse F-actin networks acquire the specific set of ABPs whose complementary biochemical activities help define their form and function (Aim II). We will investigate the underlying intrinsic molecular mechanisms by which ABPs self-sort to particular F-actin networks within a common cytoplasm, including (1) the contribution of competition and cooperation between ABPs for associating with actin filaments, and (2) whether actin assembly factors initiate self-sorting by biasing the association of particular ABPs.
Cells assemble multiple actin cytoskeleton networks simultaneously within the same cytoplasm to facilitate fundamental processes such as division, endocytosis, polarization, motility, and thus survival. We are studying how cells self-organize distinct actin filament networks with different organizations and behaviors from a common pool of actin subunits and diverse actin binding regulatory proteins. Elucidating the mechanisms of actin cytoskeleton self-organization is critical to understanding fundamental mechanisms of the behavior and function of both healthy and diseased cells.
| Kudryashova, Elena; Heisler, David B; Williams, Blake et al. (2018) Actin Cross-Linking Toxin Is a Universal Inhibitor of Tandem-Organized and Oligomeric G-Actin Binding Proteins. Curr Biol 28:1536-1547.e9 |
| Burke, Thomas A; Harker, Alyssa J; Dominguez, Roberto et al. (2017) The bacterial virulence factors VopL and VopF nucleate actin from the pointed end. J Cell Biol 216:1267-1276 |
| Christensen, Jenna R; Hocky, Glen M; Homa, Kaitlin E et al. (2017) Competition between Tropomyosin, Fimbrin, and ADF/Cofilin drives their sorting to distinct actin filament networks. Elife 6: |
| Zimmermann, Dennis; Morganthaler, Alisha N; Kovar, David R et al. (2016) In Vitro Biochemical Characterization of Cytokinesis Actin-Binding Proteins. Methods Mol Biol 1369:151-79 |
| Winkelman, Jonathan D; Suarez, Cristian; Hocky, Glen M et al. (2016) Fascin- and ?-Actinin-Bundled Networks Contain Intrinsic Structural Features that Drive Protein Sorting. Curr Biol 26:2697-2706 |
| Suarez, Cristian; Kovar, David R (2016) Internetwork competition for monomers governs actin cytoskeleton organization. Nat Rev Mol Cell Biol 17:799-810 |
| Bezanilla, Magdalena; Gladfelter, Amy S; Kovar, David R et al. (2015) Cytoskeletal dynamics: a view from the membrane. J Cell Biol 209:329-37 |
| Rotty, Jeremy D; Wu, Congying; Haynes, Elizabeth M et al. (2015) Profilin-1 serves as a gatekeeper for actin assembly by Arp2/3-dependent and -independent pathways. Dev Cell 32:54-67 |
| Suarez, Cristian; Carroll, Robert T; Burke, Thomas A et al. (2015) Profilin regulates F-actin network homeostasis by favoring formin over Arp2/3 complex. Dev Cell 32:43-53 |
| Zimmermann, Dennis; Santos, Alicja; Kovar, David R et al. (2015) Actin age orchestrates myosin-5 and myosin-6 run lengths. Curr Biol 25:2057-62 |
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