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. 2016 Dec;17(12):799-810.
doi: 10.1038/nrm.2016.106. Epub 2016 Sep 14.

Internetwork competition for monomers governs actin cytoskeleton organization

Cristian Suarez  1 , David R Kovar  1   2
Affiliations

Internetwork competition for monomers governs actin cytoskeleton organization

Cristian Suarez et al. Nat Rev Mol Cell Biol. 2016 Dec.

Abstract

Cells precisely control the formation of dynamic actin cytoskeleton networks to coordinate fundamental processes, including motility, division, endocytosis and polarization. To support these functions, actin filament networks must be assembled, maintained and disassembled at the correct time and place, and with proper filament organization and dynamics. Regulation of the extent of filament network assembly and of filament network organization has been largely attributed to the coordinated activation of actin assembly factors through signalling cascades. Here, we discuss an intriguing model in which actin monomer availability is limiting and competition between homeostatic actin cytoskeletal networks for actin monomers is an additional crucial regulatory mechanism that influences the density and size of different actin networks, thereby contributing to the organization of the cellular actin cytoskeleton.

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Figures

Figure 1
Figure 1. Functionally diverse F-actin networks in mammalian and fission yeast cells
(A) Representative F-actin network organization in a motile mammalian cell. (Aa) Arp2/3 complex generates branched F-actin networks such as lamellipodia and endocytic vesicles. (Ab – Ae) Formin and Ena/VASP assemble F-actin found in linear bundles such as filopodia (Ab – Ad) or focal adhesions (Ae). (Af) Myosin motors are associated with contractile antiparallel F-actin bundles including stress fibers. (B) Fission yeast cells contain three principal F-actin networks generated by different actin assembly factors. (Ba) Arp2/3 complex generates branched F-actin networks for endocytic actin patches. (Bb) Formin For3 generates parallel F-actin bundles for polarizing actin cables. (Bc) Formin Cdc12 generates antiparallel F-actin bundles for the cytokinetic contractile ring.
Figure 2
Figure 2. Classic model of F-actin network regulation
Signalling cues bind membrane receptors activating RhoGTPase signaling pathways. RhoGTPases activate actin assembly factors directly, with Rho GTP directly relieving autoinhibition of formin, or indirectly through nucleation promoting factors like WASP, which activates Arp2/3 complex following its own activation induced by Cdc42 GTP binding. Actin assembly factors then facilitate the nucleation and/or elongation of G-actin into branched (Arp2/3 complex) or linear (formin) actin filaments. A reserve of unassembled actin is maintained by proteins that prevent nucleation (profilin), or nucleation and elongation (Thymosin β4). F-actin networks `age' through ATP hydrolysis to ADP on actin monomers incorporated into the filament, which leads to filament disassembly. Disassembly of filaments is also facilitated by a suite of severing and depolymerizing factors and this depolymerization collectively replenishes the pool of G-actin. Arp2/3 complex, actin related protein 2 and 3 complex; GBD, GTPase-binding domain; DID, DAD interacting domain; DAD, Diaphanous autoregulatory domain; FH1, Formin homology 1; FH2, Formin homology 2; V, WH2 domain; CA, Acidic domain; PP, Polyproline domain; AIP1, Actin-interacting protein 1; CAP, adenylyl cyclase-associated protein (also known as Srv2).
Figure 3
Figure 3. Disassembly of F-actin networks releases G-actin that accumulates in remaining networks
a–b Cartoon illustrating our model of F-actin network homeostasis. Network sizes are simulated deterministically using coupled rate equations, and each network is distinguished by a set of parameter values. The starting values of fraction of total actin are based on estimates from fission yeast. As these graphs are illustrative, time is presented in arbitrary units. (a) Model of actin reorganization upon branched network disassembly. The disassembly of an Arp2/3 complex network (branched F-actin) via genetic or small molecule inhibitor perturbation releases a pool of G-actin that will incorporate into remaining formin- and or Ena/VASP-mediated linear F-actin networks. Through Arp2/3 complex-mediated branched F-actin network disassembly, G-actin concentration will initially increase, and then is followed by a reduction due to its incorporation in remaining F-actin networks. (b) Model of actin homeostasis during cytokinetic ring assembly and disassembly. Assembly of the formin-mediated contractile ring requires a reduction in Arp2/3 complex-mediated F-actin networks (such as endocytic actin patches in fission yeast). The amount of F-actin incorporated into the ring will equal its decrease in actin patches. After ring disassembly, the level of actin consumed by actin patches is restored. In this example the assembly of a formin-mediated contractile ring during mitosis coincides with a partial disassembly of Arp2/3 complex-mediated endocytic actin patches, necessary for the incorporation of G-actin in the formin-mediated contractile ring. (c–e) Examples of F-actin network homeostasis in cells and in vivo evidence for internetwork competition. (c) Fission yeast expressing the general F-actin marker Lifeact-GFP. Wild type cells (left panel) contain three principal F-actin networks: endocytic actin patches (Arp2/3 complex), polarizing actin cables and contractile rings (formins). Inhibition of Arp2/3 complex by the small molecule inhibitor CK-666 induces disappearance of patches coupled with an accumulation of actin in formin-associated networks (middle panel). Genetic inhibition of formin-mediated F-actin networks induces an increase in the number of Arp2/3 complex-mediated endocytic patches (right panel). Images were adapted with permissions from REF33. (d) A fibroblast expressing the general F-actin marker Lifeact-GFP. Disappearance of lamellipodia by Arp2/3 complex sequestration through injection of the acidic domain (WCA) of WAVE1 in the presence of constitutively active Rac1 (WCA/Rac) induces an increase in formin- and/or and Ena/VASP-generated filopodia. Images were adapted with permissions from REF47. (e) A Drosophila S2 culture cell expressing Actin-GFP. Inhibition of Arp2/3 complex by dsRNA ARP2 induces a disappearance of Arp2/3 complex-mediated lamellipodia, and an increase in Ena/VASP- and/or formin-mediated mediated filopodia formation. Images were adapted with permissions from REF51.
Figure 4
Figure 4. Updated model of F-actin homeostasis including internetwork competitive crosstalk
Extracellular stimuli activate RhoGTPase signaling pathways that activate formin-, Arp2/3 complex- or Ena/VASP-mediated F-actin networks, promoting actin assembly within these networks. These networks remain in competition with each other for G-actin from a common limited pool (red triangle). Actin associated with sequestering proteins or incorporated in other networks (such as stress fibers stabilized by myosin motors), cannot participate in competition and largely affect the internetwork competition by further restricting the amount of actin available for polymerization. Profilin favours incorporation of G-actin into formin- and Ena/VASP-dependent F-actin networks (but at the same time inhibits formin-mediated nucleation of new filaments), while inhibiting Arp2/3 complex activation via competing with WASP-VCA for G-actin binding, and tips the balance towards the formation of linear actin networks. Capping protein competes with formin and Ena/VASP for barbed ends, whereas capping protein rapidly binds free barbed ends generated by Arp2/3 complex. Disassembly of F-actin networks replenishes the G-actin pool allowing more robust polymerization and growth of networks.
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