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Review
. 2016 Aug;26(8):569-576.
doi: 10.1016/j.tcb.2016.04.001. Epub 2016 Apr 25.

Unravelling the Actin Cytoskeleton: A New Competitive Edge?

Andrew J Davidson  1 , Will Wood  2
Affiliations
Review

Unravelling the Actin Cytoskeleton: A New Competitive Edge?

Andrew J Davidson et al. Trends Cell Biol. 2016 Aug.

Abstract

Dynamic rearrangements in the actin cytoskeleton underlie a wide range of cell behaviours, which in turn contribute to many aspects of human health including embryogenesis, cancer metastasis, wound healing, and inflammation. Precise control of the actin cytoskeleton requires the coordinated activity of a diverse set of different actin regulators. However, our current understanding of the actin cytoskeleton has focused on how individual actin regulatory pathways function in isolation from one another. Recently, competition has emerged as a means by which different actin assembly factors can influence each other's activity at the cellular level. Here such findings will be used to explore the possibility that competition within the actin cytoskeleton confers cellular plasticity and the ability to prioritise multiple conflicting stimuli.

Keywords: actin; chemotaxis; competition; cytoskeleton; filopod; lamellipod.

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Figures

Figure 1
Figure 1
Increased Actin Bundle Formation following Disruption of the Arp2/3 Complex is an Evolutionary Conserved Cellular Response. (A) Schizosaccharomyces pombe expressing LifeAct-GFP and treated with either dimethyl sulfoxide (DMSO) or the Arp2/3 complex inhibitor CK-666. CK-666 treatment causes loss of Arp2/3 complex-dependent endocytic patches and an increase in actin cable formation (images obtained with permission from T.A. Burke and D.R. Kovar). (B) Dictyostelium discoideum expressing LifeAct-mRFP and treated with either DMSO or CK-666. Actin-rich ruffles are lost in Dictyostelium treated with CK-666 with filopods extended in their place (images obtained with permission from A.J. Davidson and R.H. Insall). (C) Loss of scar in LifeAct-GFP expressing Drosophila embryonic hemocytes results in lamellipod collapse and excessive filopod extension (images obtained with permission from A.J. Davidson and W. Wood). (D) Control and arpC2 null (*) mouse embryonic fibroblasts (MEFs) fixed and stained with phalloidin. Disruption of the Arp2/3 complex causes lamellipod loss (arrows highlight lamellipods in control cell) and increased actin bundles in the form of filopods and stress fibres (images obtained with permission from J.D. Rotty and J.E. Bear). All scale bars represent 10 μm.
Figure 2
Figure 2
Actin Assembly Factors Compete with Each Other over a Finite Pool of G-Actin. Monomeric G-actin is either incorporated into dendritic networks of F-actin by the Arp2/3 complex or linear, unbranched networks by the formins and/or Ena/VASP. These actin assembly factors compete with one another over a limited supply of monomeric actin. The G-actin binding protein profilin maintains homeostasis within the actin cytoskeleton by ensuring the formins and/or Ena have access to this finite pool of actin monomers. This competition can be skewed experimentally by altering the levels of G-actin, profilin, or the actin assembly factors themselves. For instance, disruption of the formins in Schizosaccharomyces pombe or Ena/VASP in mammalian cell lines stimulates the Arp2/3 complex, resulting in increased dendritic actin networks and associated structures. Increased G-actin levels or suppressed profilin also has the same effect. Conversely, disruption of the Arp2/3 complex, reduced G-actin levels, or increased profilin levels stimulates the formins or Ena/VASP, promoting excessive actin cable or filopod formation depending on the organism studied.
Figure 3
Figure 3
Key Figure: Cytoskeletal Competition as a Means to Balance and Integrate Multiple, Competing Stimuli As a general mechanism for regulating the actin cytoskeleton, competition offers several advantages including the ability to integrate multiple conflicting signals. Competition can be envisioned as a set of balance scales with stimuli acting as weights that can tip the balance towards the activation of one actin assembly factor or another. Balance scales can accommodate the addition of single large weights (A) or multiple smaller ones (B). Regardless of how much weight is added to either side, as long as one side outweighs the other the scales will tip. This represents a form of information integration whereby regardless of quantity or type, the weight of each weighing pan is subtracted from the other with any remainder determining which side the scales come down on. (C) At the molecular level, competition between different actin regulators (e.g., between formins and the Arp2/3 complex) could be mediated in several ways. Aside from G-actin, actin assembly factors could also compete for the same signalling molecules, thus limiting each other's activation. Alternatively, actin regulators could inhibit one another through direct interactions to the same effect.
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