Abstract
The cytoskeleton and its components — actin, microtubules and intermediate filaments — have been studied for decades, and multiple roles of the individual cytoskeletal substructures are now well established. However, in recent years it has become apparent that the three cytoskeletal elements also engage in extensive crosstalk that is important for core biological processes. Actin–microtubule crosstalk is particularly important for the regulation of cell shape and polarity during cell migration and division and the establishment of neuronal and epithelial cell shape and function. This crosstalk engages different cytoskeletal regulators and encompasses various physical interactions, such as crosslinking, anchoring and mechanical support. Thus, the cytoskeleton should be considered not as a collection of individual parts but rather as a unified system in which subcomponents co-regulate each other to exert their functions in a precise and highly adaptable manner.
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References
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Acknowledgements
The authors thank A. Akhmanova for frequent discussions and insight. The authors thank C. Alkemade for preparing original schematics for all the figures. G.H.K. gratefully acknowledges support by the European Research Council (Starting Grant 335672-MINICELL). M.D. gratefully acknowledges support by the European Research Council (Synergy Grant 609822-MODEL CELL).
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Nature Reviews Molecular Cell Biology thanks K. Slep and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Glossary
- Dynamic instability
-
A process of dynamic alternation between growing and shrinking states that is characteristic of microtubules and driven by the GTPase activity of tubulin.
- Cell cortex
-
A thin (~100 nm) filamentous meshwork of actin filaments and actin-binding proteins including myosin motors, which are tightly associated with the plasma membrane via proteins of the ezrin–radixin–moesin family. The cortex protects the mechanical integrity of the cell membrane and has a central role in cell shape control.
- Microtubule plus-end trackers
-
( +TIPs). Structurally diverse proteins that bind to the plus ends of growing microtubules. At least 20 different families of +TIPs exist. End-binding (EB) proteins are +TIPs that autonomously recognize growing microtubule ends. Other +TIPs bind to EB proteins through SxIP, Cap-Gly or LxxPTPh recognition motifs.+TIPs control microtubule dynamics and connect microtubules to various cellular structures, including the actin cortex, stress fibres and filopodial actin bundles.
- Catastrophes
-
The switch to rapid depolymerization triggered by the loss of the GTP cap at the growing end of the microtubule.
- Lamellipodium
-
A sheet-like membrane protrusion that spans 2–4 µm from the leading edge of migrating and spreading cells and of neuronal growth cones. It contains a dense, branched network of actin filaments that polymerize at their plus ends near the leading edge and depolymerize at the back. The part of the leading edge directly behind the lamellipodium contains a more stable network of unbranched actin filaments and is enriched in myosin II.
- Focal adhesions
-
Adhesive junctions between cells and the ECM, which are mediated by integrins, whereby integrins interact with the ECM on the extracellular side and with actin bundles via adaptor and signalling proteins through their intracellular tails. Focal adhesions can contain over 100 different proteins, collectively referred to as the integrin adhesome. Cells modify the size and composition of focal adhesions in response to changes in the molecular composition and dimensionality (2D or 3D) of the matrix and physical forces.
- Leading edge
-
The front of a migrating cell. It is characterized by actin polymerization and the formation of nascent adhesions.
- Trailing edge
-
The rear end of a migrating cell. It is characterized by stable actin bundles and the release and disassembly of adhesions.
- Stress fibres
-
Bundles of 10–30 actin filaments crosslinked by α-actinin and often containing myosin II. There are four distinct types of stress fibre. Ventral stress fibres connect focal adhesions close to the cell edge to adhesions behind or near the nucleus. They are contractile and drive tail retraction and cell shape changes in migrating cells. Dorsal stress fibres are non-contractile but transmit contractile forces to the substrate via connections to focal adhesions. Transverse arcs are curved bundles behind the lamellipodium that are not connected to focal adhesions. They have been implicated in actin retrograde flow. The perinuclear actin cap is an ensemble of stress fibres that is anchored to the nucleus and controls its shape.
- Pseudopodia
-
A type of membrane protrusion that contributes to the crawling-like cell migration of amoebas and of mammalian cells in 3D extracellular matrices. In white blood cells, pseudopodia enable the capture and engulfment of antigens. Pseudopodia are extended by the polymerization of a dense network of branched actin filaments at the leading edge and are supported by microtubules.
- Blebbing
-
A process associated with the formation of blebs, which are round protrusions of the cell membrane caused by contraction of the actomyosin cortex in conjunction with a local rupture in the actin cortex or a transient detachment of the cortex from the cell membrane. Bleb expansion is driven by intracellular pressure generated in the cytoplasm whereas bleb retraction is driven by reformation of an actin cortex followed by myosin-driven contraction. Blebbing occurs during apoptosis, can drive the 3D motility of confined cells and acts as a pressure valve in dividing cells.
- Microtubule acetylation
-
A post-translational modification associated with long-lived microtubules whereby the Lys40 residue of α-tubulin in the microtubule lumen is enzymatically modified by tubulin acetyltransferase. Acetylation confers resilience against repeated mechanical stresses, thus protecting long-lived microtubules from mechanical ageing.
- Profilin
-
A regulatory protein that promotes actin assembly by sequestering monomeric actin, converting ADP-actin monomers into ATP-actin monomers and collaborating with actin nucleators such as formin to promote actin filament elongation.
- Filopodia
-
Thin (60–200 nm) membrane protrusions that extend from the leading edge of lamellipodia in migrating cells, neuronal growth cones and epithelial sheets. They contain parallel bundles of 10–30 actin filaments crosslinked by fascin and fimbrin. Filopodia form focal adhesions with the substrate and sense the extracellular environment at their tips using cell surface receptors. In neurons, filopodia serve as precursors for dendrites.
- Navigator family
-
Microtubule-associated proteins that are expressed predominantly in the nervous system.
- ADF/cofilin
-
A family of actin-binding proteins that disassemble actin filaments by depolymerization at the minus end and by severing.
- Cytoplasmic flow
-
Refers to the movement of cytoplasm driven either by actomyosin contractility or by microtubule-based organelle movement. It is most common in plants and algae, but it also occurs during oogenesis in the fruitfly and during embryogenesis in Caenorhabditis elegans.
- Microtubule minus-end trackers
-
(–TIPs). Proteins that specifically bind to the minus end of non-centrosomal microtubules. The best-characterized proteins of the calmodulin-regulated spectrin-associated protein (CAMSAP)–Patronin–Nezha family protect minus ends from depolymerization and connect them to various cellular structures including the actin cortex at the apical surface of epithelial cells.
- Viscous drag
-
The frictional force that opposes the motion of an object in a viscous fluid. The viscous drag force is proportional to the velocity of the object, the fluid velocity and the object’s size, as expressed by Stokes’ law.
- Hertwig’s rule
-
A rule introduced by the German zoologist Oscar Hertwig in 1884 that is based on observations of the orientation of divisions of frog eggs upon controlled compression, stating that a cell divides along its long axis.
- Retraction fibres
-
Thin membrane tubes filled with actin filaments that maintain cell adhesion during mitotic rounding. They confer a memory of the cell–ECM adhesion geometry during interphase, allowing cells to orient their mitotic spindle.
- Planar cell division
-
Symmetrical cell division within the plane of an epithelial tissue. Planar alignment of the mitotic spindle is mediated by cortical cues, cell shape and mechanical tension. Coordinated planar cell divisions serve to elongate growing epithelial tissues while maintaining tissue cohesion.
- Septins
-
A family of guanine nucleotide binding proteins present in the cell as hetero-oligomeric complexes. They form higher-order filamentous structures that can interact with actin, microtubules and membranes.
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Dogterom, M., Koenderink, G.H. Actin–microtubule crosstalk in cell biology. Nat Rev Mol Cell Biol 20, 38–54 (2019). https://doi.org/10.1038/s41580-018-0067-1
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DOI: https://doi.org/10.1038/s41580-018-0067-1
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