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Role of Rho family GTPases in cell motility

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Role of Rho family GTPases in cell motility

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1. Initial cell polarisation (selection of direction)

Cdc42-GTP --> recruits formins --> nucleation of long, straight actin filaments --> extension of fillopodia --> sense and respond to extracellular cues

2. Active Rac GTPase --> formation of lamellipodia

Activated exclusively at leading edge

Promotes actin polymerisation at cell periphery

Recruits/activates Arp2/2 (via WAVE) --> stimulates nucleation of branched actin networks

3. Active Rho GTPase --> promotes formation of actin-myosin contractile bundles/stress fibres

Activated predominately at rear

Recruits/activates formins --> stimulates nucleation/elongation of long, straight actin filaments

Effectors inhibit cofilin --> actin filament stabilisation

Effectors activate myosin-II --> contractile activity --> tension

Promotes clustering of integrins and associated proteins --> formation of focal adhesions

Rac and Rho pathways are mutually antagonistic

Rac effectors inhibit Rho activity

--> cell polarisation --> directionality of movement

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Arp2/3: p906-908

Filamin: p912-913

Cell migration: p951-956

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Macrophages and neutrophils - crawl to sites of infection and engulf foreign invades as part of the innate immune response.

Osteoclasts

Fibroblasts

Predatory amoebae

Neural crest cells - during development, NCCs migrate from their site of origin in the neural tube to a variety of sites throughout the embryo.

Cancer cells - metastasis

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Actin structures: lamellipodia and fillopodia

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Actin structures: lamellipodia and fillopodia

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Lamellipodia

Thin sheet of cross-linked actin filaments that stretches out to the cell's periphery (leading edge)

Generate pushing forces that drive the cell forward

Continuous branching - off and cross-linking of actin generates the protrusive force needed to overcome the compressive force of the plasma membrane

Fillopodia

Core of actin filaments in a tight, parallel bundle

Function as antennae for cells to probe their environment

Stress fibres

Bundles of antiparallel actin filaments associated with non-muscle myosin II

Interact with myosin to generate contractile forces that drive the cell forward

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Arp2/3: facilitates nucleation of branched actin networks, driving the leading edge forward in a protrusion

Binds to - end of actin filaments

Highly concentrated near the front of the lamellipodia, where nucleation is most active

Filamin: cross-links actin filaments into a three dimensional network in lamellipodia

Formins: facilitate the nucleation of long, straight actin filaments in fillopodia

Fimbrin/fascin: link and reinforce tight parallel bundles in fillopodia

α-actinin: link and reinforce (less tight) antiparallel bundles in stress fibres

Profilin: promotes polymerisation at the + end

Cofilin: binds older (ADP-bound) coils and twists them tighter, applying mechanical stress that stimulates filament disassembly --> accelerates turnover of the leading edge

--> abundant supply of actin monomers

Dense branched actin network excludes organelles so must be dismantled for the cell to move forward

Adaptor proteins: create adhesions, bind to intergrins and link the actin cytoskeleton to the substratum

Myosin: mediate contractile forces on stress fibers to generate traction

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Polarity: the actin filaments in the meshwork are mostly orientated with the + end facing forward

Dynamic instability: allows lamellipodia to be rapidly assembled and disassembled

Treadmilling: the lamellipodia meshwork as a whole undergoes treadmilling, assembling at the front and disassembling at the back

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1. After determining its direction of motion, the cell extends a protrusion in this direction via actin polymerisation at the leading edge

2. The cell adheres its leading edge to the surface on which it is moving and de-adheres at the trailing edge

3. The whole cell body is pulled forward by contractile forces generated at the rear of the cell

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Specialised macrophages that patrol tiny vessels in the liver called sinusoids, recycling old red blood cells and ingesting pathogens.

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Cell polarity is exhibited by all motile cells

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Cell polarity is exhibited by all motile cells

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Certain structures (ie. lamellipodium) only form at the front other the cells, whereas others only form at the rear

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Monomeric GTPases (activated by extracellular factors binding to receptor --> intracellular signalling cascade)

Cdc42: involved in filopodia formation

Rac1: regulates lamellipodia formation

RhoA: interacts with myosin ands aids the formation of stress fibres and focal adhesion

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Cell motility is important for wiring the complex patterns of neuronal connectivity in the brain. A developing axon navigates towards its synaptic target with the help of the "growth cone" at its tip. The dynamics of the growth cones' actin (red) and microtubule (green) cytoskeleton steers the axon and is essential for directional migration.

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1. Wound created 😢

2. Platelets recruited to site to form fibrin site that seals the wound

3. Macrophages and neutrophils crawl to the site to clear debris and kill invasive species, mitigating infection

4. Epithelial cells in surrounding tissue undergo a Epithelial-mesenchymal transition (EMT) and become motile to cover the wound in a process called re-epithelialization

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Steering cell migration: lamellipodium dynamics and the regulation of directional persistence

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Steering cell migration: lamellipodium dynamics and the regulation of directional persistence

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Nature Reviews Molecular Cell Biology 15, 577-590 (2014) Cite this article

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Key Points

Lamellipodial protrusion depends on the force generated by actin polymerization. Actin polymerization is the sum of the activities of nucleators - for example, the actin-related protein 2/3 (ARP2/3) complex - and elongators - formins and ENA/VASP proteins.

Small GTPases, such as RAC and CDC42, control both actin nucleators and actin elongators; RAC activates the WASP family verprolin-homologous protein (WAVE) complex upstream of the ARP2/3 complex independently of the activation of the formin FMNL2 by CDC42, but RAC may coordinate ARP2/3 with ENA/VASP proteins by inducing a complex between WAVE and lamellipodin.

The speed of cell migration depends on the turnover of actin branched junctions and on the elongation of actin networks.

An intrinsic instability of lamellipodia is due to ARP2/3 inhibitory proteins, such as Arpin, which is also activated downstream of RAC.

The persistence of lamellipodia is the major controller of cell directionality.

Directional persistence (that is, the characteristic time during which a cell sustains its migration in the same direction) is the combinatory result of several intertwined positive- and negative-feedback loops that sustain or stop actin polymerization at the leading edge.

Abstract

Membrane protrusions at the leading edge of cells, known as lamellipodia, drive cell migration in many normal and pathological situations. Lamellipodial protrusion is powered by actin polymerization, which is mediated by the actin-related protein 2/3 (ARP2/3)-induced nucleation of branched actin networks and the elongation of actin filaments. Recently, advances have been made in our understanding of positive and negative ARP2/3 regulators (such as the SCAR/WAVE (SCAR/WASP family verprolin-homologous protein) complex and Arpin, respectively) and of proteins that control actin branch stability (such as glial maturation factor (GMF)) or actin filament elongation (such as ENA/VASP proteins) in lamellipodium dynamics and cell migration. This Review highlights how the balance between actin filament branching and elongation, and between the positive and negative feedback loops that regulate these activities, determines lamellipodial persistence. Importantly, directional persistence, which results from lamellipodial persistence, emerges as a critical factor in steering cell migration.

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References

1. Loisel, T. P., Boujemaa, R., Pantaloni, D. & Carlier, M. F. Reconstitution of actin-based motility of Listeria and Shigella using pure proteins. Nature 401, 613-616 (1999).

2. Stramer, B. et al. Clasp-mediated microtubule bundling regulates persistent motility and contact repulsion in Drosophila macrophages in vivo. J. Cell Biol. 189, 681-689 (2010).

3. Law, A. L. et al. Lamellipodin and the Scar/WAVE complex cooperate to promote cell migration in vivo. J. Cell Biol. 203, 673-689 (2013). This paper shows that lamellipodin directly interacts with the WAVE complex downstream of activated RAC, thereby controlling lamellipodium formation and the speed and persistence of cell migration in vitro , and both mesenchymal and epithelial collective cell migration in vivo.

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5. Block, J. et al. FMNL2 drives actin-based protrusion and migration downstream of Cdc42. Curr. Biol. 22, 1005-1012 (2012). This study provides good evidence that FMNL2 is the first formin to robustly localize to the edge of lamellipodia as an N -myristoylated protein downstream of CDC42. It also shows that FMNL2 predominantly elongates actin filaments, thereby increasing cell migration speed.

6. Lebensohn, A. M. & Kirschner, M. W. Activation of the WAVE complex by coincident signals controls actin assembly. Mol. Cell 36, 512-524 (2009). This paper describes in vitro reconstitution of activation of the WAVE complex using purified components. To obtain full activation, prenylated RAC, PtdIns(3,4,5)P 3 -containing liposomes and the phosphorylated WAVE complex were required.

7. Koronakis, V. et al. WAVE regulatory complex activation by cooperating GTPases Arf and Rac1. Proc. Natl Acad. Sci. USA 108, 14449-14454 (2011). This paper describes the cooperativity of active ARF proteins and active RAC for efficient WAVE complex activation in cell extracts. ARF proteins are activated downstream of PtdIns(3,4,5)P 3 in cell extracts. The requirement for ARF proteins specifically refers to ARF1, ARF5 or ARL1.

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Acknowledgements

Work in the authors' laboratories is supported by grants from BBSRC (BB/G00319X/1; BB/F011431/1; BB/J000590/1) (M.K.), Wellcome Trust (077429/Z/05/Z; 082907/Z/07/Z) (M.K.), Agence Nationale de la Recherche (A.G.), Institut National du Cancer (A.G.) and Association pour la Recherche sur le Cancer (A.G.).

Author information

Authors and Affiliations

1. Randall Division of Cell & Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London, SE1 1UL, UK

Matthias Krause

2. Laboratoire d'Enzymologie et Biochimie Structurales, CNRS UPR3082, Gif-sur-Yvette, 91190, France

Alexis Gautreau

Corresponding authors

Correspondence to Matthias Krause or Alexis Gautreau.

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Competing interests

The authors declare no competing financial interests.

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Further information

Cell Migration Gateway

Glossary

Integrin

A member of a large family of transmembrane proteins, which exist in the plasma membrane as heterodimers of α- and β-subunits and mediate the interaction of cells with the extracellular matrix.

Invadopodia

Invasive protrusions of tumour cells that locally secrete proteases to degrade the extracellular matrix, which thereby enables them to penetrate the basement membrane.

Blebs

Outward membrane bulges that form owing to weakening of the actin cortex and high intracellular pressure.

Lamellipodium persistence

Characteristic time during which a lamellipodium persists.

WCA domain

The carboxy-terminal domain of nucleation-promoting factors that activate the actin-related protein 2/3 (ARP2/3) complex and delivers the first actin molecule of the branched junction.

Liposomes

Artificial lipid membranes that form vesicles.

Prenylated

When a protein is conjugated to a fatty acid (prenyl group) that anchors proteins to membranes.

BAR domain

A conserved protein domain that forms a banana-shaped dimer, which senses curved membranes or induces curvature corresponding to its shape.

Trans-Golgi network

(TGN). A compartment of the Golgi apparatus from which various post-Golgi vesicles are generated.

Guanine nucleotide exchange factor

(GEF). A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a small GTP-binding protein.

Exocyst complex

A dynamic complex of proteins that permit the polarized tethering of post-Golgi vesicles to the plasma membrane.

PH domain

(Pleckstrin homology domain). A small signal transduction domain that binds to phosphoinositide lipids in membranes.

Barbed end

The most dynamic end of an actin filament, which is usually elongated.

Guided migration

Migration that is biased by external cues.

FH1 and FH2 domains

The two characteristic formin homology domains of formins. FH1 associates with, and delivers profilin-actin to, FH2 dimers that promote elongation of actin filaments by staying associated with barbed ends.

Random migration

Migration that is not biased by external cues.

Cell translocation

Active displacement of cells.

Fluorescence recovery after photobleaching

(FRAP). A method by which one localized pool of fluorescent proteins is rendered non-fluorescent by high-energy illumination. The way in which fluorescence recovers gives an indication of the exchange rates (flow) of the remaining fluorescent molecules. This flow cannot be seen in the steady-state distribution of fluorescent proteins.

WD40 repeat

A protein motif composed of a 40-amino-acid repeat that forms a blade of a characteristic β-propeller structure.

Directional persistence

Characteristic time during which cells sustain their migration in one direction. Directional persistence is a descriptor, like cell speed, of all kinds of cell migration, even random migration.

Directionality

The orientation of cell migration. This parameter is important in guided migration but not in random migration. Directionality should not be confused with directional persistence.

Microtubule-organizing centre

A large macromolecular assembly that nucleates and tethers microtubules.

GTPase-activating proteins

(GAPs). Proteins that inactivate small GTP-binding proteins by increasing their rate of GTP hydrolysis.

F-BAR domain

A special type of BAR domain that is located at the amino terminus of proteins and which usually senses or induces invaginations of the plasma membrane.

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Krause, M., Gautreau, A. Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nat Rev Mol Cell Biol 15, 577-590 (2014). https://doi.org/10.1038/nrm3861
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# data[].attributes.attachment_link.title
Steering cell migration: lamellipodium dynamics and the regulation of directional persistence - Nature Reviews Molecular Cell Biology

# data[].attributes.attachment_link.description
Lamellipodial protrusion is powered by actin polymerization that is mediated through the actin-related protein 2/3 (ARP2/3)-induced nucleation of branched actin networks and the elongation of actin filaments. These processes are regulated by positive and negative feedback loops centred around the GTPase RAC, and the balance between them determines lamellipodial and directional persistence during cell migration.

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Filopodia: molecular architecture and cellular functions

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Filopodia: molecular architecture and cellular functions

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Nature Reviews Molecular Cell Biology 9, 446-454 (2008) Cite this article

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Key Points

Filopodia are thin (diameter 0.1-0.3 μm) finger-like, actin-rich structures often found protruding from the lamellipodial actin network.

Filopodia are involved in numerous cellular processes, including cell migration, wound healing, adhesion to the extracellular matrix, guidance towards chemoattractants, neuronal growth-cone pathfinding and embryonic development.

The small GTPases CDC42 and RIF induce filopodia formation in cells. RIF activates actin polymerization through Dia2 formin. CDC42 might regulate filopodia formation by activating actin-filament nucleation through WASP/N-WASP and membrane deformation through IRSp53.

During filopodia formation, actin filaments are protected from capping and their barbed ends are clustered together by so-called tip-complex proteins, which include ENA/VASPs, Dia2 formin and myosin-X.

Two models for the mechanism of filopodia formation have been presented. In the so-called 'convergent elongation model' the filopodial actin filaments are derived from the ARP2/3-nucleated lamellipodial actin network, whereas an alternative model proposes that actin filaments in filopodia are nucleated at filopodial tips by formins. In this review we present a working model for filopodia formation that combines the 'convergent elongation model' and the ' de novo nucleation model'.

Abstract

Filopodia are thin, actin-rich plasma-membrane protrusions that function as antennae for cells to probe their environment. Consequently, filopodia have an important role in cell migration, neurite outgrowth and wound healing and serve as precursors for dendritic spines in neurons. The initiation and elongation of filopodia depend on the precisely regulated polymerization, convergence and crosslinking of actin filaments. The increased understanding of the functions of various actin-associated proteins during the initiation and elongation of filopodia has provided new information on the mechanisms of filopodia formation in distinct cell types.

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References

1. Gupton, S. L. & Gertler, F. B. Filopodia: the fingers that do the walking. Sci. STKE. 2007, re5 (2007).

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Acknowledgements

The authors thank P. Hotulainen and J. Saarikangas for comments on the manuscript. We apologize to the people whose original articles could not be referred to due to space limitations.

Author information

Authors and Affiliations

1. Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

Pieta K. Mattila

2. Institute of Biotechnology, PO BOX 56, University of Helsinki, 00014, Finland

Pieta K. Mattila & Pekka Lappalainen

Corresponding author

Correspondence to Pekka Lappalainen.

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DATABASES

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FURTHER INFORMATION

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Glossary

Lamellipodium

A cellular protrusion that is composed of a branched F-actin meshwork with, typically, 70° angles between the filaments. It results from ARP2/3 complex-mediated filament nucleation and branching. Branching frequency is highest when in close proximity to the plasma membrane, resulting in short filaments pushing against the membrane.

Barbed end

Actin filaments are polar structures. Based on the arrowhead pattern created when myosin binds actin filaments, the rapidly growing filament end is called the barbed end and the slowly growing end is called the pointed end.

Stress fibre

A contractile structure that is composed of antiparallel arrays of actin filaments associated with myosin II bundles. Stress fibres provide the contractile force that contributes to cell morphogenesis and migration.

Retrograde flow

The phenomenon whereby the speed of actin polymerization is typically faster than the velocity of cell protrusions, which leads to the sliding of actin filaments backwards with respect to the substratum.

Microspike

A short filopodium that is almost completely embedded in the cell cortex or leading edge.

Focal adhesion

A flat, elongated structure that forms cell-substrate adhesions. Focal adhesions are composed of a large number of signalling and adhesion molecules and they are associated with the ends of actin stress fibres in a wide variety of cultured adherent cells.

Adherens junction

A specialized intercellular junction of the plasma membrane, in which cadherin molecules of adjacent cells interact in a Ca ²⁺-dependent manner. Actin filaments are linked to this structure through catenins, which are located underneath the junction.

Tectum

The midbrain roof is a retinorecipient region, referred to as the optic tectum in lower vertebrates and the superior colliculus in mammals.

I-BAR domain

A lipid-binding and deforming protein domain, which is also known as an insulin-receptor substrate p53 (IRSp53)/missing-in-metastasis (MIM) (IM)-domain.

Capping activity

Many actin-binding proteins (for example, gelsolin, EPS8, twinfilin and tropomodulin) bind to filament ends where they inhibit actin-monomer association and/or dissociation and therefore display capping activity. Uncapping activity occurs when a protein is capable of removing a capping protein from the filament end, whereas anti-capping activity occurs if a protein protects filament ends from capping proteins.

PH domain

(Pleckstrin homology). A small signal transduction domain that binds phosphatidylinositol phosphates.

SH3 domain

A small globular protein domain that interacts with Pro-rich peptides and is found in many signalling and cytoskeletal proteins.

WH2 domain

A small actin-monomer-binding protein domain that was originally identified from WASP-family proteins.

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Mattila, P., Lappalainen, P. Filopodia: molecular architecture and cellular functions. Nat Rev Mol Cell Biol 9, 446-454 (2008). https://doi.org/10.1038/nrm2406
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# data[].attributes.attachment_link.title
Filopodia: molecular architecture and cellular functions - Nature Reviews Molecular Cell Biology

# data[].attributes.attachment_link.description
Filopodia are thin, actin-rich, finger-like structures that are involved in numerous cellular processes, such as cell migration, wound healing, neurite outgrowth and embryonic development. But what are the mechanisms that regulate filopodia formation in distinct cell types? Filopodia are thin, actin-rich plasma-membrane protrusions that function as antennae for cells to probe their environment.

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Video: the role of actin in cell motility

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Video: the role of actin in cell motility

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Cancer cells can reactivate the cytoskeletal mechanisms of motility to metastasize to other tissues

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In animals, almost all cell locomotion occurs by crawling

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In animals, almost all cell locomotion occurs by crawling

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Exception: sperm