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Foot and mouth: podosomes, invadopodia and circular dorsal ruffles

Nature Reviews Molecular Cell Biology volume 5, pages 647–657 (2004)Cite this article

Key Points

  • The plasma membrane of many motile cells undergoes highly regulated protrusions and invaginations that support the formation of podosomes, invadopodia and circular dorsal ruffles/waves. Although similar in appearance and in their formation — which is mediated by a highly conserved actin–membrane apparatus — these transient surface membrane distortions are distinct. Their function is to help the cell as it migrates through, attaches to, and invades the extracellular matrix.

  • Invadopodia are convolutions and extensions of the ventral plasma membrane that contacts the substratum. These structures represent specific sites where degradation of the underlying matrix occurs, and might also be secretory sites to which nascent protease-containing carriers are targeted for release. Invadopodia are prominent in cells that actively migrate and invade surrounding tissues, such as metastatic tumour cells.

  • Podosomes, which are less well defined than invadopodia, are also formed along the cell base. These structures share many components and features with invadopodia and might represent a modification of invadopodia in cells that are cultured on an artificial substrate such as glass.

  • Circular dorsal ruffles/waves are formed on the dorsal surface of cells after stimulation of receptor tyrosine kinases including the epidermal growth factor receptor or the platelet-derived growth factor receptor. Circular dorsal ruffles/waves use many of the same components as invadopodia and podosomes, but are transient, appear to reorganize the surrounding actin cytoskeleton, and might have an endocytic function as opposed to a secretory one.

Abstract

The plasma membrane of many motile cells undergoes highly regulated protrusions and invaginations that support the formation of podosomes, invadopodia and circular dorsal ruffles. Although they are similar in appearance and in their formation — which is mediated by a highly conserved actin–membrane apparatus — these transient surface membrane distortions are distinct. Their function is to help the cell as it migrates, attaches and invades.

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Figure 1: Podosome structures.
Figure 2: Invadopodia form and function.
Figure 3: The N-WASP–Arp2/3–cortactin–dynamin complex and its functions.
Figure 4: Circular dorsal ruffles/waves.
Figure 5: Growth-factor stimulation, kinase signalling and circular-dorsal-ruffle/wave formation.

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Acknowledgements

Work in the R.B. laboratory is supported by the Italian Association for Cancer Research (AIRC, Milano, Italy). Work in the M.A.M. laboratory is supported by funding from the National Institutes of Health and Mayo Foundation. We thank A. Teti and M. Baldassarre for insightful discussions and K. Simmons for help and editorial advice during the preparation of this review.

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Authors and Affiliations

  1. Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), Italy

    Roberto Buccione

  2. Department of Biochemistry and Molecular Biology, Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota, USA

    James D. Orth & Mark A. McNiven

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  1. Roberto Buccione
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  2. James D. Orth
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  3. Mark A. McNiven
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Correspondence to Mark A. McNiven.

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DATABASES

Interpro

ankyrin repeat

PH domain

SH3 domain

VCA

OMIM

Wiskott–Aldrich syndrome

Swiss-Prot

ASAP1

Cdc42

cortactin

dynamin-2

EGF

EPS8

fascin

gelsolin

Grb2

N-WASP

MMP2

MT1-MMP

Nck2

PAK1

α-PDGF receptor

β-PDGF receptor

PYK2

Rac1

RhoA

vinculin

WAVE2

Glossary

LAMELLIPODIA

Broad, flat protrusions at the leading edge of a moving cell that are enriched with a branched network of actin filaments.

FILOPODIA

Thin cellular processes containing long, unbranched, parallel bundles of actin filaments.

PHAGOCYTIC CUP

A cup-like extension of peripheral membrane and cytoplasm that partially encircles foreign particles or bacteria during the early stages of the phagocytic process.

LEADING EDGE

The thin margin of a lamellipodium spanning the area of the cell from the plasma membrane to about 1 μm back into the lamellipodium.

Arp2/3 COMPLEX

A complex that consists of two actin-related proteins, Arp2 and Arp3, along with five smaller proteins. When activated, the Arp2/3 complex binds to the side of an existing actin filament and nucleates the assembly of a new actin filament. The resulting branch structure is Y-shaped.

RHO-FAMILY GTPases

Ras-related small GTPases involved in controlling the polymerization of actin.

EXTRACELLULAR MATRIX

(ECM). The complex, multi-molecular material that surrounds cells. The ECM comprises a scaffold on which tissues are organized, it provides cellular microenvironments and it regulates a variety of cellular functions.

MACROPINOCYTOSIS

An actin-dependent process by which cells engulf large volumes of fluids.

FOCAL ADHESION

A cell-to-substrate adhesion structure that anchors the ends of actin microfilaments (stress fibres) and mediates strong attachment to substrates.

STRESS FIBRES

Also termed 'actin-microfilament bundles', these are bundles of parallel filaments that contain F-actin and other contractile molecules, and often stretch between cell attachments as if under stress.

MONOCYTE

Large leukocytes with a horseshoe-shaped nucleus. They derive from pluripotent stem cells and become phagocytic macrophages when they enter tissues.

OSTEOCLAST

A mesenchymal cell that can differentiate into a bone-degrading cell.

MACROPHAGE

Any cell of the mononuclear-phagocyte system that is characterized by its ability to phagocytose foreign particulate and colloidal material.

DOMINANT-NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

SH3 DOMAIN

(Src-homology-3). A protein sequence of ∼50 amino acids that recognizes and binds sequences that are rich in proline.

CLATHRIN

The main component of the coat that is associated with clathrin-coated vesicles, which are involved in membrane transport both in the endocytic and biosynthetic pathways.

ADAPTOR PROTEINS

Proteins that augment cellular responses by recruiting other proteins to a complex. They usually contain several protein–protein interaction domains.

METALLOPROTEINASE

A proteinase that has a metal ion at its active site.

ACTIN COMET TAIL

An actin tail at one end of an endosome that propels the organelle inwards. First described for the intracellular movement of Listeria sp.

RESORPTION LACUNA

The contained, low-pH subosteoclastic environment that is delimited by a dense circumferential ring of actin that forms a tight adhesive contact, or sealing zone. Lytic enzymes and H+ that promote bone erosion are secreted into this sealed environment.

TPA

(12,13-tetradecanoyl phorbol acetate). Also known as phorbol myristoyl acetate, this is the most common phorbol ester. Phorbol esters are polycyclic esters that are isolated from croton oil. They are potent co-carcinogens or tumour promoters because they mimic diacylglycerol, and thereby irreversibly activate protein kinase C.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

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

PLECKSTRIN-HOMOLOGY (PH) DOMAIN

A sequence of 100 amino acids that is present in many signalling molecules and binds to lipid products of phosphatidyl-inositol 3-kinase. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.

GTPase-ACTIVATING PROTEINS

(GAPs). Proteins that inactivate small GTP-binding proteins, such as Ras-family members, by increasing their rate of GTP hydrolysis.

MOTOGENS

Compounds that induce cell motility.

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Buccione, R., Orth, J. & McNiven, M. Foot and mouth: podosomes, invadopodia and circular dorsal ruffles. Nat Rev Mol Cell Biol 5, 647–657 (2004). https://doi.org/10.1038/nrm1436

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