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Mechanisms and roles of podosomes and invadopodia

Abstract

Cell invasion into the surrounding extracellular matrix or across tissue boundaries and endothelial barriers occurs in both physiological and pathological scenarios such as immune surveillance or cancer metastasis. Podosomes and invadopodia, collectively called ‘invadosomes’, are actin-based structures that drive the proteolytic invasion of cells, by forming highly regulated platforms for the localized release of lytic enzymes that degrade the matrix. Recent advances in high-resolution microscopy techniques, in vivo imaging and high-throughput analyses have led to considerable progress in understanding mechanisms of invadosomes, revealing the intricate inner architecture of these structures, as well as their growing repertoire of functions that extends well beyond matrix degradation. In this Review, we discuss the known functions, architecture and regulatory mechanisms of podosomes and invadopodia. In particular, we describe the molecular mechanisms of localized actin turnover and microtubule-based cargo delivery, with a special focus on matrix-lytic enzymes that enable proteolytic invasion. Finally, we point out topics that should become important in the invadosome field in the future.

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Fig. 1: Invadosome architecture and maturation stages.
Fig. 2: Mechanisms of invadosome extension and dynamics.
Fig. 3: Regulation of invadosome activity in proteolysis of the ECM.

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Acknowledgements

S.L. and P.C. thank A. Mordhorst for expert technical assistance, the UKE Microscopy Imaging Facility for support with imaging and M. Aepfelbacher for continuous support. Work on podosomes and matrix metalloproteinases in the S.L. laboratory is supported by the Deutsche Forschungsgemeinschaft (LI925/8-1 and CRC877/B13), and work on invadopodia in the J.C. laboratory is supported by grants from the US National Cancer Institute (CA216248 and CA255153). The authors apologize to all authors whose work has not been mentioned due to space limitations.

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Correspondence to Stefan Linder or John Condeelis.

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Invadosome consortium: http://www.invadosomes.org/

Supplementary information

Glossary

Sealing zone

A band of close attachment between bone-resorbing osteoclasts and underlying bone, consisting of densely packed podosome cores.

Resorption lacuna

The space delineated by the sealing zone of osteoclasts into which lytic enzymes and protons are secreted to induce degradation of bone.

(N-)WASP

(Neural) Wiskott–Aldrich syndrome protein, a nucleation promotion factor that activates the ARP2/3 complex to induce formation of branched actin networks.

ARP2/3 complex

A seven-subunit complex containing two actin-related proteins (ARP2 and ARP3) which binds to the sides of actin filaments and nucleates a daughter filament, giving rise to branched actin networks.

Cortactin

An actin-binding protein that also recruits the ARP2/3 complex, thus facilitating formation and supporting stabilization of branched actin networks in invadosomes.

Cofilin

A member of the ADF/cofilin family of proteins involved in actin filament severing; supports actin nucleation and turnover at invadosomes.

Formin

A member of a family of proteins involved in nucleation and regulation of unbranched actin filaments.

Discoidin domain receptor 1

(DDR1). A receptor tyrosine kinase that is activated by contact with collagen and is present in linear invadosomes.

ADAM proteins

A family of transmembrane proteins that cleave a variety of cell surface-associated substrates.

Phorbol ester

A class of tetracyclic diterpenoids known to induce tumours; used to induced podosome formation through activation of protein kinase C, which regulates phosphorylation cascades through the MEK–ERK pathway.

Motin family

A family of proteins involved in cytoskeletal organization, serving as scaffolds for polarity-organizing proteins and signalling cascades.

RANKL

Receptor activator of NF-κB ligand, a protein of the tumour necrosis factor family which induces differentiation of monocytes to osteoclasts by binding to RANK.

Supervillin

A member of the villin protein family that localizes to the podosome cap and regulates actomyosin contractility.

Tumour microenvironment of metastasis doorways

Portals for tumour cell intravasation and dissemination composed of a vascular endothelial cell, a macrophage and a Mena-expressing tumour cell with invadopodia, all in direct and stable cell–cell contact, the densities of which are prognostic for distant metastasis.

MenaINV

An invasion-promoting isoform of Mena required for tumour cell invadopodium assembly, invasion and dissemination.

Treadmilling

Turnover of actin filaments in the steady state, driven by net growth on the plus end and net shrinkage at the minus end of filaments.

Multinucleated giant cells

Multinucleated cells arising from cell fusion; multinucleated giant cells of monocytic origin are used as osteoclast models.

NCK1

An upstream activator of N-WASP localized to tumour cell invadopodia but not podosomes and is important for invadopodium formation and activity.

DAAM1

Dishevelled-associated activator of morphogenesis 1, a member of the formin family that regulates invadopodium extension through a signalling cascade involving integrins and RHO.

PYK2

A cytoplasmic protein tyrosine kinase, a member of the focal adhesion kinase (FAK) family, expressed in haematopoietic cells and part of the podosome ring structure.

Gelsolin

A member of the gelsolin/villin family of proteins involved in severing of actin filaments.

Exocyst complex

An octameric protein complex involved in trafficking of vesicles, and especially in their targeting and tethering to the plasma membrane.

GIT1

A GTPase-activating protein for ARF family GTPases.

Microtubule-associated proteins

A group of proteins that can bind to microtubules or tubulin dimers, often regulating stability or disassembly of microtubules or attachment to other structures such as invadosomes (see also the glossary entry “+TIPs”).

+TIPs

A diverse group of proteins that are present at the growing end of microtubules.

Cortical microtubule-stabilizing complexes

(CMSCs). Multiprotein complexes involved in capturing microtubules at the cell cortex, thus supporting exocytosis; prominent members include KANK1, liprins and ELKS.

SNARE proteins

Proteins that mediate membrane fusion, which includes the formation of a complex between vesicle-localized SNAREs and target membrane-localized SNAREs.

Nesprin 2

An actin-binding protein located in the outer nuclear membrane linking the nucleoskeleton to the cytoskeleton.

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Linder, S., Cervero, P., Eddy, R. et al. Mechanisms and roles of podosomes and invadopodia. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00530-6

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