Trends in Cell Biology
ReviewThe matrix corroded: podosomes and invadopodia in extracellular matrix degradation
Introduction
Cells form a variety of adhesive structures to connect with their environment. Podosomes and invadopodia, two types of actin-rich adhesions, are unique, as they not only establish contact to the substratum but are also involved in matrix degradation 1, 2, 3, 4, 5. Consequently, they are mostly found in invasive cell types. Podosomes, for example, are formed in monocytic cells, such as macrophages [6], dendritic cells [7] or osteoclasts [8], whereas invadopodia are typically found in carcinoma cells 4, 9. More recently, other cell types, such as endothelial cells and smooth muscle cells, have been shown to form podosomes upon stimulation with cytokines 3, 10 or phorbol esters 5, 11. Finally, podosome-type adhesions are also found in fibroblasts that have been transformed with oncogenes encoding protein tyrosine kinases, such as v-Src [12].
Podosomes and invadopodia are now receiving widespread attention (Online Supplementary Figure 1), as they could be involved in physiological events, such as monocyte extravasation and tissue transmigration 13, 14, or in pathological conditions, such as atherosclerosis 2, 3, 15 or cancer 14, 16, 17. Many novel components and additional pathways regulating their formation and function have been discovered in the past few years. Indeed, the field has diversified to such a degree that not all aspects can be sufficiently addressed within the scope of this article. This review therefore focuses especially on extracellular matrix degradation by podosomes and invadopodia (for more background information, see Refs 13, 14, 16, 18, 19, 20, 21, 22). Another important question concerns the relationship between podosomes and invadopodia. Accordingly, this review also collects the current knowledge about similarities of and differences between both structures. For brevity, the term ‘podosomes and invadopodia’ will be mostly replaced by ‘PTA(s)’, for podosome-type adhesion(s), when both structures are being referred to.
Section snippets
Polka dots, rosettes and rootlets: PTA formation in various cell types
Podosome-type adhesions are dot-like, with a core of actin and associated proteins embedded in a ring structure containing adhesion plaque proteins, such as vinculin or talin 13, 18. They are also enriched in integrins 13, 14, enabling them to form bridges between the cytoskeleton and the extracellular matrix.
Despite sharing a comparable molecular make-up 14, 22, PTAs come in a variety of shapes and sizes. At one end of the spectrum are the podosomes of monocytic cells 6, 7, 8, endothelial
Cytoskeletal crossroads: PTA-associated signal transduction
PTA regulation comprises a network of signal transduction pathways. Extracellular signals triggering their formation include cytokines and growth factors, such as vascular endothelial growth factor (VEGF) [3], transforming growth factor β (TGFβ) [10], epidermal growth factor (EGF) [4] and colony stimulating factor 1 (CSF-1) [25]. However, the most crucial signal is attachment to the substratum, as PTAs are formed only in adherent cells [13]. Subsequent activation of integrins 26, 27, 28 and
Ammunition for degradation: proteinases in matrix turnover
Invadopodia of carcinoma cells 4, 9, 51 and PTAs of transformed fibroblasts 1, 59 have been recognized early on as structures that degrade matrix proteins, such as fibronectin, collagen and laminin [60]. By contrast, ‘classical’ podosomes have only recently been shown to possess matrix-degrading activity, for example in human endothelial cells 3, 5, 10, in both murine and human macrophages [61] and in smooth muscle cells [2].
In contrast to experimental settings using defined, uniform
Podosomes versus invadopodia: a multifaceted relationship
It is unclear whether podosomes and invadopodia are distinct structures or whether they are two similar manifestations of the cellular response to contact with the substratum. However, given the many differences between both structures (Box 1), a definition of invadopodia simply as ‘supersized’ podosomes falls short of the mark.
Two general possibilities can be considered: The first is that certain cell types can only form podosomes or invadopodia and not both. This would fit with the observed
PTAs reloaded: concluding remarks and future research
During the last years, substantial progress has been made in understanding podosome and invadopodia regulation. Novel extracellular cues (e.g. growth factors) governing PTA formation have been identified, additional pathways regulating growth (e.g. WIP or PAKs) and dynamics (e.g. HDAC6 or KIF1C) of these structures have been mapped, and the knowledge about well-known master switches, such as GTPases, has been expanded. Moreover, podosomes and invadopodia are now being recognized as potentially
Acknowledgements
The author thanks Inés Antón, Elisabeth Genot and Isabelle Maridonneau-Parini for stimulating discussions, Roberto Buccione, Sara Courtneidge, Mario Gimona, Gareth Jones, Arnaud Labrousse, Violaine Moreau, Vanessa van Vliet and Hideki Yamaguchi for contributing images, and Jürgen Heesemann and Peter C. Weber for continuous support. Work in the S.L. laboratory referred to here has been supported by grants from the Deutsche Forschungsgemeinschaft (SFB 413, GRK 438), Friedrich Baur Stiftung and
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