Experimental Cell Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Review Article
Feel the force: Podosomes in mechanosensing Stefan Linder n, Christiane Wiesner Institut für medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
art ic l e i nf o
a b s t r a c t
Article history: Received 23 November 2015 Accepted 28 November 2015
Cells interact with their environment through highly localized contact structures. Podosomes represent a subgroup of cell-matrix contacts, which is especially prominent in cells of the monocytic lineage such as monocytes, macrophages and dendritic cells, but also in a variety of other cell types. Comparable to other adhesion structures, podosomes feature a complex architecture, which forms the basis for their extensive repertoire of sensory and effector functions. These functions are mainly linked to interactions with the extracellular matrix and comprise well known properties such as cell-matrix adhesion and extracellular matrix degradation. A more recent discovery is the ability of podosomes to act as mechanosensory devices, by detecting rigidity and topography of the substratum. In this review, we focus especially on the molecular events involved in mechanosensing by podosomes, the structural elements of podosomes that enable this function, as well as the intra- and extracellular signals generated downstream of podosome mechanosensing. & 2015 Published by Elsevier Inc.
Keywords: Podosomes Invadosomes Actin Myosin Formins Contractility Rigidity Topography
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Input: substrate properties detected by podosomes . . . . . . . . . . . 3. Sensor: mechanosensitive architecture of podosomes. . . . . . . . . . 4. Output: intra- and extracellular signals generated at podosomes. 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction To interact with their environment, cells form a variety of localized contact structures. These cell-matrix contacts contain transmembrane proteins that bind extracellular matrix (ECM) components, adapter proteins that mediate linkage to the cytoskeleton, and also cytoskeletal proteins that confer stability and are able to convert extracellular cues to intracellular signals. Cellsubstrate contacts thus enable cells to bind to extracellular matrix, gather information about the current environment and also to transduce this information to elicit an appropriate cellular response. n
Corresponding author. E-mail address:
[email protected] (S. Linder).
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Podosomes are cell-matrix contact structures, which, together with invadopodia, form the invadosome type of cell adhesions. They are especially prominent in cells of the monocytic lineage such as monocytes, macrophages and dendritic cells, but also in endothelial cells, smooth muscle cells, and neural crest cells. (For comprehensive reviews on invadosomes, see [1,2]; for information on other cell-matrix contacts such as focal contacts, focal adhesions, and fibrillar adhesions, and a comparison to podosomes, see [3,4]). Like other cell-matrix adhesions such as focal adhesions [5,6], podosomes feature a multitude of components and a complex architecture. A crucial and defining component is the core of actin filaments, which are nucleated by Arp2/3 complex [7,8]. This core structure is surrounded by adhesion plaque proteins such as paxillin, talin or vinculin [9,10]. In immunfluorescence imaging, these proteins are visible as a ring around the podosome core, thus
http://dx.doi.org/10.1016/j.yexcr.2015.11.026 0014-4827/& 2015 Published by Elsevier Inc.
Please cite this article as: S. Linder, C. Wiesner, Feel the force: Podosomes in mechanosensing, Exp Cell Res (2015), http://dx.doi.org/ 10.1016/j.yexcr.2015.11.026i
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giving rise to the classical view of podosomes featuring a bipartite architecture. Use of superresolution imaging, however, revealed that this ring actually consists of discrete clusters that surround the actin core [11]. These clusters are anchored to the extracellular matrix by integrins [10,12] while the core structure is anchored to the matrix by another transmembrane protein, CD44 [13]. Interestingly, podosomes are mostly present not as isolated organelles, but can form a variety of superstructures. In macrophages, actin cables link individual podosomes into higher-ordered groups. Osteoclasts can form a variety of superstructures such as motile rings, podosome belts at the cell periphery and also sealing zones on bone material. In endothelial cells, podosomes are mostly present in the formed of fused rosettes (for an overview, see [1]). It should also be noted that macrophages have been shown to form podosome equivalents within 3D environments, which were accordingly named «3D podosomes» [14,15]. However, the internal architecture of these structures is currently unclear. The local enrichment of transmembrane proteins such as integrins and CD44 identified podosomes early on as structures involved in cell-matrix adhesion. In addition, podosomes are also sites of local enrichment and secretion of matrix-lytic enzymes, in particular of matrix metalloproteinases (MMPs) [16,17], and are thus able to function as matrix-degrading devices that facilitate cell invasion [18]. It is currently unclear how these two seemingly contradictory functions are regulated spatiotemporally, but it is likely that not all podosomes in a cell fulfill both functions at the same time. Recent research has also led to the identification of several other abilities of podosomes, including antigen sampling [19], transmigration [20], and cell protrusion stabilization [21,22], some of which still await closer inspection or confirmation [23]. Of particular interest is their ability to act as mechanosensory devices, by detecting and reporting rigidity and topography of the substratum. The physicochemical events involved in mechanosensing, as well as the underlying structural properties of podosomes enabling this function, are discussed in the following.
2. Input: substrate properties detected by podosomes Monocytic cells such as macrophages, dendritic cells or osteoclasts are the prototypic cell type harboring podosomes. During their migration in the body, these cells encounter varying environments that range from twodimensional substrates such as vessel walls or bone surface to the threedimensional meshwork of
extracellular matrix fibers [24]. Accordingly, podosomes as the predominant adhesion structures in these cells contact a variety of substrates that present a range of physicochemical properties. One of the most important substrate properties is rigidity. In the body, rigidity ranges from the strong stiffness of bone ( 102– 103 kPa), which is encountered by osteoclasts, to the high pliability of brain tissue ( 0.1–1 kPa), which is relevant for monocyte-derived microglia cells. In vitro, podosomes have been studied on glass or plastic surfaces, which show a stiffness even higher than that of bone ( 107–108 kPa), and also on gelatin matrices, which are more pliable ( 1 kPa) [25]. The range of in vitro experimental conditions thus approximately covers the variety of matrix stiffness that is encountered by cells in vivo. Still, most studies use a limited range of substrates, which may lead to omission of effects that become apparent only on other stiffness regimes. The rigidity of a matrix is clearly based on its actual substance. While this is an intrinsic property, tunable parameters that influence rigidity include substrate density and crosslinking. These can be influenced, respectively, through the number of matrix fibers within a certain volume of ECM, or through the number of crosslinks that covalently connect individual fibers (Fig. 1), with the latter activity being performed by enzymes such as tissue transglutaminase [26]. Indeed, traction force microscopy of fibroblast invadosomes showed that these structures are mechanosensory devices that respond to substrate rigidity by local force generation [27,28]. Topography or surface roughness is another relevant substrate parameter that can be sensed by podosomes. Initial observations in human dendritic cells on micropatterned substrates showed an alignment of podosomes along surface discontinuities [29] (Fig. 1). Considering the size of podosomes (0.5–1.0 mm diameter, [30]) and the dimensions of these discontinuities (distance between edges o2 mm, [29]), detection of substrate topography seems to involve sensing of discontinuities in the size range of podosomes. The underlying mechanism is currently unclear, but it is likely to involve detection of local alterations in membrane curvature. Moreover, studies using osteoclasts demonstrated the formation of small and unstable sealing zone-like structures on glass, but of larger and more stable sealing zones on bone [31,32]. These differences are apparently based on different roughness, i.e. topography, of both substrates. Sealing zone-like structures can detect surface discontinuities that are lager than 3 mm, i.e. larger than individual podosomes. These results show that topography sensing can also proceed on the level of podosome superstructures,
Fig. 1. Input: substrate properties detected by podosomes comprise rigidity and topography. Substrate rigidity is critically influenced by the density of matrix fibers and the number of crosslinks. Discontinuities in matrix topography lead to changes in plasma membrane curvature, which are preferred sites of podosome formation. By contrast, podosomes in a cell seeded on even substratum show a more uniform distribution.
Please cite this article as: S. Linder, C. Wiesner, Feel the force: Podosomes in mechanosensing, Exp Cell Res (2015), http://dx.doi.org/ 10.1016/j.yexcr.2015.11.026i
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and not only on the level of individual podosomes. In conclusion, podosomes are able to sense the rigidity of the substratum they have been formed on, whereas substrate topography determines the sites of podosome formation. Podosomes can thus be viewed as active sensors of rigidity, but as more passive reporters of topography. Both rigidity and topography are apparently sensed on the level of individual podosomes and also on the level of higher-ordered groups or superstructures. Moreover, the actual composition of the substrate most probably influences the engagement of specific matrix receptors within podosomes, such as α5β1 intregrin on fibronectin or αvβ3 integrin on vitronectin [33]. Therefore, also this property of the substratum is likely to influence the activity of substrate receptors and thus the nature of both incoming and outgoing signals at podosomes.
3. Sensor: mechanosensitive architecture of podosomes In order to work as substrate-sensing devices, podosomes have to contain mechanosensitive and -transducing elements as part of their structure. Indeed, podosomes display an intricate architecture that consists of a variety of substructures (Fig. 2). In addition to the core of Arp2/3-generated (i.e. branched) F-actin, they also contain unbranched actin filaments [34,35] that connect the top of the core to the clusters of plaque proteins at the plasma membrane («lateral fibers»). A further subset of unbranched actin filaments connects individual podosomes with each other («connecting cables»), thus linking them into higher-ordered groups [36]. A more recently discovered substructure is the podosome cap on top of the actin core. To date, the formins FMNL1 [37] and INF2 [38], and also supervillin [36] and fascin [39] have been localized to this substructure. In a current model, growth of the podosome core by actin polymerization would exert a pushing force on the underlying plasma membrane [40]. Mechanical coupling of the core and the lateral actin fibers would then lead to the generation of a counter force, pulling on the lateral fibers and thus also on the plaque proteins of the ring (Figs. 2 and 3). Combined, cycles of force generation, transduction and relaxation would enable podosomes to repeatedly probe the substratum in a drill-like fashion and thus function as mechanosensors. Proof for the validity of this model comes from experiments
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using atomic force microscopy (AFM) and showing that macrophage podosomes undergo internal cycles of stiffness, which are based on both actin polymerization and myosin contractility [41]. While this initial study used AFM to probe the apical sides of cells, follow-up experiments used cells plated on pliable Formvar matrix, followed by inversion of cells, thus accessing also the ventral cell side. It could thus be shown that the cycles of podosome stiffness coincide with the local deformation of matrix underneath podosome cores [42], thus identifying podosomes as partially protrusive organelles. (Note that protrusion of podosomes mostly reflects a transient net movement of the core structure, and not extensive longitudinal growth of the organelle, as in the case of invadopodia). Another method to capture this contractility-based movement of podosomes is the measurement of podosomal F-actin intensity in a defined plane of focus. Depending in part on the vertical movement of podosomes, F-actin intensity varies constantly within the plane of measurement, thus enabling quantification of podosome oscillations. In keeping with the above mentioned results [41], inhibition of myosin contractility by addition of the inhibitor blebbistain leads to almost complete abrogation of podosome oscillations [38,43]. Together with actin polymerization, actomyosin-based contractility is thus essential for the mechanosensing ability of podosomes. As actomyosin contractility is based on unbranched actin filaments, only podosome substructures containing unbranched F-actin are potential mediators of this contractility. Considering the architecture of podosomes (Fig. 2), lateral fibers and connecting cables thus emerge as potential force transducers at or between podosomes. Indeed, both sets of unbranched actin filaments contain myosin and are thus potentially contractile [36,38]. Moreover, detection of phosphorylated myosin light chain (pMLC), a reporter of myosin activity [44], at and between podosomes in macrophages [36,38] or dendritic cells [45] further substantiates the model of actomyosin-contractility enabling mechanosensing of podosomes. In consequence, factors that influence either the formation or turnover of unbranched actin filaments, the activity of myosin at these filaments, and also the mechanical coupling of the filaments with the core structure are likely to impact on podosome mechanosensing. Unbranched actin filaments are nucleated most likely not by Arp2/3 complex, but by formins [46]. In addition to actin nucleation, and depending on the specific family member,
Fig. 2. Sensor: mechanosensitive substructures of podosomes. Podosomes consist of a core of branched actin filaments and a surrounding ring of adhesion plaque proteins such as vinculin. The structure is anchored to the plasma membrane by transmembrane proteins including integrins and CD44. Two additional subsets of unbranched actin filaments contain myosin and are the basis for actomyosin contractility at individual podosomes (lateral fibers) or between podosomes (connecting cables). Both sets of F-actin are apparently anchored and/or regulated by the cap structure on top of the actin core.
Please cite this article as: S. Linder, C. Wiesner, Feel the force: Podosomes in mechanosensing, Exp Cell Res (2015), http://dx.doi.org/ 10.1016/j.yexcr.2015.11.026i
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Fig. 3. Output: intra- and extracellular signals generated at podosomes. Intracellular signaling: Actin polymerization within the podosome core exerts forces on the plasma membrane and the underlying substratum. Depending on the rigidity of the substrate, this leads to substrate deformation (left) and temporary protrusion of the podosome. On matrix with higher rigidity (left), protrusion is not possible, and growth of the core leads to forces on the lateral actomyosin fibers, followed by stretching of mechanosensitive proteins within the podosome ring. Subsequent exposure of cryptic binding sites leads to additional recruitment of proteins, and increased intracellular signaling (black and gray arrows). Extracellular signaling: On rigid matrix, signaling by ring proteins might involve the recruitment or stabilization of microtubule plus ends, thus facilitating microtubule-dependent delivery of vesicles that contain matrix-lytic enzymes such as matrix metalloproteinases. This is followed by local exposure or release of MMPs, leading to matrix degradation.
formins can also contain several other actin-related activities such as elongation, bundling or severing of F-actin [46]. In particular, the formins INF2 and FHOD1 have recently been identified as factors that regulate lateral actin fibers or connecting cables, respectively, at macrophage podosomes. While FHOD1 seems to exert its activity mainly through bundling of the connecting cables, INF2 activity was shown to be crucial for regulation of podosome oscillations [38]. The known biochemical activities of INF2 in actin polymerization and also severing could also confer the necessary flexibility to lateral actin cables to function in a spring-like manner, as proposed by the current model of podosome mechanosensing [40, 42, 47]. Intriguingly, INF2 is present at the cap structure on top of the podosome core und would thus be in an ideal position not only to regulate growth of lateral actin fibers, but also to couple these filaments to the core structure. Furthermore, myosin activity at podosomes is also influenced by supervillin, and enhanced levels of supervillin lead to increased activity of myosin IIA at macrophage podosomes [36]. A potential effect of supervillin on podosome oscillation/mechanosensing has not been explored so far. Still, also supervillin is localized at the cap structure of podosomes, which could point to a central role of this subdomain in the regulation of actomyosin contractility and thus also of mechanosensing at podosomes. In conclusion, the specific architecture of podosomes seems to enable these structures to act as mechanosensory devices that are able probe the substratum through repeated cycles of actomyosin contractility. Indeed, rigidity sensing by podosomes was shown to involve feedback loops, as macrophages form less podosomes per area on matrices of decreasing stiffness, which is accompanied by reduced myosin contractility and also by a reduction in protrusive force [42]. Further analyses showed that podosomes act as a concerted group, as the protrusion force of podosome next neighbors is correlated [48]. This coupling is probably achieved through the connecting actin cables that link individual podosomes into higher-ordered groups [1,48]. Podosomes are thus able to respond to substrate cues not only as isolated organelles, but also on the level of internally connected superstructures [31,32].
4. Output: intra- and extracellular signals generated at podosomes Recent work has led to the identification of important substrate properties that are perceived by podosomes, and also of the structural elementes that allow podosomes to work as mechanosensors. In contrast, it is less clear how podosomes transduce this information into intracellular signals to elicit a cellular response. Still, the presence of mechanosensitive proteins at podosomes, combined with current knowledge on mechanotransduction at cell-matrix contacts in general, forms a valid basis for speculations. Mechanosensitive proteins, i.e. proteins whose conformation is altered upon the application of tension, include talin and p130Cas, both of which can also be found at the ring structure of podosomes [9,49]. Tension-induced stretching of these proteins leads to the exposure of cryptic binding sites, thus allowing additional interaction with binding partners or regulators. Accordingly, tensioninduced stretching of talin leads to exposure of a binding site for vinculin [50], which is in line with the finding that vinculin levels within focal adhesions correlate with applied traction forces [51]. Similarly, tension-induced stretching of p130Cas leads to the exposure of a phosphorylation site by Src kinase [52]. Cas is thus able to induce further downstream signaling, which is likely to also involve RhoGTPase pathways [53]. The forces required for this molecular stretching are in the pN range [52], and thus well covered by the forces generated by podosome mechanonsensory protrusion (10–100 nN; [42]). Collectively, the activities of Cas and talin, and also of other proteins such as paxillin and zyxin, would result in the generation of intracellular signals, thus transducing mechanical forces generated during substrate sensing into proteochemical signals. Finally, an important point concerns the potential interdependence or co-regulation of the various podosome functions. It is conceivable that not all podosomes fulfill all functions at the same time or to a similar degree. In particular, it is unclear how cell-matrix adhesion and matrix degradation, two apparently contradictory functions, are regulated in time and space.
Please cite this article as: S. Linder, C. Wiesner, Feel the force: Podosomes in mechanosensing, Exp Cell Res (2015), http://dx.doi.org/ 10.1016/j.yexcr.2015.11.026i
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Considering the fact that degradation of extracellular matrix material would only become necessary on stiff or densely crosslinked matrix (Fig. 3), it is tempting to speculate that the mechanosensory function of podosomes could be used to regulate their ability to degrade matrix material. A possible link could be envisioned through the mechanosensory-dependent stretching of adhesion plaque proteins, which could expose binding sites for adaptor molecules that regulate the capturing/interaction with microtubules. The microtubule system provides the basis for intracellular trafficking of vesicles that contain matrix-lytic enzymes, and in particular the matrix metalloproteinase MT1-MMP, a key regulator of podosome-associated matrix degradation [17]. Interaction of podosome components with microtubule plus tip proteins such as CLASPs or CLIP-170 could thus be used to capture or stabilize microtubule plus tips at podosomes, thus promoting the acquisition of matrix-degrading enzymes, followed by localized matrix degradation.
5. Conclusions Podosomes are multifunctional organelles that fulfill a variety of tasks, in particular mechanosensing and degradation of the extracellular matrix. The unique architecture of podosomes, consisting of interlinked sets of branched and unbranched actin filaments, forms the basis for their function as mechanosensory devices. Podosomes are thus able to sense and report specific properties of the matrix such as rigidity and topography. Probing of the matrix by a growing actin core probably generates actomyosinbased contractility at lateral actin fibers. Tension-induced stretching of mechanosensitive proteins at the podosome ring subsequently leads to the generation of intra- and extracellular signals, allowing the cell to respond to the perceived specific properties of its environment. Respective downstream signaling is likely to include recruitment of matrix-lytic enzymes, and could thus link these two key activities of podosomes. It will be extremely interesting to see how these and other abilities of podosomes are coordinated spatiotemporally. For this, further molecular dissection and ultrastructural analysis of the intricate architecture of podosomes, both on the level of individual podosomes and also of podosome superstructures, will be crucial.
Acknowledgments The authors apologize to all whose work was not mentioned owing to space limitations. The support of Deutsche Forschungsgemeinschaft (LI925/2-2, LI925/3-2) and of Wilhelm Sander-Stiftung (2014.135.1) is gratefully acknowledged.
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