Figure 7: Model depicting the interplay of actin network and myosin IIA at podosomes.

The amount of core and ring components in existing podosomes fluctuates, reflecting their variable protruding activity over time. In small podosome cores, paxillin and talin are already present at their maximum level. At this stage, vinculin and zyxin levels are relatively low, as the tension on the actin network is still low. As podosomes grow vertically by actin polymerization at the base of the core (owing to the impenetrable glass substrate), tension is generated within the actin network and transmitted to talin and paxillin, thereby further driving the recruitment of the tension-sensitive vinculin and zyxin to reinforce the podosome and facilitate its protrusive activity. Vinculin binds to talin and paxillin, whereas zyxin seems recruited to actin filaments more proximal to the core since disruption of the actin filaments by cytoD did not displace zyxin from the ring. Only by stably connecting the ring and the core are the actin filaments within podosomes able to function as a tension transmission system that preserves ring integrity without myosin IIA-mediated contractility. The connection of the actin network to the ring most likely occurs through talin and vinculin, whereas the main players cross-linking the network filaments to the core are still debated (unknown cross-link protein). Additionally, proteins such as alpha-actinin are present to further organize and cross-link the actin filaments. Myosin IIA cross-links the actin network filaments and is essential for core shrinkage by either generating contractility or directly unbundling and depolymerizing the actin network, thereby inducing podosome core instability. The delicate balance between actin polymerization in the core and myosin IIA activity in the ring facilitates core oscillations. Consequently, as core and ring are coupled via the actin network, ring oscillations also take place.