Life cycle

1) Podosomes are formed on the intracellular ventral side of cells. They arise in zones of low acto-myosin contractility, which is regulated by a p190RhoGAP-mediated inactivation of Rho-associated protein kinase (ROCK).

2) An interaction of lipids, integrins, RhoGTPases and scaffolding proteins such as Tks5 initiate further signalling cascades.This leads to activation of (N-)WASP, which in turn activates the actin nucleating Arp2/3 complex to initiate polymerization of actin filaments and thus podosome core growth. An initial podosome ring is formed around the core via the recruitment and binding of talin-1 and p130Cas to the intracellular domain of integrins.

3) The assembly of the structure is completed after the formation of podosome cap and cables and the podosome is fully functional as an adhesive, mechanosensitive and degradative structure. Of note, the exact sequence of events leading to a fully assembled podosome has not been fully determined yet.

4) Fully developed podosomes act as a mechanosensory hub which, among others, enables the  recruitment of microtubules to sites of adhesions. The subsequent transport of vesicles delivers matrix-degrading enzymes, especially matrix metalloproteinases such as MT1-MMP, MMP-2, and -9.

5) The delivered proteolytic enzymes are exposed to the extracellular membrane (ECM) underneath the core and enable the degradative capability of podosomes. Enzymes like MMPs and DNAse X cleave proteins like collagen, gelatin and fibronectin and thus degrade the ECM of the surrounding tissue.

6) The end of the podosome life is initiated by a hyperactivation of myosin IIA via the cap protein supervillin, and also RhoA-dependent activation of ROCK. The hypertension of the cables limits core growth and likely increases recruitment and activation of actin-depolymerizing factors, which leads to a dissociation of podosomes.

7) After dissolution of the podosome structure, MT1-MMP can remain at the membrane in the form of “islets”, which can serve as initiation points for the re-emergence of podosomes. The podosome life cycle can thus start over with initial actin polymerization to build the podosome core.

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