What mechanisms drive podosome disassembly?2018-02-06T10:43:16+00:00

What mechanisms drive podosome disassembly?

The short lifespan of the average podosome means that their turnover rate is high. Novel super-resolution analysis of microscopy images have shown dynamic structural changes occur within tens of seconds and accompany podosome disassembly. These changes involve the assembly of struts and occur in two different disassembly scenarios. In the first instance, a break in the podosome structure is followed by retraction and unwinding of this segment, aided by the formation of small struts (250nm in diameter). In the second instance, larger struts (450nm in diameter) form repeatedly and correlate with the movement of talin from the periphery to the center of the podosome until it is removed [1].

The specific cascade of events leading to disassembly and turnover of the podosome architecture are not fully understood. Podosome disassembly is suggested to involve myosin IIA-induced contractions, affecting first the adhesive ring and then the actin core, as illustrated in dendritic cells where myosin IIA is the predominant myosin isoform [2].

Rho GTPases, which are known to regulate podosome formation [3], are also implicated in podosome disassembly, upstream of myosin IIA activity. Specifically, the downregulation of Rac1 and Cdc42 activity and the upregulation of RhoA activity are suggested to regulate myosin IIA, with RhoA targeting myosin IIA through its effector Rho kinase [2]. Conversely, the inhibition of myosin II activity has been shown to promote podosome formation, with a concomitant loss of focal adhesions [24]. An inverse relationship between the ability of a cell to form and maintain podosomes and its ability to form and maintain FAs has been demonstrated in several instances [4] [5][6].

The calcium-dependent cysteine protease, calpain, is also implicated in podosome disassembly [7]. Inhibition of this enzyme in dendritic cells promotes the stabilization of podosomes and the accumulation of podosome components, including F-actin, WASP (Wiskott Aldrich Syndrome protein), β2 integrin and the integrin-associated proteins talin, paxillin and vinculin. Furthermore several podosome resident proteins, namely Pyk2 (protein tyrosine kinase 2 beta), WASP and talin, were shown to be cleaved by calpain, providing a mechanism by which calpain can induce disassembly of the podosome architecture and promote dendritic cell motility [7]. The calpain-dependent cleavage of WASP only occurs following the release of WASP from the WIP-WASP complex (personal communication, Prof Gareth Jones).

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References

  1. Cox S, Rosten E, Monypenny J, Jovanovic-Talisman T, Burnette DT, Lippincott-Schwartz J, Jones GE, and Heintzmann R. Bayesian localization microscopy reveals nanoscale podosome dynamics. Nat. Methods 2011; 9(2):195-200. [PMID: 22138825]
  2. van Helden SFG, Oud MM, Joosten B, Peterse N, Figdor CG, and van Leeuwen FN. PGE2-mediated podosome loss in dendritic cells is dependent on actomyosin contraction downstream of the RhoA-Rho-kinase axis. J. Cell. Sci. 2008; 121(Pt 7):1096-106. [PMID: 18334555]
  3. Burns S, Thrasher AJ, Blundell MP, Machesky L, and Jones GE. Configuration of human dendritic cell cytoskeleton by Rho GTPases, the WAS protein, and differentiation. Blood 2001; 98(4):1142-9. [PMID: 11493463]
  4. Clark K, Langeslag M, van Leeuwen B, Ran L, Ryazanov AG, Figdor CG, Moolenaar WH, Jalink K, and van Leeuwen FN. TRPM7, a novel regulator of actomyosin contractility and cell adhesion. EMBO J. 2006; 25(2):290-301. [PMID: 16407977]
  5. Ory S, Destaing O, and Jurdic P. Microtubule dynamics differentially regulates Rho and Rac activity and triggers Rho-independent stress fiber formation in macrophage polykaryons. Eur. J. Cell Biol. 2002; 81(6):351-62. [PMID: 12113476]
  6. Chou H, Antón IM, Holt MR, Curcio C, Lanzardo S, Worth A, Burns S, Thrasher AJ, Jones GE, and Calle Y. WIP regulates the stability and localization of WASP to podosomes in migrating dendritic cells. Curr. Biol. 2006; 16(23):2337-44. [PMID: 17141616]
  7. Calle Y, Carragher NO, Thrasher AJ, and Jones GE. Inhibition of calpain stabilises podosomes and impairs dendritic cell motility. J. Cell. Sci. 2006; 119(Pt 11):2375-85. [PMID: 16723743]