Abstract
Summaryp21-Activated kinase 4 (PAK4), a serine/threonine kinase, is purported to localize to podosomes: transient adhesive structures that degrade the extracellular matrix to facilitate rapid myeloid cell migration. We find that treatment of transforming growth factor β (TGF-β)-differentiated monocytic (THP-1) cells with a PAK4-targeted inhibitor significantly reduces podosome formation and induces the formation of focal adhesions. This switch in adhesions confers a diminution of matrix degradation and reduced cell migration. Furthermore, reduced PAK4 expression causes a significant reduction in podosome number that cannot be rescued by kinase-dead PAK4, supporting a kinase-dependent role. Concomitant with PAK4 depletion, phosphorylation of Akt is perturbed, whereas a specific phospho-Akt signal is detected within the podosomes. Using superresolution analysis, we find that PAK4 specifically localizes in the podosome ring, nearer to the actin core than other ring proteins. We propose PAK4 kinase activity intersects with the Akt pathway at the podosome ring:core interface to drive regulation of macrophage podosome turnover.
Highlights
p21-Activated kinase 4 (PAK4) was found to partially colocalize with podosome F-actin cores in primary macrophages, and short hairpin RNA-mediated knockdown of PAK4 reduced podosome numbers (Gringel et al, 2006)
PAK4 kinase activity was shown to play an essential role in the maturation of invadopodia—a cell adhesion structure related to podosomes (Nicholas et al, 2016)
PAK4 Kinase Activity Drives Podosome Formation Given that the function of PAK1 and PAK4 kinase activity in podosomes remains unclear (Gringel et al, 2006) and that PAK1 and PAK4 show distinct roles in invadopodia dynamics (Nicholas et al, 2016), we decided to exploit a recently developed PAK4targeted small-molecule ATP-competitive inhibitor (Whale et al, 2013) and a PAK1-specific inhibitor (IPA-3) (Viaud and Peterson, 2009) to elucidate the requirement for PAK1/PAK4 kinase activity in podosome turnover
Summary
The differential role of PAK family proteins in podosome function has not been previously evaluated. Foxall et al demonstrate that PAK4 rather than PAK1 plays a pivotal role and use super resolution microscopy to position PAK4 at the podosome ring:core interface. 2019, Cell Reports 29, 3385–3393 December 10, 2019 a 2019 The Author(s).
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