PAK4 Kinase Activity Plays a Crucial Role in the Podosome Ring of Myeloid Cells

Elizabeth Foxall, Adela Staszowska, Liisa M Hirvonen, Mirella Georgouli, Mariacristina Ciccioli, Alexander Rimmer, Lynn Williams, Yolanda Calle, Victoria Sanz Moreno, Susan Cox, Gareth E Jones, Claire M Wells

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Abstract

p21-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.

Original languageEnglish
Pages (from-to)3385-3393.e6
JournalCell Reports
Volume29
Issue number11
DOIs
Publication statusPublished - 10 Dec 2019
Externally publishedYes

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  • Cite this

    Foxall, E., Staszowska, A., Hirvonen, L. M., Georgouli, M., Ciccioli, M., Rimmer, A., Williams, L., Calle, Y., Moreno, V. S., Cox, S., Jones, G. E., & Wells, C. M. (2019). PAK4 Kinase Activity Plays a Crucial Role in the Podosome Ring of Myeloid Cells. Cell Reports, 29(11), 3385-3393.e6. https://doi.org/10.1016/j.celrep.2019.11.016