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

Foxall, E; Staszowska, A; Hirvonen, LM; Georgouli, M; Ciccioli, M; Rimmer, A; Williams, L; ... Wells, CM; + view all (2019) PAK4 Kinase Activity Plays a Crucial Role in the Podosome Ring of Myeloid Cells. Cell Reports , 29 (11) 3385-3393.e6. 10.1016/j.celrep.2019.11.016. Green open access

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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.

Type: Article
Title: PAK4 Kinase Activity Plays a Crucial Role in the Podosome Ring of Myeloid Cells
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2019.11.016
Publisher version: https://doi.org/10.1016/j.celrep.2019.11.016
Language: English
Additional information: Copyright © 2019 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: AKT, PAK4, adhesion, migration, podosome, superresolution microscopy
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10088636
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