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

TY - JOUR

T1 - PAK4 Kinase Activity Plays a Crucial Role in the Podosome Ring of Myeloid Cells

AU - Foxall, Elizabeth

AU - Staszowska, Adela

AU - Hirvonen, Liisa M.

AU - Georgouli, Mirella

AU - Ciccioli, Mariacristina

AU - Rimmer, Alexander

AU - Williams, Lynne

AU - Calle, Yolanda

AU - Sanz Moreno, Victoria

AU - Cox, Susan

AU - Jones, Gareth E.

AU - Wells, Claire M.

PY - 2019/12/10

Y1 - 2019/12/10

N2 - 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. 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.

AB - 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. 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.

KW - AKT

KW - PAK4

KW - adhesion

KW - migration

KW - podosome

KW - superresolution microscopy

UR - http://www.scopus.com/inward/record.url?scp=85076038772&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.11.016

DO - 10.1016/j.celrep.2019.11.016

M3 - Article

SN - 2211-1247

VL - 29

SP - 3385-3393.e6

JO - Cell Reports

JF - Cell Reports

IS - 11

ER -