TY - JOUR
T1 - PAK4 suppresses PDZ-RhoGEF activity to drive invadopodia maturation in melanoma cells
AU - Nicholas, Nicole
AU - Pipili, Aikaterini
AU - Lesjak, Michaela Silvia
AU - Ameer-Beg, Simon
AU - Geh, Jenny
AU - Healy, Ciaran
AU - MacKenzie Ross, Alistair
AU - Parsons, Madeline
AU - Nestle, Frank Oliver
AU - Lacy, K.
AU - Wells, Claire Marie
PY - 2016/9/27
Y1 - 2016/9/27
N2 - Cancer cells are thought to use actin rich invadopodia to facilitate matrix degradation. Formation and maturation of invadopodia requires the co-ordained activity of Rho-GTPases, however the molecular mechanisms that underlie the invadopodia lifecycle are not fully elucidated. Previous work has suggested a formation and disassembly role for Rho family effector p-21 activated kinase 1 (PAK1) however, related family member PAK4 has not been explored. Systematic analysis of isoform specific depletion using in vitro and in vivo invasion assays revealed there are differential invadopodia-associated functions. We consolidated a role for PAK1 in the invadopodia formation phase and identified PAK4 as a novel invadopodia protein that is required for successful maturation. Furthermore, we find that PAK4 (but not PAK1) mediates invadopodia maturation likely via inhibition of PDZ-RhoGEF. Our work points to an essential role for both PAKs during melanoma invasion but provides a significant advance in our understanding of differential PAK function.
AB - Cancer cells are thought to use actin rich invadopodia to facilitate matrix degradation. Formation and maturation of invadopodia requires the co-ordained activity of Rho-GTPases, however the molecular mechanisms that underlie the invadopodia lifecycle are not fully elucidated. Previous work has suggested a formation and disassembly role for Rho family effector p-21 activated kinase 1 (PAK1) however, related family member PAK4 has not been explored. Systematic analysis of isoform specific depletion using in vitro and in vivo invasion assays revealed there are differential invadopodia-associated functions. We consolidated a role for PAK1 in the invadopodia formation phase and identified PAK4 as a novel invadopodia protein that is required for successful maturation. Furthermore, we find that PAK4 (but not PAK1) mediates invadopodia maturation likely via inhibition of PDZ-RhoGEF. Our work points to an essential role for both PAKs during melanoma invasion but provides a significant advance in our understanding of differential PAK function.
U2 - 10.18632/oncotarget.12282
DO - 10.18632/oncotarget.12282
M3 - Article
SN - 1949-2553
VL - 7
SP - 70881
EP - 70897
JO - Oncotarget
JF - Oncotarget
IS - 43
ER -
