Journal
ONCOTARGET
Volume 7, Issue 43, Pages 70881-70897Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12282
Keywords
PAK; melanoma; invadopodia; RhoA; PDZ-RhoGEF
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Funding
- National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust
- Breast Cancer Now [2014NovPR356]
- BBSRC [BB/1022074/1]
- King's College London
- BBSRC [BB/I022074/1] Funding Source: UKRI
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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.
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