PAK4 suppresses PDZ-RhoGEF activity to drive invadopodia maturation in melanoma cells
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Nicole S. Nicholas1,2, Aikaterini Pipili1,2, Michaela S. Lesjak1, Simon M. Ameer-Beg1, Jenny L. C. Geh3, Ciaran Healy3, Alistair D. MacKenzie Ross3, Maddy Parsons4, Frank O. Nestle2,5, Katie E. Lacy2,5, Claire M. Wells1
1Division of Cancer Studies, New Hunts House, Guy’s Campus, King’s College London, London, UK
2National Institute for Health Research (NIHR) Biomedical Research Centre, Guy’s and St Thomas’s Hospital and King’s College London, London, UK
3Department of Plastic and Reconstructive Surgery, Guy’s and St Thomas’ Hospital, London, UK
4Randall Division, New Hunts House, Guy’s Campus, King’s College London, London, UK
5St Johns Institute of Dermatology, Guy’s Hospital, London, UK
Claire M. Wells, email: email@example.com
Keywords: PAK, melanoma, invadopodia, RhoA, PDZ-RhoGEF
Received: April 11, 2016 Accepted: September 14, 2016 Published: September 27, 2016
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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