PAK4 suppresses PDZ-RhoGEF activity to drive invadopodia maturation in melanoma cells

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// Nicole S. Nicholas 1, 2 , Aikaterini Pipili 1, 2 , Michaela S. Lesjak 1 , Simon M. Ameer-Beg 1 , Jenny L. C. Geh 3 , Ciaran Healy 3 , Alistair D. MacKenzie Ross 3 , Maddy Parsons 4 , Frank O. Nestle 2, 5 , Katie E. Lacy 2, 5 , Claire M. Wells 1 1 Division of Cancer Studies, New Hunts House, Guy’s Campus, King’s College London, London, UK 2 National Institute for Health Research (NIHR) Biomedical Research Centre, Guy’s and St Thomas’s Hospital and King’s College London, London, UK 3 Department of Plastic and Reconstructive Surgery, Guy’s and St Thomas’ Hospital, London, UK 4 Randall Division, New Hunts House, Guy’s Campus, King’s College London, London, UK 5 St Johns Institute of Dermatology, Guy’s Hospital, London, UK Correspondence to: Claire M. Wells, email: claire.wells@kcl.ac.uk Keywords: PAK, melanoma, invadopodia, RhoA, PDZ-RhoGEF Received: April 11, 2016     Accepted: September 14, 2016     Published: September 27, 2016 ABSTRACT 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.