title: PAK4 suppresses PDZ-RhoGEF activity to drive invadopodia maturation in melanoma cells.
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.
authors.affiliation: Division of Cancer Studies, New Hunts House, Guy's Campus, King's College London, London, UK.|National Institute for Health Research (NIHR) Biomedical Research Centre, Guy's and St Thomas's Hospital and King's College London, London, UK.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Nicholas
authors.affiliation: Division of Cancer Studies, New Hunts House, Guy's Campus, King's College London, London, UK.|National Institute for Health Research (NIHR) Biomedical Research Centre, Guy's and St Thomas's Hospital and King's College London, London, UK.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Pipili
authors.affiliation: Division of Cancer Studies, New Hunts House, Guy's Campus, King's College London, London, UK.
authors.forename: Michaela S
authors.initials: MS
authors.lastname: Lesjak
authors.affiliation: Division of Cancer Studies, New Hunts House, Guy's Campus, King's College London, London, UK.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ameer-Beg
authors.affiliation: Department of Plastic and Reconstructive Surgery, Guy's and St Thomas' Hospital, London, UK.
authors.forename: Jenny L C
authors.initials: JL
authors.lastname: Geh
authors.affiliation: Department of Plastic and Reconstructive Surgery, Guy's and St Thomas' Hospital, London, UK.
authors.forename: Ciaran
authors.initials: C
authors.lastname: Healy
authors.affiliation: Department of Plastic and Reconstructive Surgery, Guy's and St Thomas' Hospital, London, UK.
authors.forename: Alistair D
authors.initials: AD
authors.lastname: MacKenzie Ross
authors.affiliation: Randall Division, New Hunts House, Guy's Campus, King's College London, London, UK.
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre, Guy's and St Thomas's Hospital and King's College London, London, UK.|St Johns Institute of Dermatology, Guy's Hospital, London, UK.
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre, Guy's and St Thomas's Hospital and King's College London, London, UK.|St Johns Institute of Dermatology, Guy's Hospital, London, UK.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lacy
authors.affiliation: Division of Cancer Studies, New Hunts House, Guy's Campus, King's College London, London, UK.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Wells
mesh_terms: D000199:Actins; D000818:Animals; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D000069261:Podosomes / Q000473:pathology*; D020033:Protein Isoforms / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000473:pathology*; D015027:Zebrafish; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C577234:ARHGEF11 protein, human; D000199:Actins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; C116367:PAK4 protein, human; C515903:PAK1 protein, human; D054462:p21-Activated Kinases
keywords: PAK; PDZ-RhoGEF; RhoA; invadopodia; melanoma