title: p27Kip1promotes invadopodia turnover and invasion through the regulation of the PAK1/Cortactin pathway.
abstract: p27Kip1(p27) is a cyclin-CDK inhibitor and negative regulator of cell proliferation. p27 also controls other cellular processes including migration and cytoplasmic p27 can act as an oncogene. Furthermore, cytoplasmic p27 promotes invasion and metastasis, in part by promoting epithelial to mesenchymal transition. Herein, we find that p27 promotes cell invasion by binding to and regulating the activity of Cortactin, a critical regulator of invadopodia formation. p27 localizes to invadopodia and limits their number and activity. p27 promotes the interaction of Cortactin with PAK1. In turn, PAK1 promotes invadopodia turnover by phosphorylating Cortactin, and expression of Cortactin mutants for PAK-targeted sites abolishes p27's effect on invadopodia dynamics. Thus, in absence of p27, cells exhibit increased invadopodia stability due to impaired PAK1-Cortactin interaction, but their invasive capacity is reduced compared to wild-type cells. Overall, we find that p27 directly promotes cell invasion by facilitating invadopodia turnover via the Rac1/PAK1/Cortactin pathway.
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université Toulouse III Paul Sabatier, Toulouse, France.|CNRS ERL5294, Toulouse, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Jeannot
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université Toulouse III Paul Sabatier, Toulouse, France.|CNRS ERL5294, Toulouse, France.
authors.forename: Ada
authors.initials: A
authors.lastname: Nowosad
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université Toulouse III Paul Sabatier, Toulouse, France.|CNRS ERL5294, Toulouse, France.
authors.forename: Renaud T
authors.initials: RT
authors.lastname: Perchey
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université Toulouse III Paul Sabatier, Toulouse, France.|CNRS ERL5294, Toulouse, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Callot
authors.affiliation: 3P5 proteomics facility of the Université Paris Descartes, Inserm U1016 Institut Cochin, Sorbonne Paris Cité, Paris, France.
authors.forename: Evangeline
authors.initials: E
authors.lastname: Bennana
authors.affiliation: National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Katsube
authors.affiliation: 3P5 proteomics facility of the Université Paris Descartes, Inserm U1016 Institut Cochin, Sorbonne Paris Cité, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.affiliation: 3P5 proteomics facility of the Université Paris Descartes, Inserm U1016 Institut Cochin, Sorbonne Paris Cité, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Guillonneau
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université Toulouse III Paul Sabatier, Toulouse, France.|CNRS ERL5294, Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Manenti
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université Toulouse III Paul Sabatier, Toulouse, France.|CNRS ERL5294, Toulouse, France.
authors.forename: Arnaud
authors.identifier: 0000-0002-9599-3943
authors.initials: A
authors.lastname: Besson
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D051356:Cortactin / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000069261:Podosomes / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: C495868:CTTN protein, human; D051356:Cortactin; D050760:Cyclin-Dependent Kinase Inhibitor p27; C515903:PAK1 protein, human; D054462:p21-Activated Kinases
keywords: PAK; cancer biology; cell biology; cortactin; human; invadopodia; invasion; mouse; p27/Kip1