title: PDK1-mediated activation of MRCKα regulates directional cell migration and lamellipodia retraction.
abstract: Directional cell migration is of paramount importance in both physiological and pathological processes, such as development, wound healing, immune response, and cancer invasion. Here, we report that 3-phosphoinositide-dependent kinase 1 (PDK1) regulates epithelial directional migration and invasion by binding and activating myotonic dystrophy kinase-related CDC42-binding kinase α (MRCKα). We show that the effect of PDK1 on cell migration does not involve its kinase activity but instead relies on its ability to bind membrane phosphatidylinositol (3,4,5)-trisphosphate. Upon epidermal growth factor (EGF) stimulation, PDK1 and MRCKα colocalize at the cell membrane in lamellipodia. We demonstrate that PDK1 positively modulates MRCKα activity and drives its localization within lamellipodia. Likewise, the retraction phase of lamellipodia is controlled by PDK1 through an MRCKα-dependent mechanism. In summary, we discovered a functional pathway involving PDK1-mediated activation of MRCKα, which links EGF signaling to myosin contraction and directional migration.
authors.affiliation: Department of Oncology and Center for Molecular Systems Biology, University of Turin, Turin 10060, Italy Laboratory of Cell Migration, Candiolo Cancer Institute FPO-IRCCS, Candiolo 10060, Italy.
authors.forename: Paolo Armando
authors.initials: PA
authors.lastname: Gagliardi
authors.affiliation: Department of Oncology and Center for Molecular Systems Biology, University of Turin, Turin 10060, Italy Laboratory of Cell Migration, Candiolo Cancer Institute FPO-IRCCS, Candiolo 10060, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: di Blasio
authors.affiliation: Department of Oncology and Center for Molecular Systems Biology, University of Turin, Turin 10060, Italy Laboratory of Cell Migration, Candiolo Cancer Institute FPO-IRCCS, Candiolo 10060, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Puliafito
authors.affiliation: Department of Oncology and Center for Molecular Systems Biology, University of Turin, Turin 10060, Italy Laboratory of Cell Migration, Candiolo Cancer Institute FPO-IRCCS, Candiolo 10060, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Seano
authors.affiliation: Department of Oncology and Center for Molecular Systems Biology, University of Turin, Turin 10060, Italy Laboratory of Cell Migration, Candiolo Cancer Institute FPO-IRCCS, Candiolo 10060, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sessa
authors.affiliation: Department of Oncology and Center for Molecular Systems Biology, University of Turin, Turin 10060, Italy Laboratory of Cell Migration, Candiolo Cancer Institute FPO-IRCCS, Candiolo 10060, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Chianale
authors.affiliation: Institute of Molecular and Cell Biology, A-STAR, Singapore 138673, Singapore.
authors.forename: Thomas
authors.initials: T
authors.lastname: Leung
authors.affiliation: Department of Oncology and Center for Molecular Systems Biology, University of Turin, Turin 10060, ItalyDepartment of Oncology and Center for Molecular Systems Biology, University of Turin, Turin 10060, Italy Laboratory of Cell Migration, Candiolo Cancer Institute FPO-IRCCS, Candiolo 10060, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
authors.affiliation: Department of Oncology and Center for Molecular Systems Biology, University of Turin, Turin 10060, ItalyDepartment of Oncology and Center for Molecular Systems Biology, University of Turin, Turin 10060, Italy Laboratory of Cell Migration, Candiolo Cancer Institute FPO-IRCCS, Candiolo 10060, Italy luca.primo@ircc.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Primo
mesh_terms: D020134:Catalytic Domain; D002462:Cell Membrane / Q000201:enzymology; D002465:Cell Movement; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D065636:Myotonin-Protein Kinase; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport; D011554:Pseudopodia / Q000201:enzymology* / Q000648:ultrastructure; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D004815:Epidermal Growth Factor; C105518:CDC42BPA protein, human; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases
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