title: Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration.
abstract: Inhibition of αvβ3 integrin or expression of oncogenic mutants of p53 promote invasive cell migration by enhancing endosomal recycling of α5β1 integrin under control of the Rab11 effector Rab-coupling protein (RCP). In this paper, we show that diacylglycerol kinase α (DGK-α), which phosphorylates diacylglycerol to phosphatidic acid (PA), was required for RCP to be mobilized to and tethered at the tips of invasive pseudopods and to allow RCP-dependent α5β1 recycling and the resulting invasiveness of tumor cells. Expression of a constitutive-active mutant of DGK-α drove RCP-dependent invasion in the absence of mutant p53 expression or αvβ3 inhibition, and conversely, an RCP mutant lacking the PA-binding C2 domain was not capable of being tethered at pseudopod tips. These data demonstrate that generation of PA downstream of DGK-α is essential to connect expression of mutant p53s or inhibition of αvβ3 to RCP and for this Rab11 effector to drive the trafficking of α5β1 that is required for tumor cell invasion through three-dimensional matrices.
authors.affiliation: Beatson Institute for Cancer Research, G61 1BD Glasgow, Scotland, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Rainero
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Caswell
authors.forename: Patricia A J
authors.initials: PA
authors.lastname: Muller
authors.forename: Joan
authors.initials: J
authors.lastname: Grindlay
authors.forename: Mary W
authors.initials: MW
authors.lastname: McCaffrey
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Zhang
authors.forename: Michael J O
authors.initials: MJ
authors.lastname: Wakelam
authors.forename: Karen H
authors.initials: KH
authors.lastname: Vousden
authors.forename: Andrea
authors.initials: A
authors.lastname: Graziani
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002478:Cells, Cultured; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D010712:Phosphatidic Acids / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D039081:Integrin alpha5beta1; D008565:Membrane Proteins; D010712:Phosphatidic Acids; C488966:RAB11FIP1 protein, human; D019852:Diacylglycerol Kinase