title: DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior.
abstract: The small guanosine triphosphatase Rab13 functions in exocytic vesicle trafficking in epithelial cells. Alterations in Rab13 activity have been observed in human cancers, yet the mechanism of Rab13 activation and its role in cancer progression remain unclear. In this paper, we identify the DENN domain protein DENND2B as the guanine nucleotide exchange factor for Rab13 and develop a novel Förster resonance energy transfer-based Rab biosensor to reveal activation of Rab13 by DENND2B at the leading edge of migrating cells. DENND2B interacts with the Rab13 effector MICAL-L2 at the cell periphery, and this interaction is required for the dynamic remodeling of the cell's leading edge. Disruption of Rab13-mediated trafficking dramatically limits the invasive behavior of epithelial cells in vitro and the growth and migration of highly invasive cancer cells in vivo. Thus, blocking Rab13 activation by DENND2B may provide a novel target to limit the spread of epithelial cancers.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute; and Department of Biochemistry, Goodman Cancer Centre; McGill University, Montreal, Quebec H3A 0G4, Canada.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Ioannou
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute; and Department of Biochemistry, Goodman Cancer Centre; McGill University, Montreal, Quebec H3A 0G4, Canada.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Bell
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute; and Department of Biochemistry, Goodman Cancer Centre; McGill University, Montreal, Quebec H3A 0G4, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Girard
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute; and Department of Biochemistry, Goodman Cancer Centre; McGill University, Montreal, Quebec H3A 0G4, Canada.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Chaineau
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute; and Department of Biochemistry, Goodman Cancer Centre; McGill University, Montreal, Quebec H3A 0G4, Canada.
authors.forename: Jason N R
authors.initials: JN
authors.lastname: Hamlin
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute; and Department of Biochemistry, Goodman Cancer Centre; McGill University, Montreal, Quebec H3A 0G4, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Daubaras
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute; and Department of Biochemistry, Goodman Cancer Centre; McGill University, Montreal, Quebec H3A 0G4, Canada.
authors.forename: Anie
authors.initials: A
authors.lastname: Monast
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute; and Department of Biochemistry, Goodman Cancer Centre; McGill University, Montreal, Quebec H3A 0G4, Canada.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Anatomy and Structural Biology, Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, NY 10461.
authors.forename: Louis
authors.initials: L
authors.lastname: Hodgson
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute; and Department of Biochemistry, Goodman Cancer Centre; McGill University, Montreal, Quebec H3A 0G4, Canada peter.mcpherson@mcgill.ca.
authors.forename: Peter S
authors.initials: PS
authors.lastname: McPherson
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C528177:MICALL2 protein, human; D008840:Microfilament Proteins; C484190:RAB31 protein, human; D025521:Tumor Suppressor Proteins; D020691:rab GTP-Binding Proteins