title: Vang-like protein 2 and Rac1 interact to regulate adherens junctions.
abstract: The Wnt planar cell polarity (Wnt/PCP) pathway signals through small Rho-like GTPases to regulate the cytoskeleton. The core PCP proteins have been mapped to the Wnt/PCP pathway genetically, but the molecular mechanism of their action remains unknown. Here, we investigate the function of the mammalian PCP protein Vang-like protein 2 (Vangl2). RNAi knockdown of Vangl2 impaired cell-cell adhesion and cytoskeletal integrity in the epithelial cell lines HEK293T and MDCK. Similar effects were observed when Vangl2 was overexpressed in HEK293T, MDCK or C17.2 cells. The effects of Vangl2 overexpression could be blocked by knockdown of the small GTPase Rac1 or by dominant-negative Rac1. In itself, knockdown of Rac1 impaired cytoskeletal integrity and reduced cell-cell adhesion. We found that Vangl2 bound and re-distributed Rac1 within the cells but did not alter Rac1 activity. Moreover, both transgenic mouse embryos overexpressing Vangl2 in neural stem cells and loop-tail Vangl2 loss-of-function embryos displayed impaired adherens junctions, a cytoskeletal unit essential for neural tube rigidity and neural tube closure. In vivo, Rac1 was re-distributed within the cells in a similar way to that observed by us in vitro. We propose that Vangl2 affects cell adhesion and the cytoskeleton by recruiting Rac1 and targeting its activity in the cell to adherens junctions.
authors.affiliation: Neonatal Unit, Department of Woman and Child Health, SE-171 76, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Lindqvist
authors.forename: Zachi
authors.initials: Z
authors.lastname: Horn
authors.forename: Vitezslav
authors.initials: V
authors.lastname: Bryja
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schulte
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papachristou
authors.forename: Rieko
authors.initials: R
authors.lastname: Ajima
authors.forename: Cecilia
authors.initials: C
authors.lastname: Dyberg
authors.forename: Ernest
authors.initials: E
authors.lastname: Arenas
authors.forename: Terry P
authors.initials: TP
authors.lastname: Yamaguchi
authors.forename: Hugo
authors.initials: H
authors.lastname: Lagercrantz
authors.forename: Thomas
authors.initials: T
authors.lastname: Ringstedt
mesh_terms: D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004285:Dogs; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431577:Ltap protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C468513:VANGL2 protein, human; D020830:rac1 GTP-Binding Protein