title: GTP exchange factor Vav regulates guided cell migration by coupling guidance receptor signalling to local Rac activation.
abstract: Guided cell migration is a key mechanism for cell positioning in morphogenesis. The current model suggests that the spatially controlled activation of receptor tyrosine kinases (RTKs) by guidance cues limits Rac activity at the leading edge, which is crucial for establishing and maintaining polarized cell protrusions at the front. However, little is known about the mechanisms by which RTKs control the local activation of Rac. Here, using a multidisciplinary approach, we identify the GTP exchange factor (GEF) Vav as a key regulator of Rac activity downstream of RTKs in a developmentally regulated cell migration event, that of the Drosophila border cells (BCs). We show that elimination of the vav gene impairs BC migration. Live imaging analysis reveals that vav is required for the stabilization and maintenance of protrusions at the front of the BC cluster. In addition, activation of the PDGF/VEGF-related receptor (PVR) by its ligand the PDGF/PVF1 factor brings about activation of Vav protein by direct interaction with the intracellular domain of PVR. Finally, FRET analyses demonstrate that Vav is required in BCs for the asymmetric distribution of Rac activity at the front. Our results unravel an important role for the Vav proteins as signal transducers that couple signalling downstream of RTKs with local Rac activation during morphogenetic movements.
authors.affiliation: Centro Andaluz de Biología del Desarrollo CSIC-Universidad Pablo de Olavide, Sevilla 41013, Spain.
authors.forename: Cecilia H
authors.initials: CH
authors.lastname: Fernández-Espartero
authors.forename: Damien
authors.initials: D
authors.lastname: Ramel
authors.forename: Marganit
authors.initials: M
authors.lastname: Farago
authors.forename: Marianne
authors.initials: M
authors.lastname: Malartre
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Luque
authors.forename: Shiran
authors.initials: S
authors.lastname: Limanovich
authors.forename: Shulamit
authors.initials: S
authors.lastname: Katzav
authors.forename: Gregory
authors.initials: G
authors.lastname: Emery
authors.forename: María D
authors.initials: MD
authors.lastname: Martín-Bermudo
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002465:Cell Movement / Q000235:genetics; D022081:Cell Surface Extensions / Q000235:genetics; D002478:Cells, Cultured; D004331:Drosophila melanogaster / Q000166:cytology / Q000502:physiology*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D004794:Enzyme Repression / Q000235:genetics; D005260:Female; D009024:Morphogenesis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D020798:Two-Hybrid System Techniques
chemical_list: D051567:Proto-Oncogene Proteins c-vav; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt
keywords: Migration; Rac; Vav