GTP exchange factor Vav regulates guided cell migration by coupling guidance receptor signalling to local Rac activation

et al.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 fo 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, usinga 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.Research in M.D.M.-B. laboratory is funded by the Spanish Ministerio de Ciencia y Tecnología (MCYT) [grant numbers BFU2004-02840/BMC, BFU2010-16669 and CSD-2007-00008 to M.D.M.-B.], by the EMBO Young Investigator Programme and by the Junta de Andalucía [grant numbers P06-CVI-01592 and P09-CVI-5058]. C.H.F.-E. is supported by a fellowship funded by the Consolider Project Grant [grant number CSD-2007-00008] and M.M. was supported by a Juan de la Cierva contract. The institutional support from the Junta de Andalucía to the CABD is acknowledged. S.K. is supported by the German-Israeli-Foundation (GIF). G.E. is funded by the Canadian Institutes for Health Research [grant number MOP-114899] by the Natural Sciences and Engineering Research Council of Canada and holds a Canada Research Chair (Tier II) in Vesicular Trafficking and Cell Signaling.Peer Reviewe