Introduction: Diplomacy, Audible and Resonant

Introduction to special forum, "The Diplomat's Soundworld.

Introduction: Diplomacy, Audible and Resonant

Introduction to special forum, "The Diplomat's Soundworld.

Immune and Smooth Muscle Cells Interactions in Atherosclerosis: How to Target a Breaking Bad Dialogue?

International audienc

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

The NPM-ALK oncogene interacts, activates and uses PIKfyve to increase invasiveness.

International audienceNPM-ALK is a chimeric tyrosine kinase detected in most anaplastic large cell lymphomas which results from the reciprocal translocation t(2,5)(p23;q35) that fuses the N-terminal domain of nucleophosmin (NPM) to the catalytic domain of the ALK receptor. The constitutive activity of the kinase is responsible for its oncogenicity through the stimulation of several downstream signaling pathways leading to cell proliferation, migration and survival. We previously demonstrated that the high level of phosphatidylinositol 5-phosphate (PtdIns5P) measured in NPM-ALK expressing cells is controlled by the phosphoinositide kinase PIKfyve, a lipid kinase known for its role in vesicular trafficking. Here, we show that PIKfyve associates with NPM-ALK and that the interaction involves the 181-300 region of the oncogene. Moreover, we demonstrate that the tyrosine kinase activity of the oncogene controls PIKfyve lipid kinase activity, but is dispensable for the formation of the complex. Silencing or inhibition of PIKfyve, by using siRNA or the PIKfyve inhibitor YM201636, have no effect on NPM-ALK-mediated proliferation and migration, but strongly reduce invasive capacities of NPM-ALK expressing cells and their capacity to degrade the extracellular matrix. Accordingly, immunofluorescence studies confirm a perturbation of MMP-9 localization at the cell surface and defect in maturation. Altogether, these results suggest a role for PIKfyve in NPM-ALK mediated invasion

PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress

International audienceCells subjected to stress situations mobilize specific membranes and proteins to initiate autophagy. Phosphatidylinositol-3-phosphate (PI3P), a crucial lipid in membrane dynamics, is known to be essential in this context. In addition to nutriments deprivation, autophagy is also triggered by fluid-flow induced shear stress in epithelial cells, and this specific autophagic response depends on primary cilium (PC) signaling and leads to cell size regulation. Here we report that PI3KC2α, required for ciliogenesis and PC functions, promotes the synthesis of a local pool of PI3P upon shear stress. We show that PI3KC2α depletion in cells subjected to shear stress abolishes ciliogenesis as well as the autophagy and related cell size regulation. We finally show that PI3KC2α and VPS34, the two main enzymes responsible for PI3P synthesis, have different roles during autophagy, depending on the type of cellular stress: while VPS34 is clearly required for starvation-induced autophagy, PI3KC2α participates only in shear stress-dependent autophagy