A RAB35-p85/PI3K axis controls oscillatory apical protrusions required for efficient chemotactic migration

• DOI: 10.1038/s41467-018-03571-8
• Publication Date: 2018-04-11T14:01:26Z
• Authors: Salvatore Corallino; Chiara Malinverno; Beate Neumann; Christian Tischer; Andrea Palamidessi; Emanuela Frittoli; Magdalini Panagio...; Andrea Disanza; Gema Malet-Engra; Paulina Nastaly; Camilla Galli; Chiara Luise; Giovanni Bertalot; Salvatore Pece; Pier Paolo Di Fiore; Nils Gauthier; Aldo Ferrari; Paolo Maiuri; Giorgio Scita
• Keywords: Platelet-Derived Growth Factor; 0301 basic medicine; RAB35; directional Migration; 0303 health sciences; Science; Chemotaxis; Q; Primary Cell Culture; Gene Expression; Epithelial Cells; Fibroblasts; Article; Molecular Imaging; Class Ia Phosphatidylinositol 3-Kinase; Actin Cytoskeleton; Mice; 03 medical and health sciences; rab GTP-Binding Proteins; Cell Line, Tumor; Animals; Humans; HeLa Cells; Signal Transduction

AbstractHow cells move chemotactically remains a major unmet challenge in cell biology. Emerging evidence indicates that for interpreting noisy, shallow gradients of soluble cues a system must behave as an excitable process. Here, through an RNAi-based, high-content screening approach, we identify RAB35 as necessary for the formation of growth factors (GFs)-induced waves of circular dorsal ruffles (CDRs), apically restricted actin-rich migratory protrusions. RAB35 is sufficient to induce recurrent and polarized CDRs that travel as propagating waves, thus behaving as an excitable system that can be biased to control cell steering. Consistently, RAB35 is essential for promoting directed chemotactic migration and chemoinvasion of various cells in response to gradients of motogenic GFs. Molecularly, RAB35 does so by directly regulating the activity of p85/PI3K polarity axis. We propose that RAB35 is a molecular determinant for the control of an excitable, oscillatory system that acts as a steering wheel for GF-mediated chemotaxis and chemoinvasion.