title: Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration.
abstract: The small GTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively. Coordination of these processes is critical to achieve spatial restriction of intracellular signaling, which is essential for a variety of polarized functions. Here, we show that clathrin- and Rab5-mediated endocytosis are required for the activation of Rac induced by motogenic stimuli. Rac activation occurs on early endosomes, where the RacGEF Tiam1 is also recruited. Subsequent recycling of Rac to the plasma membrane ensures localized signaling, leading to the formation of actin-based migratory protrusions. Thus, membrane trafficking of Rac is required for the spatial resolution of Rac-dependent motogenic signals. We further demonstrate that a Rab5-to-Rac circuitry controls the morphology of motile mammalian tumor cells and primordial germinal cells during zebrafish development, suggesting that this circuitry is relevant for the regulation of migratory programs in various cells, in both in vitro settings and whole organisms.
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Palamidessi
authors.forename: Emanuela
authors.initials: E
authors.lastname: Frittoli
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Garré
authors.forename: Mario
authors.initials: M
authors.lastname: Faretta
authors.forename: Marina
authors.initials: M
authors.lastname: Mione
authors.forename: Ilaria
authors.initials: I
authors.lastname: Testa
authors.forename: Alberto
authors.initials: A
authors.lastname: Diaspro
authors.forename: Letizia
authors.initials: L
authors.lastname: Lanzetti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scita
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D002966:Clathrin / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D004625:Embryo, Nonmammalian / Q000166:cytology; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D015027:Zebrafish; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; D002966:Clathrin; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D020696:rab5 GTP-Binding Proteins