Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration.
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.
Palamidessi
Andrea
A
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
Frittoli
Emanuela
E
Garré
Massimiliano
M
Faretta
Mario
M
Mione
Marina
M
Testa
Ilaria
I
Diaspro
Alberto
A
Lanzetti
Letizia
L
Scita
Giorgio
G
Di Fiore
Pier Paolo
PP
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*
D000199:Actins; D002966:Clathrin; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D020696:rab5 GTP-Binding Proteins