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• W2949098669 abstract "Rab GTPases are critical regulators of membrane trafficking and not surprisingly defects in Rabs contribute to various human diseases. For example, Rab13 is associated with several phenotypes associated with cancer, but the regulation of Rab13 in membrane trafficking is poorly understood. The general objective of this doctoral research was to study the function and regulation of Rab13 in endosomal trafficking. Rabs cycle between an active GTP-bound form and an inactive GDP-bound form. Upon activation by guanine nucleotide exchange factors, Rabs associate with membranes where they recruit effector molecules to mediate their downstream response. However, the spatio-temporal activation of Rab13 was unknown. Furthermore, the DENN-domain is an evolutionarily conserved protein module that functions enzymatically as guanine nucleotide exchange factors for Rabs. Here, we identified the DENN containing protein DENND2B as guanine nucleotide exchange factor for Rab13 and uncover a mechanism whereby activation of Rab13 by DENND2B in a complex with the Rab13 effector MICAL-L2 at the cell periphery drives cancer cell migration, invasion, and tumor metastasis. Furthermore, active Rabs typically anchor to membranes using a hydrophobic prenyl modification and dissociate from membranes upon inactivation. Here we discovered that Rab13 traffics on vesicles in its inactive form as part of a protein complex independent of prenylation. Therefore, in this doctoral thesis we have provided a detailed characterization of the regulation of Rab13 in endosomal trafficking. %%%%Les proteines de type Rab GTPases sont des regulateurs essentiels dans le trafic intracellulaire membranaire. Il n'est donc pas surprenant de constater que leur mauvais fonctionnement puisse causer differentes pathologies chez l'humain. A titre d'exemple, Rab13 est associee a plusieurs phenotypes observes dans les cancers mais son fonctionnement dans le trafic cellulaire n'est toujours pas elucide. L'objectif de cette these de doctorat etait de mettre en lumiere la fonction et la regulation de Rab13 dans le trafic endosomal. Les proteines de type Rab oscillent entre une forme active liee au nucleotide GTP et une forme inactive liee au nucleotide GDP. Apres avoir ete activees par les facteurs d'echange du nucleotide guanine, les Rabs s'associent aux membranes d'ou elles recrutent d'autres molecules effectrices afin d'initier leur reponse cellulaire. Toutefois, la reponse spatio-temporelle de Rab13 etait jusqu'a maintenant inconnue. Nous avons decouvert la proteine DENND2B comme etant le facteur d'echange guanidique pour Rab13. De plus, nous egalement revele un mecanisme d'activation par lequel Rab13 et DENND2B en complexe proteique avec la proteine MICAL-L2 favorise la migration des cellules cancereuses, l'invasion et le processus metastatique. De plus, les formes actives des proteines Rabs se lient aux membranes par leur modification hydrophique de type prenylique pour ensuite s'en dissocier lors de leur inactivation. Nos travaux demontrent que Rab13 trafique sur…" @default.
• W2949098669 created "2019-06-27" @default.
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• W2949098669 date "2016-01-01" @default.
• W2949098669 modified "2023-09-24" @default.
• W2949098669 title "The regulation of Rab13 in endosomal trafficking" @default.
• W2949098669 hasPublicationYear "2016" @default.
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