title: Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide exchange activity of RIN1.
abstract: RIN1 was originally identified by its ability to inhibit activated Ras and likely participates in multiple signaling pathways because it binds c-ABL and 14-3-3 proteins, in addition to Ras. RIN1 also contains a region homologous to the catalytic domain of Vps9p-like Rab guanine nucleotide exchange factors (GEFs). Here, we show that this region is necessary and sufficient for RIN1 interaction with the GDP-bound Rabs, Vps21p, and Rab5A. RIN1 is also shown to stimulate Rab5 guanine nucleotide exchange, Rab5A-dependent endosome fusion, and EGF receptor-mediated endocytosis. The stimulatory effect of RIN1 on all three of these processes is potentiated by activated Ras. We conclude that Ras-activated endocytosis is facilitated, in part, by the ability of Ras to directly regulate the Rab5 nucleotide exchange activity of RIN1.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75390, USA.
authors.forename: G G
authors.initials: GG
authors.lastname: Tall
authors.forename: M A
authors.initials: MA
authors.lastname: Barbieri
authors.forename: P D
authors.initials: PD
authors.lastname: Stahl
authors.forename: B F
authors.initials: BF
authors.lastname: Horazdovsky
mesh_terms: D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D006224:Cricetinae; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000502:physiology; D005347:Fibroblasts; D005656:Fungal Proteins / Q000737:chemistry; D015870:Gene Expression / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D029701:Saccharomyces cerevisiae Proteins; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D005656:Fungal Proteins; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; C490451:Rin1 protein, mouse; D029701:Saccharomyces cerevisiae Proteins; C099285:VPS9 protein, S cerevisiae; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; D018631:ras Proteins