Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide exchange activity of RIN1.
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.
Tall
G G
GG
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75390, USA.
Barbieri
M A
MA
Stahl
P D
PD
Horazdovsky
B F
BF
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*
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