title: Developmentally regulated GTP-binding protein 2 coordinates Rab5 activity and transferrin recycling.
abstract: The small GTPase Rab5 regulates the early endocytic pathway of transferrin (Tfn), and Rab5 deactivation is required for Tfn recycling. Rab5 deactivation is achieved by RabGAP5, a GTPase-activating protein, on the endosomes. Here we report that recruitment of RabGAP5 is insufficient to deactivate Rab5 and that developmentally regulated GTP-binding protein 2 (DRG2) is required for Rab5 deactivation and Tfn recycling. DRG2 was associated with phosphatidylinositol 3-phosphate-containing endosomes. It colocalized and interacted with EEA1 and Rab5 on endosomes in a phosphatidylinositol 3-kinase-dependent manner. DRG2 depletion did not affect Tfn uptake and recruitment of RabGAP5 and Rac1 to Rab5 endosomes. However, it resulted in impairment of interaction between Rab5 and RabGAP5, Rab5 deactivation on endosomes, and Tfn recycling. Ectopic expression of shRNA-resistant DRG2 rescued Tfn recycling in DRG2-depleted cells. Our results demonstrate that DRG2 is an endosomal protein and a key regulator of Rab5 deactivation and Tfn recycling.
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Muralidharan
authors.initials: M
authors.lastname: Mani
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Unn Hwa
authors.initials: UH
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Nal Ae
authors.initials: NA
authors.lastname: Yoon
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Medical Science, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Myoung Seok
authors.initials: MS
authors.lastname: Ko
authors.affiliation: Inam Institute for Brain Science, Wonkwang University Sanbon Hospital, Gunpo 435-040, Korea.
authors.forename: Wongi
authors.initials: W
authors.lastname: Seol
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Hun Taeg
authors.initials: HT
authors.lastname: Chung
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Byung Ju
authors.initials: BJ
authors.lastname: Lee
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-060, Korea.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Moon
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-060, Korea.
authors.forename: Wha Ja
authors.initials: WJ
authors.lastname: Cho
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea jwpark@ulsan.ac.kr.
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Park
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008561:Membrane Fusion; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014168:Transferrin / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C409877:DRG2 protein, human; D020690:GTPase-Activating Proteins; D018129:Phosphatidylinositol Phosphates; D014168:Transferrin; D033921:Vesicular Transport Proteins; C055525:phosphatidylinositol 3-phosphate; C078418:developmentally regulated GTP-binding protein; D019869:Phosphatidylinositol 3-Kinases; D019204:GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins