A GTPase-activating protein controls Rab5 function in endocytic trafficking.
Rab-family GTPases are conserved regulators of membrane trafficking that cycle between inactive GDP-bound and activated GTP-bound states. A key determinant of Rab function is the lifetime of the GTP-bound state. As Rabs have a low intrinsic rate of GTP hydrolysis, this process is under the control of GTP-hydrolysis-activating proteins (GAPs). Due to the large number of Rabs and GAPs that are encoded by the human genome, it has proven difficult to assign specific functional relationships to these proteins. Here, we identify a Rab5-specific GAP (RabGAP-5), and show that RN-Tre (previously described as a Rab5 GAP) acts on Rab41. RabGAP-5 overexpression triggers a loss of the Rab5 effector EEA1 from endosomes and blocks endocytic trafficking. By contrast, depletion of RabGAP-5 results in increased endosome size, more endosome-associated EEA1, and disrupts the trafficking of EGF and LAMP1. RabGAP-5 therefore limits the amount of activated Rab5, and thereby regulates trafficking through endosomes.
Haas
Alexander K
AK
Max-Planck Institute of Biochemistry, Department of Cell Biology, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Fuchs
Evelyn
E
Kopajtich
Robert
R
Barr
Francis A
FA
D048868:Adaptor Proteins, Signal Transducing; D002462:Cell Membrane / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*; D052118:Lysosomal-Associated Membrane Protein 1
D048868:Adaptor Proteins, Signal Transducing; D004815:Epidermal Growth Factor; D020690:GTPase-Activating Proteins; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D015514:Oncogene Proteins, Fusion; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C100665:USP6NL protein, human; C093846:early endosome antigen 1; C490163:RAB41 protein, human