Cell Biology
RUTBC2 Protein, a Rab9A Effector and GTPase-activating Protein for Rab36*

https://doi.org/10.1074/jbc.M112.362558Get rights and content
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Rab GTPases regulate vesicle budding, motility, docking, and fusion. In cells, their cycling between active, GTP-bound states and inactive, GDP-bound states is regulated by the action of opposing enzymes called guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). The substrates for most RabGAPs are unknown, and the potential for cross-talk between different membrane trafficking pathways remains uncharted territory. Rab9A and its effectors regulate recycling of mannose 6-phosphate receptors from late endosomes to the trans Golgi network. We show here that RUTBC2 is a TBC domain-containing protein that binds to Rab9A specifically both in vitro and in cultured cells but is not a GAP for Rab9A. Biochemical screening of Rab protein substrates for RUTBC2 revealed highest GAP activity toward Rab34 and Rab36. In cells, membrane-associated RUTBC2 co-localizes with Rab36, and expression of wild type RUTBC2, but not the catalytically inactive, RUTBC2 R829A mutant, decreases the amount of membrane-associated Rab36 protein. These data show that RUTBC2 can act as a Rab36 GAP in cells and suggest that RUTBC2 links Rab9A function to Rab36 function in the endosomal system.

Background: Rab GTPases control membrane traffic, and identification of Rab regulators is incomplete.

Results: RUTBC2 binds Rab9A, enhances GTP hydrolysis by Rab34 and Rab36 in vitro, and is a GAP for Rab36 in cells.

Conclusion: These data suggest a connection between Rab9A and Rab36 as part of a cascade of membrane traffic steps.

Significance: This represents the first assignment of a molecular function for RUTBC2.

Cell Biology
Endosomes
GTPase
Membrane Trafficking
Rab Proteins
GTPase-activating Protein

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*

This work was supported, in whole or in part, by National Institutes of Health Grant DK37332 (to S. R. P.).

1

Supported in part by National Institutes of Health Training Grant GM007276.

2

Present address: MRC Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom.