TBC-2 Regulates RAB-5/RAB-7-mediated Endosomal Trafficking in<i>Caenorhabditis elegans</i>

Chotard, Laëtitia; Mishra, Ashwini K.; Sylvain, Marc-André; Tuck, Simon; Lambright, David G.; Rocheleau, Christian E.

doi:10.1091/mbc.e09-11-0947

Cited by 81 publications

(151 citation statements)

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“…Furthermore, this implies that we could identify Rab interactors such as their GAPs by looking for mutants exhibiting phenotypes similar to those of Rab mutants. Among 20 TBC GAP domaincontaining proteins, only two have been characterized (Mukhopadhyay et al 2007;Chotard et al 2010). Our finding provides an insight that may be useful for discovering more GAPs for these Rabs.…”

Section: Discussionmentioning

confidence: 79%

“…This suggests that those bodies may be grinder components accumulating in the muscle because of slow trafficking at low temperature. In fact, Chotard et al (2010) showed that the mutant of tbc-2, which encodes another RabGAP in C. elegans, accumulates enormous RAB-7-positive late endosome in the intestine containing refractile materials. These results strongly suggest that the refractile bodies can be a common phenotype in endosomal trafficking mutants and that EAT-17 regulates endosomal trafficking.…”

Section: Discussionmentioning

confidence: 99%

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The Jaw of the Worm: GTPase-activating Protein EAT-17 Regulates Grinder Formation in Caenorhabditis elegans

et al. 2013

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Constitutive transport of cellular materials is essential for cell survival. Although multiple small GTPase Rab proteins are required for the process, few regulators of Rabs are known. Here we report that EAT-17, a novel GTPase-activating protein (GAP), regulates RAB-6.2 function in grinder formation in Caenorhabditis elegans. We identified EAT-17 as a novel RabGAP that interacts with RAB-6.2, a protein that presumably regulates vesicle trafficking between Golgi, the endoplasmic reticulum, and plasma membrane to form a functional grinder. EAT-17 has a canonical GAP domain that is critical for its function. RNA interference against 25 confirmed and/or predicted RABs in C. elegans shows that RNAi against rab-6.2 produces a phenotype identical to eat-17. A directed yeast twohybrid screen using EAT-17 as bait and each of the 25 RAB proteins as prey identifies RAB-6.2 as the interacting partner of EAT-17, confirming that RAB-6.2 is a specific substrate of EAT-17. Additionally, deletion mutants of rab-6.2 show grinder defects identical to those of eat-17 loss-of-function mutants, and both RAB-6.2 and EAT-17 are expressed in the terminal bulb of the pharynx where the grinder is located. Collectively, these results suggest that EAT-17 is a specific GTPase-activating protein for RAB-6.2. Based on the conserved function of Rab6 in vesicular transport, we propose that EAT-17 regulates the turnover rate of RAB-6.2 activity in cargo trafficking for grinder formation. C ELLS constitutively transport newly synthesized proteins, lipids, and other molecules to their periphery through vesicle trafficking. As the process is conserved from yeast to humans, it is essential for the function and survival of cells. Rab GTPases are small GTP binding proteins that regulate the transport of vesicles between different compartments of the cell (Zerial and McBride 2001;Jordens et al. 2005;Grosshans et al. 2006). Rab6's are localized to Golgi membranes to mark and target both anterograde cargos from Golgi to post-Golgi compartments (such as the plasma membrane) and retrograde cargos from early/recycling endosomes to Golgi and the endoplasmic reticulum (Jasmin et al. 1992;Martinez et al. 1994Martinez et al. , 1997Girod et al. 1999;Opdam et al. 2000;Del Nery et al. 2006). For fast turnover, Rabs require guanine nucleotide exchange factors (Rab GEFs) for activation and GTPase-activating proteins (Rab GAPs) to turn off activity (Grosshans et al. 2006). While the role of Rab6 in membrane trafficking is well established, very few GAPs or GEFs for Rab6 have been identified; thus their physiological importance is largely unknown. The physiological roles of RabGAPs were addressed only recently in flies (Houalla et al. 2010;Uytterhoeven et al. 2011) and worms (Chotard et al. 2010). In those cases, removing the function of the RabGAPs produced phenotypes almost identical to those of removing the relevant Rabs, showing the fundamental roles of RabGAPs in modulating Rab functions. Currently, the only identified GAP for Rab6 is GAPCenA in humans,...

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

The Jaw of the Worm: GTPase-activating Protein EAT-17 Regulates Grinder Formation in Caenorhabditis elegans

et al. 2013

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“…In C. elegans Mon1 can shut down the previous GEF and TBC-2 has been identified as a GAP for RAB-5, that needs RAB-7 to localize on the late endosome. 22,23 Mammalian RabGAP-5 specifically blocks the EGF uptake in early endocytosis by deactivating Rab5. 24 In yeast, no specific GAP for Vps21 has been identified so far.…”

Section: Rab-mediated Tethering In Yeast Endocytosismentioning

confidence: 99%

Rab GTPases and tethering in the yeast endocytic pathway

2011

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“…Examples of Rab5 GAP proteins are RabGap5, RN-tre (Pfeffer, 2005), and TBC-2 (Chotard et al, 2010), among others (Figure 1.10). Multiple Rab5 GEFs have been identified.…”

Section: Signal Transduction and Endocytosismentioning

confidence: 99%

“…Rab5 is inactivated by the interaction with GAPs proteins, such as RabGap5 (Haas et al, 2005), RN-tre (Albert et al, 1999), and TBC-2 (Chotard et al, 2010), by promoting the hydrolization of GTP into GDP. GEF proteins, such as Rabex5, Alsin2, Vps9p and Rin1, promote the exchange of GDP into GTP activating Rab5.…”

Section: Signaling Regulation By Rin Proteinsmentioning

confidence: 99%

Novel Insights into the Mechanisms of Regulation of Tyrosine Kinase Receptors by Ras Interference 1

Galvis¹

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iii DEDICATION I want to dedicate this dissertation, and everything it represents, to my family. To my husband, my parents, and my siblings. I can't thank you enough for the love and support; you made this journey a lot easier. Thanks for helping me make this dream come true.Quiero dedicarle esta tesis, y todo lo que representa, a mi familia. A mi esposo, mis papas y mis hermanos. No tengo como agradecerles por todo el amor y el apoyo; ustedes hicieron de este, un camino mucho mas facil de recorrer.Muchas gracias por ayudarme a hacer este sueño realidad. Taken together, the data indicate a potential molecular mechanism by which proteins or small molecules regulate selective and specific RTK intracellular membrane trafficking and signaling during cell growth and differentiation in normal and pathological conditions.

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TBC-2 Regulates RAB-5/RAB-7-mediated Endosomal Trafficking inCaenorhabditis elegans

Cited by 81 publications

References 55 publications

The Jaw of the Worm: GTPase-activating Protein EAT-17 Regulates Grinder Formation in Caenorhabditis elegans

The Jaw of the Worm: GTPase-activating Protein EAT-17 Regulates Grinder Formation in Caenorhabditis elegans

Rab GTPases and tethering in the yeast endocytic pathway

Novel Insights into the Mechanisms of Regulation of Tyrosine Kinase Receptors by Ras Interference 1

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