SH3 interactome conserves general function over specific form

X, Xin; Gfeller, David; Cheng, Jackie; Tonikian, Raffi; Sun, Lin; Guo, Ailan; Lopez, Lianet; Pavlenco, Alevtina; Akintobi, A.; Zhang, Yingnan; Rual, Jean François; Currell, Bridget; Seshagiri, Somasekar; Hao, Tong; Yang, Xinping; Shen, Yun; Salehi‐Ashtiani, Kourosh; Li, Jingjing; Cheng, Aaron T.; Bouamalay, Dryden; Lugari, Adrien; Hill, David E.; Grimes, Mark L.; Drubin, David G.; Grant, Barth D.; Vidal, Marc; Boone, Charles; Sidhu, Sachdev S.; Bader, Gary D.

doi:10.1038/msb.2013.9

Cited by 71 publications

(80 citation statements)

References 93 publications

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“…Rab7 interacts with Vps34 in mammalian cells (Stein et al, 2003), and thus, it is possible that RAB-5 and/or RAB-7 regulate TBC-2 localization via recruitment of VPS-34 during early to late endosome maturation. In C. elegans, RAB-10, AMPH-1 (amphiphysin) and CED-10 (Rac1) bind to TBC-2 and regulate its localization in the recycling pathway (Liu and Grant, 2015;Sasidharan et al, 2012;Xin et al, 2013;Sun et al, 2012). However, neither rab-10, amph-1 nor ced-10 mutants have been reported to display phenotypes that would be consistent with regulating early to late endosome trafficking with TBC-2 and VPS-34.…”

Section: Discussionmentioning

confidence: 99%

The VPS34 PI3K negatively regulates RAB-5 during endosome maturation

Law

Seo

Wang

et al. 2017

Journal of Cell Science

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The GTPase Rab5 and phosphatidylinositol-3 phosphate [PI(3)P] coordinately regulate endosome trafficking. Rab5 recruits Vps34, the class III phosphoinositide 3-kinase (PI3K), to generate PI(3)P and recruit PI(3)P-binding proteins. Loss of Rab5 and loss of Vps34 have opposite effects on endosome size, suggesting that our understanding of how Rab5 and PI(3)P cooperate is incomplete. Here, we report a novel regulatory loop whereby Caenorhabditis elegans VPS-34 inactivates RAB-5 via recruitment of the TBC-2 Rab GTPase-activating protein. We found that loss of VPS-34 caused a phenotype with large late endosomes, as with loss of TBC-2, and that Rab5 activity (mice have two Rab5 isoforms, Rab5a and Rab5b) is increased in Vps34-knockout mouse embryonic fibroblasts (Vps34 is also known as PIK3C3 in mammals). We found that VPS-34 is required for TBC-2 endosome localization and that the pleckstrin homology (PH) domain of TBC-2 bound PI(3)P. Deletion of the PH domain enhanced TBC-2 localization to endosomes in a VPS-34-dependent manner. Thus, PI(3)P binding of the PH domain might be permissive for another PI(3)P-regulated interaction that recruits TBC-2 to endosomes. Therefore, VPS-34 recruits TBC-2 to endosomes to inactivate RAB-5 to ensure the directionality of endosome maturation.

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Section: Discussionmentioning

confidence: 99%

The VPS34 PI3K negatively regulates RAB-5 during endosome maturation

Law

Seo

Wang

et al. 2017

Journal of Cell Science

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“…It was also shown that mammalian TOCA-1 coimmunoprecipitates with mammalian ABI-1 in HeLa cells (31). Interestingly, recently published yeast two-hybrid and phage display analysis of the C. elegans SH3-ome identified another component of the WAVE complex, WVE-1/Wave1, as a high-probability TOCA-1-binding protein (37). Using a GST-pull-down assay, we found that the SH3 domains of TOCA-1 and TOCA-2 bound to WVE-1, whereas the W585K mutation in the TOCA-2 SH3 domain abrogated such binding ( Fig.…”

Section: Cdc-42 and Anterior Par Complex Proteins Are Required For MImentioning

confidence: 99%

A TOCA/CDC-42/PAR/WAVE functional module required for retrograde endocytic recycling

Bai

Grant

2015

Proc. Natl. Acad. Sci. U.S.A.

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Endosome-to-Golgi transport is required for the function of many key membrane proteins and lipids, including signaling receptors, small-molecule transporters, and adhesion proteins. The retromer complex is well-known for its role in cargo sorting and vesicle budding from early endosomes, in most cases leading to cargo fusion with the trans-Golgi network (TGN). Transport from recycling endosomes to the TGN has also been reported, but much less is understood about the molecules that mediate this transport step. Here we provide evidence that the F-BAR domain proteins TOCA-1 and TOCA-2 (Transducer of Cdc42 dependent actin assembly), the small GTPase CDC-42 (Cell division control protein 42), associated polarity proteins PAR-6 (Partitioning defective 6) and PKC-3/atypical protein kinase C, and the WAVE actin nucleation complex mediate the transport of MIG-14/Wls and TGN-38/TGN38 cargo proteins from the recycling endosome to the TGN in Caenorhabditis elegans. Our results indicate that CDC-42, the TOCA proteins, and the WAVE component WVE-1 are enriched on RME-1-positive recycling endosomes in the intestine, unlike retromer components that act on early endosomes. Furthermore, we find that retrograde cargo TGN-38 is trapped in early endosomes after depletion of SNX-3 (a retromer component) but is mainly trapped in recycling endosomes after depletion of CDC-42, indicating that the CDC-42-associated complex functions after retromer in a distinct organelle. Thus, we identify a group of interacting proteins that mediate retrograde recycling, and link these proteins to a poorly understood trafficking step, recycling endosome-to-Golgi transport. We also provide evidence for the physiological importance of this pathway in WNT signaling.retromer | endocytic recycling | endosome | toca | wave

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“…TOE-2 is distantly related to vertebrate proteins that contain a GAP domain in addition to their DEP domain (Arur et al, 2009). Although TOE-2 lacks a GAP domain, it can bind to the worm ortholog of GRAF, which contains a RhoGAP domain (Xin et al, 2009(Xin et al, , 2013. It is not known whether this interaction is relevant in the context of the Q.p lineage, but it suggests that TOE-2 might regulate Rho-family GTPases.…”

Section: Toe-2 Localizes Dynamically During the Divisions Of Q And Qpmentioning

confidence: 99%

The DEP domain-containing protein TOE-2 promotes apoptosis in the Q lineage of C. elegans through two distinct mechanisms

2014

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Neuroblast divisions in the nematode Caenorhabditis elegans often give rise to a larger neuron and a smaller cell that dies. We have previously identified genes that, when mutated, result in neuroblast divisions that generate daughter cells that are more equivalent in size. This effect correlates with the survival of daughter cells that would normally die. We now describe a role for the DEP domain-containing protein TOE-2 in promoting the apoptotic fate in the Q lineage. TOE-2 localized at the plasma membrane and accumulated in the cleavage furrow of the Q.a and Q.p neuroblasts, suggesting that TOE-2 might position the cleavage furrow asymmetrically to generate daughter cells of different sizes. This appears to be the case for Q.a divisions where loss of TOE-2 led to a more symmetric division and to survival of the smaller Q.a daughter. Localization of TOE-2 to the membrane is required for this asymmetry, but, surprisingly, the DEP domain is dispensable. By contrast, loss of TOE-2 led to loss of the apoptotic fate in the smaller Q.p daughter but did not affect the size asymmetry of the Q.p daughters. This function of TOE-2 required the DEP domain but not localization to the membrane. We propose that TOE-2 ensures an apoptotic fate for the small Q.a daughter by promoting asymmetry in the daughter cell sizes of the Q.a neuroblast division but by a mechanism that is independent of cell size in the Q.p division.

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SH3 interactome conserves general function over specific form

Abstract: The Caenorhabditis elegans SH3 domain interactome was mapped and compared with the yeast SH3 interactome. Orthologous SH3 domain-mediated interactions are highly rewired, but the general function of the SH3 domain network is conserved between the two species

Cited by 71 publications

References 93 publications

The VPS34 PI3K negatively regulates RAB-5 during endosome maturation

The VPS34 PI3K negatively regulates RAB-5 during endosome maturation

A TOCA/CDC-42/PAR/WAVE functional module required for retrograde endocytic recycling

The DEP domain-containing protein TOE-2 promotes apoptosis in the Q lineage of C. elegans through two distinct mechanisms

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