Rabconnectin-3 Is a Functional Regulator of Mammalian Notch Signaling

Sethi, Nilay; Yan, Yan; Quek, Debra Q Y; Schüpbach, Trudi; Kang, Yibin

doi:10.1074/jbc.m110.158634

Cited by 65 publications

(77 citation statements)

References 27 publications

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“…This cleavage defect upon V-ATPase inhibition could be due to the dependence of ␥-secretase on an acidic environment to cleave the Notch receptor, or it could be that the acidic pH generated by the V-ATPase serves to activate cofactors that stimulate cleavage. Similar effects were also observed in normal and transformed human cell lines, as well as during mouse development (86,92,178,198). In Notch-addicted breast tumor cell lines, V-ATPase inhibition reduced cell proliferation (86).…”

Section: V-atpase and Notch Signalingsupporting

confidence: 62%

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The Function of V-ATPases in Cancer

Stransky

Cotter

Forgac

2016

Physiological Reviews

238

268

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The vacuolar ATPases (V-ATPases) are a family of proton pumps that couple ATP hydrolysis to proton transport into intracellular compartments and across the plasma membrane. They function in a wide array of normal cellular processes, including membrane traffic, protein processing and degradation, and the coupled transport of small molecules, as well as such physiological processes as urinary acidification and bone resorption. The V-ATPases have also been implicated in a number of disease processes, including viral infection, renal disease, and bone resorption defects. This review is focused on the growing evidence for the important role of V-ATPases in cancer. This includes functions in cellular signaling (particularly Wnt, Notch, and mTOR signaling), cancer cell survival in the highly acidic environment of tumors, aiding the development of drug resistance, as well as crucial roles in tumor cell invasion, migration, and metastasis. Of greatest excitement is evidence that at least some tumors express isoforms of V-ATPase subunits whose disruption is not lethal, leading to the possibility of developing anti-cancer therapeutics that selectively target V-ATPases that function in cancer cells.

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Section: V-atpase and Notch Signalingsupporting

confidence: 62%

“…The NICD translocates to the nucleus where it alters gene transcription to alter cell identity and growth (228). Correct processing and trafficking of the Notch receptor requires V-ATPase function (40, 86,155,178,206,207,223). Notch receptor expression is also impaired by prolonged V-ATPase inhibition (198).…”

Section: V-atpase and Notch Signalingmentioning

confidence: 98%

The Function of V-ATPases in Cancer

Stransky

Cotter

Forgac

2016

Physiological Reviews

238

268

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“…Dmxl2 binds both GDP/GTP exchange protein and GTPase-activating protein for the Rab3 small G protein family that regulates Ca 2+ -dependent exocytosis of neurotransmitters [25,26], Dmxl2 is also a functional regulator of mammalian Notch signalling [27], and thereby modulating neurogenesis [28,29]. Its upregulation by p60TRP may cause enhanced neuronal synaptic activities resulting in increased synaptic plasticity.…”

Section: Discussionmentioning

confidence: 99%

Brain-Site-Specific Proteome Changes Induced by Neuronal P60TRP Expression

Manavalan

Mishra²,

Sze³

et al. 2013

Neurosignals

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p60 transcription regulator protein (p60TRP) facilitates the processing of the amyloid precursor protein towards the non-amyloidogenic pathway by inhibiting the β-secretase action. This protein was initially identified to be downregulated in the temporal lobe of brains from Alzheimer's disease patients. p60TRP is one of the G-protein-coupled receptor (GPCR)-associated proteins which directly influences the signalling capacity of GPCRs. In the present study, we investigated the brain-region-specific proteome profile of transgenic p60TRP mice to gain an insight into the molecular events mediated by the long-term effect of neuronal p60TRP overexpression on brain proteome changes and its potential implication for neuronal functions in the central nervous system. Using a proteomics research approach based on isobaric tags for relative and absolute quantitation, we identified 2,025 proteins, whereby 1,735 proteins were quantified, out of which 56 were found to be significantly altered in the cortex and/or hippocampus of neuronal transgenic neuronal p60TRP mice. Our data suggests that in vivo overexpression of neuronal p60TRP significantly affects cognitive and neuroprotective capacities.

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“…Rabconnectin-3 functions in regulated assembly of V-ATPase (Einhorn et al, 2012;Seol et al, 2001;Sethi et al, 2010;Yan et al, 2009). One prediction from our analysis of Rbcn-3 is that V-ATPase would be required for intracellular lumen formation.…”

Section: V-atpase Is Required For Intracellular Lumen Formationmentioning

confidence: 99%

Intracellular lumen formation in Drosophila proceeds via a novel subcellular compartment

Nikolova

Metzstein

2015

Development

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Cellular tubes have diverse morphologies, including multicellular, unicellular and subcellular architectures. Subcellular tubes are found prominently within the vertebrate vasculature, the insect breathing system and the nematode excretory apparatus, but how such tubes form is poorly understood. To characterize the cellular mechanisms of subcellular tube formation, we have refined methods of high pressure freezing/freeze substitution to prepare Drosophila larvae for transmission electron microscopic (TEM) analysis. Using our methods, we have found that subcellular tube formation may proceed through a previously undescribed multimembrane intermediate composed of vesicles bound within a novel subcellular compartment. We have also developed correlative light/TEM procedures to identify labeled cells in TEM-fixed larval samples. Using this technique, we have found that Vacuolar ATPase (V-ATPase) and the V-ATPase regulator Rabconnectin-3 are required for subcellular tube formation, probably in a step resolving the intermediate compartment into a mature lumen. In general, our ultrastructural analysis methods could be useful for a wide range of cellular investigations in Drosophila larvae.

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Rabconnectin-3 Is a Functional Regulator of Mammalian Notch Signaling

Cited by 65 publications

References 27 publications

The Function of V-ATPases in Cancer

The Function of V-ATPases in Cancer

Brain-Site-Specific Proteome Changes Induced by Neuronal P60TRP Expression

Intracellular lumen formation in Drosophila proceeds via a novel subcellular compartment

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