Orexin/Hypocretin Activates mTOR Complex 1 (mTORC1) via an Erk/Akt-independent and Calcium-stimulated Lysosome v-ATPase Pathway

Wang, Zhiqiang; Liu, Shimeng; Kakizaki, Miyo; Hirose, Yuuki; Ishikawa, Yukiko; Funato, Hiromasa; Yanagisawa, Masashi; Yu, Yonghao; Liu, Qinghua

doi:10.1074/jbc.m114.600015

Cited by 42 publications

(33 citation statements)

References 68 publications

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“…Interestingly, the V-ATPase has been found to be involved in mTORC1 activation in response to a number of stimuli, including growth factors and GPCR activation (213,219). EGF was shown to increase V-ATPase activity by stimulating increased assembly (39).…”

Section: Growth Growthmentioning

confidence: 99%

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The Function of V-ATPases in Cancer

Stransky

Cotter

Forgac

2016

Physiological Reviews

225

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: Growth Growthmentioning

confidence: 99%

“…V-ATPase function is necessary for activation of mechanistic target of rapamycin complex 1 (mTORC1) (11,30,51,74,112,190,213,219,229,233). The mTOR pathway is one of the most frequently dysregulated pathways in cancer (93).…”

Section: E Mtorc1 Activation and The Role Of The V-atpase In Nutrienmentioning

confidence: 99%

The Function of V-ATPases in Cancer

Stransky

Cotter

Forgac

2016

Physiological Reviews

225

268

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“…We next asked how Gq/11 signaling enhances mTOR signaling. Orexin/GPCR signaling activates mTOR via calcium influx (22). Upon light stimulation, expression of melanopsin in RGCs can result in neuronal depolarization, the triggering of action potentials, and calcium influx into neurons.…”

Section: Neuronal Activity In Rgcs Modulated By Melanopsin Overexpresmentioning

confidence: 99%

Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling

Yang

Zhang

et al. 2016

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

101

109

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Cell-type-specific G protein-coupled receptor (GPCR) signaling regulates distinct neuronal responses to various stimuli and is essential for axon guidance and targeting during development. However, its function in axonal regeneration in the mature CNS remains elusive. We found that subtypes of intrinsically photosensitive retinal ganglion cells (ipRGCs) in mice maintained high mammalian target of rapamycin (mTOR) levels after axotomy and that the light-sensitive GPCR melanopsin mediated this sustained expression. Melanopsin overexpression in the RGCs stimulated axonal regeneration after optic nerve crush by up-regulating mTOR complex 1 (mTORC1). The extent of the regeneration was comparable to that observed after phosphatase and tensin homolog (Pten) knockdown. Both the axon regeneration and mTOR activity that were enhanced by melanopsin required light stimulation and Gq/11 signaling. Specifically, activating Gq in RGCs elevated mTOR activation and promoted axonal regeneration. Melanopsin overexpression in RGCs enhanced the amplitude and duration of their light response, and silencing them with Kir2.1 significantly suppressed the increased mTOR signaling and axon regeneration that were induced by melanopsin. Thus, our results provide a strategy to promote axon regeneration after CNS injury by modulating neuronal activity through GPCR signaling.axon regeneration | neuronal activity | melanopsin | GPCR | mTOR S evered axons in the adult mammalian CNS do not spontaneously regenerate to restore lost functions. The failure of axons to regenerate is mainly attributed to the diminished growth capacity of neurons as well as an inhibitory environment (1-6). Optic nerves have been extensively studied for mechanisms regulating axon regeneration in CNS. When presented with permissive substrates such as a sciatic nerve graft, only axons of small populations of retinal ganglion cells (RGCs) regrow into the graft (7). When the intrinsic growth program is boosted, distinct subtypes of RGCs regenerate their axons (8). These findings indicate that the differential responses of RGCs to axotomy and growth stimulation are related to their intrinsic properties. One of the critical determinants of the intrinsic regenerative abilities of adult RGCs is neuronal mammalian target of rapamycin (mTOR) activity (9). In retinal axons, the loss of the potential to regrow is accompanied by down-regulation of mTOR activity in RGCs with maturation, and further reduction after axotomy. However, a small percentage of RGCs maintain high mTOR activation levels after optic nerve crush (9, 10). One can ask whether specific subsets of RGCs differ in their ability to maintain mTOR activation. Deciphering the physiological mechanism behind the mTOR maintenance could help elucidate the differential responses of neurons to injury signals and develop strategies to promote axon regeneration.Type 1 melanopsin expressing intrinsically photosensitive retinal ganglion cells (M1 ipRGCs) and αRGCs are resistant to axotomy-induced cell death (8, 11). M1 ipRGCs mainl...

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“…Specifically, the neuropeptide orexin, lack of which induces the chronic sleep disorder narcolepsy, signals through the orexin/GPCR to affect mTORC1 activity independently of TSC1/2. Further, the receptor was described as an Erk/Akt-independent, calciumstimulated, v-ATPase-mediated mTORC1 activator [59]. This study demonstrated that the orexin/GPCR activates mTORC1 pathways in mouse brains and multiple recombinant cell lines that express orexin 1 and orexin 2 receptors.…”

Section: Lysosomal Sensing Of Cellular Signalingmentioning

confidence: 90%

“…This study demonstrated that the orexin/GPCR activates mTORC1 pathways in mouse brains and multiple recombinant cell lines that express orexin 1 and orexin 2 receptors. The orexin/GPCR coordinates extracellular Ca 2+ influx and the v-ATPase/Rag GTPases to activate mTORC1 excluding the involvement of Akt and Erk [59]. However, it is unclear whether orexin/GPCR-mediated Ca 2+ signaling is relayed through v-ATPase or if its function is simply required to sense amino acid levels in cells.…”

Section: Lysosomal Sensing Of Cellular Signalingmentioning

confidence: 99%

Cellular metabolism and lysosomal mTOR signaling

Nnah¹,

Khayati²,

Dobrowolski³

2015

Cell Death in Therapy

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Over the last few years extensive studies have linked the activity of mTORC1 to lysosomal function. These observations propose an intriguing integration of cellular catabolism, sustained by lysosomes, with anabolic processes, largely controlled by mTORC1. Interestingly, lysosomal function directly affects mTORC1 activity and is regulated by ZKSCAN3 and TFEB, two transcription factors and substrates of mTORC1. Thus, the lysosomal mTOR signaling complex represents a hub of cellular energy metabolism, and its dysregulation may lead to a number of human diseases. Here, we discuss the recent developments and highlight the open questions in this growing field.

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Orexin/Hypocretin Activates mTOR Complex 1 (mTORC1) via an Erk/Akt-independent and Calcium-stimulated Lysosome v-ATPase Pathway

Cited by 42 publications

References 68 publications

The Function of V-ATPases in Cancer

The Function of V-ATPases in Cancer

Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling

Cellular metabolism and lysosomal mTOR signaling

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