Rheb signaling and tumorigenesis: <scp>mTORC1</scp> and new horizons

Armijo, Marisol E.; Campos, Tânia Maria Mendonça; Fuentes-Villalobos, Francisco; Palma, Mario; Pincheira, Roxana; Castro, Ariel F.

doi:10.1002/ijc.29707

Cited by 27 publications

(14 citation statements)

References 101 publications

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“…Rheb regulates mTORC1 activity in response to various stimuli including growth factors and specific nutrients 1 – 5 . The mTORC1 signalling is upregulated in a number of human diseases including cancers and is a target for anti-cancer therapy 6 . Mutations disrupting a negative Rheb regulator lead to a tumour syndrome called tuberous sclerosis, and Rheb itself is overexpressed or mutated in various cancers 5 , 6 .…”

Section: Introductionmentioning

confidence: 99%

Extensive molecular tinkering in the evolution of the membrane attachment mode of the Rheb GTPase

Záhonová

Petrželková

Valach

et al. 2018

Sci Rep

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Rheb is a conserved and widespread Ras-like GTPase involved in cell growth regulation mediated by the (m)TORC1 kinase complex and implicated in tumourigenesis in humans. Rheb function depends on its association with membranes via prenylated C-terminus, a mechanism shared with many other eukaryotic GTPases. Strikingly, our analysis of a phylogenetically rich sample of Rheb sequences revealed that in multiple lineages this canonical and ancestral membrane attachment mode has been variously altered. The modifications include: (1) accretion to the N-terminus of two different phosphatidylinositol 3-phosphate-binding domains, PX in Cryptista (the fusion being the first proposed synapomorphy of this clade), and FYVE in Euglenozoa and the related undescribed flagellate SRT308; (2) acquisition of lipidic modifications of the N-terminal region, namely myristoylation and/or S-palmitoylation in seven different protist lineages; (3) acquisition of S-palmitoylation in the hypervariable C-terminal region of Rheb in apusomonads, convergently to some other Ras family proteins; (4) replacement of the C-terminal prenylation motif with four transmembrane segments in a novel Rheb paralog in the SAR clade; (5) loss of an evident C-terminal membrane attachment mechanism in Tremellomycetes and some Rheb paralogs of Euglenozoa. Rheb evolution is thus surprisingly dynamic and presents a spectacular example of molecular tinkering.

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Section: Introductionmentioning

confidence: 99%

Extensive molecular tinkering in the evolution of the membrane attachment mode of the Rheb GTPase

Záhonová

Petrželková

Valach

et al. 2018

Sci Rep

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“…Phosphorylation of mTOR, a key downstream mediator of RTK/Ras signaling in the mTORC1 and mTORC2 complexes in the control of ribosome biogenesis and protein synthesis, has been repeatedly found in chordoma (32). The small GTPase Rheb activates mTORC1 and can act upon overexpression as a protooncogene (33,34). col2a1a:KalTA4 embryos injected with UAS:rheb developed notably larger vacuolated notochord cells ( Fig.…”

Section: Overexpression Of Rtk Genes Found Activated In Human Chordommentioning

confidence: 86%

Active Receptor Tyrosine Kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish

D'Agati

Cabello

Frontzek

et al. 2018

Preprint

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The aberrant activation of developmental processes triggers diverse cancer types. Chordoma is a rare, aggressive tumor arising from transformed notochord remnants. Several potentially oncogenic factors, including several receptor tyrosine kinase (RTK) genes, have been found deregulated in chordoma, yet causation remains uncertain. In particular, sustained expression of the developmental notochord transcription factor Brachyury is hypothesized as key driver of chordoma; nonetheless, experimental evidence for an oncogenic role of Brachyury in chordoma and its prognostic impact remains missing. Here, we developed and applied a zebrafish chordoma model to identify the notochord-transforming potential of implicated genes in vivo. We find that Brachyury, including a form with augmented transcriptional activity, is insufficient to initiate notochord hyperplasia. In contrast, the chordoma-implicated RTKs EGFR and KDR/VEGFR2 are sufficient to transform notochord cells within two to five days of development. Transcriptome and structural analysis of transformed notochords revealed that the aberrant activation of RTK/Ras signaling attenuates processes required for notochord differentiation, including of the unfolded protein response. Our results provide first in vivo indication against a tumor-initiating potential of Brachyury in the notochord, and imply activated RTK signaling as possibly initiating event in chordoma. These results provide a mechanistic framework for the pursuit of chemotherapeutic compounds to combat this aggressive tumor type.

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“…To evaluate the impact of Insulin signaling reduction in neurons, we measure dRheb mRNA by qPCR. dRheb is the molecular link between insulin signaling pathway and TOR kinase, and it reflects the Insulin pathway activity (reviewed in (Armijo et al, 2016)): dRheb mRNA levels drop down when Insulin signaling is low (Garami et al, 2003). We analyzed dRheb expression levels in control and GB brains.…”

Section: Gb Secreted Impl2 Reduces Neuronal Insulin Signalingmentioning

confidence: 99%

Insulin signaling mediates neurodegeneration in glioma

Jarabo

Pablo

Herranz

et al. 2020

Preprint

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Cell to cell communication facilitates tissue development and physiology. Under pathological conditions, brain tumors disrupt glia-neuron communication signals in which in consequence, promotes tumor expansion at expenses of healthy tissue. The glioblastoma is the most aggressive and frequent brain tumor. This type of glioma expands and infiltrates in the brain, causing neuronal degeneration and neurological decay, among other symptoms. Here we describe how glioblastoma produce ImpL2, an antagonist of the insulin pathway, which is regulated by the microRNA miR-8. ImpL2 targets neighboring neurons and causes mitochondrial disruption as well as synapse loss, an early symptom of neurodegeneration. Furthermore, glioblastoma progression requires insulin pathway attenuation in neurons. Restoration of neuronal insulin activity is sufficient to rescue this synapse loss and delay the premature death caused by glioma. Therefore, signals from GB to neuron emerge as a potential field of study to prevent neurodegeneration and anti-tumoral strategies. A. (2006). Age-independent synaptogenesis by phosphoinositide 3 kinase.

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Rheb signaling and tumorigenesis: mTORC1 and new horizons

Cited by 27 publications

References 101 publications

Extensive molecular tinkering in the evolution of the membrane attachment mode of the Rheb GTPase

Extensive molecular tinkering in the evolution of the membrane attachment mode of the Rheb GTPase

Active Receptor Tyrosine Kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish

Insulin signaling mediates neurodegeneration in glioma

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