ArfGAP1 inhibits mTORC1 lysosomal localization and activation

Meng, Delong; Yang, Qianmei; Melick, Chase H.; Park, Brenden C.; Hsieh, Ting Sung; Curukovic, Adna; Jeong, Mi‐Hyeon; Zhang, Junmei; James, Nicholas G.; Jewell, Jenna L.

doi:10.15252/embj.2020106412

Cited by 20 publications

(11 citation statements)

References 76 publications

(152 reference statements)

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“…This process is dependent on ADP‐ribosylation factor GTPase‐activating protein 1 (ARFGAP1). ARFGAP1 binds to mTORC1 to stop lysosomal localisation in the absence of amino acids; overexpression of ARFGAP1 prevents the recruitment of mTORC1 to the lysosomal surface and inhibits downstream signalling, whereas the loss of ARFGAP1 promotes mTORC1 activity, even in the absence of amino acids [ 33 ].…”

Section: The Lysosomal Surface–the Home Of Mtorc1 Activationmentioning

confidence: 99%

The mTOR–lysosome axis at the centre of ageing

et al. 2021

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Age‐related diseases represent some of the largest unmet clinical needs of our time. While treatment of specific disease‐related signs has had some success (for example, the effect of statin drugs on slowing progression of atherosclerosis), slowing biological ageing itself represents a target that could significantly increase health span and reduce the prevalence of multiple age‐related diseases. Mechanistic target of rapamycin complex 1 (mTORC1) is known to control fundamental processes in ageing: inhibiting this signalling complex slows biological ageing, reduces age‐related disease pathology and increases lifespan in model organisms. How mTORC1 inhibition achieves this is still subject to ongoing research. However, one mechanism by which mTORC1 inhibition is thought to slow ageing is by activating the autophagy–lysosome pathway. In this review, we examine the special bidirectional relationship between mTORC1 and the lysosome. In cells, mTORC1 is located on lysosomes. From this advantageous position, it directly controls the autophagy–lysosome pathway. However, the lysosome also controls mTORC1 activity in numerous ways, creating a special two‐way relationship. We then explore specific examples of how inhibition of mTORC1 and activation of the autophagy–lysosome pathway slow the molecular hallmarks of ageing. This body of literature demonstrates that the autophagy–lysosome pathway represents an excellent target for treatments that seek to slow biological ageing and increase health span in humans.

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Section: The Lysosomal Surface–the Home Of Mtorc1 Activationmentioning

confidence: 99%

The mTOR–lysosome axis at the centre of ageing

et al. 2021

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“…Two highly connected subgraphs are obtained as shown in Figure 3, which include the following 14 genes: ITG1, HSPA5, ACTB, ATP5F1B, CCT5, GAPDH, ARPC1A, GNA12, ARFGAP1, INS, CDC42, BSG, ARFGAP3, and ARF1. Among these 14 genes, it has recently been reported that ARFGAP1 is a predictive factor for pancreatic cancer [38], and GAPDH has been used as a reference gene in fetal rat pancreas analysis [39]. In Figure S2.4 in Supplementary Additional File 2, only the androgen receptor (AR) transcription factor was reported by Metascape.…”

Section: Resultsmentioning

confidence: 99%

A new machine learning based computational framework identifies therapeutic targets and unveils influential genes in pancreatic islet cells

Turki

Taguchi

2022

Preprint

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Pancreatic islets comprise a group of cells that produce hormones regulating blood glucose levels. Particularly, the alpha and beta islet cells produce glucagon and insulin to stabilize blood glucose. When beta islet cells are dysfunctional, insulin is not secreted, inducing a glucose metabolic disorder. Identifying effective therapeutic targets against the disease is a complicated task and is yet not conclusive. To close the wide gap between understanding the molecular mechanism of pancreatic islet cells and providing effective therapeutic targets, we present a computational framework to identify potential therapeutic targets against pancreatic disorders. First, we downloaded three transcriptome expression profiling datasets pertaining to pancreatic islet cells (GSE87375, GSE79457, GSE110154) from the Gene Expression Omnibus database. For each dataset, we extracted expression profiles for two cell types. We then provided the extracted expression profile along with the cell types to our proposed constrained optimization problem of a support vector machine and to other existing methods, selecting important genes from the expression profiles. Finally, we performed (1) an evaluation from a classification perspective showing the superiority of our methods against the baseline; and (2) an enrichment analysis showing that our methods achieved better outcomes. Results for the three datasets included 44 unique genes and 10 unique transcription factors (SP1, HDAC1, EGR1, E2F1, AR, STAT6, RELA, SP3, NFKB1, and ESR1) that have been reported related to pancreatic islet functions, diseases, and therapeutic targets.

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“…4 e). On the other hand, recent reports have revealed a novel role of Arf1 in mTORC1 activation on the amino acid sensing pathway 25 – 27 . Intriguingly, Arf1 plays an important role in the regulation of mTORC1 by glutamine and asparagine while the well-characterized Rag GTPase pathway mediates mTORC1 activation downstream of leucine, arginine, methionine, and some other amino acids 28 – 34 .…”

Section: Discussionmentioning

confidence: 99%

Arf1 facilitates mast cell proliferation via the mTORC1 pathway

Kotani

Sumiyoshi

Sasada

et al. 2022

Sci Rep

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Mast cells are one of major players in allergic responses. Mast cell activation via the high affinity IgE receptor (FcεRI) causes degranulation and release of de novo synthesized proinflammatory cytokines in a process that involves vesicle trafficking. Considering that the GTPase ADP-ribosylation factor 1 (Arf1) orchestrates and maintains membrane traffic and organelle structure, it seems likely that Arf1 contributes to mast cell activation. Actually, it has been reported that pharmaceutical blockade of the Arf1 pathway suppresses cytokine secretion and mast cell degranulation. However, physiological roles of Arf1 in mast cells remain elusive. Here, by using a genetic approach, we demonstrate that Arf1 is required for optimal mTORC1 activation upon IL-3 and facilitates mast cell proliferation. On the other hand, contrary to our expectation, Arf1-deficiency had little impact on FcεRI-induced degranulation nor cytokine secretion. Our findings reveal an unexpected role of Arf1 in mast cell expansion and its potential as a therapeutic target in the mast cell proliferative disorders.

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ArfGAP1 inhibits mTORC1 lysosomal localization and activation

Cited by 20 publications

References 76 publications

The mTOR–lysosome axis at the centre of ageing

The mTOR–lysosome axis at the centre of ageing

A new machine learning based computational framework identifies therapeutic targets and unveils influential genes in pancreatic islet cells

Arf1 facilitates mast cell proliferation via the mTORC1 pathway

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