mTOR complex 1 activity is required to maintain the canonical endocytic recycling pathway against lysosomal delivery

Dauner, Kristin; Eid, Walaa; Raghupathy, Riya; Presley, John F.; Zha, Xiaohui

doi:10.1074/jbc.m116.771451

Cited by 26 publications

(19 citation statements)

References 24 publications

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“…Despite a slight mRNA increase, a significant decrease in protein expression supports the evidence that mTOR blockade impairs receptor recycling and directs EGFR to the degradative route. This observation is in line with the literature data demonstrating that mTOR activity is necessary for the recycling route of Transferrin receptors and plasma membrane lipids [ 41 ]. Indeed, mTORC1 inactivation reduces the expression of hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a component of Endosomal Sorting Complex Required for Transport (ESCRT), which is crucial for lysosomal targeting of ubiquitylated cargoes [ 41 ].…”

Section: Discussionsupporting

confidence: 93%

“…This observation is in line with the literature data demonstrating that mTOR activity is necessary for the recycling route of Transferrin receptors and plasma membrane lipids [ 41 ]. Indeed, mTORC1 inactivation reduces the expression of hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a component of Endosomal Sorting Complex Required for Transport (ESCRT), which is crucial for lysosomal targeting of ubiquitylated cargoes [ 41 ]. This event leads to transferrin receptors and sphingomyelin delivery to lysosomes, independently of canonical autophagy.…”

Section: Discussionsupporting

confidence: 93%

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mTOR Inhibition Leads to Src-Mediated EGFR Internalisation and Degradation in Glioma Cells

Colella

Colardo

Iannone

et al. 2020

Cancers

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Epidermal Growth Factor receptor (EGFR) is a tyrosine kinase receptor widely expressed on the surface of numerous cell types, which activates several downstream signalling pathways involved in cell proliferation, migration and survival. EGFR alterations, such as overexpression or mutations, have been frequently observed in several cancers, including glioblastoma (GBM), and are associated to uncontrolled cell proliferation. Here we show that the inhibition of mammalian target of Rapamycin (mTOR) mediates EGFR delivery to lysosomes for degradation in GBM cells, independently of autophagy activation. Coherently with EGFR internalisation and degradation, mTOR blockade negatively affects the mitogen activated protein/extracellular signal-regulated kinase (MAPK)/ERK pathway. Furthermore, we provide evidence that Src kinase activation is required for EGFR internaliation upon mTOR inhibition. Our results further support the hypothesis that mTOR targeting may represent an effective therapeutic strategy in GBM management, as its inhibition results in EGFR degradation and in proliferative signal alteration.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

mTOR Inhibition Leads to Src-Mediated EGFR Internalisation and Degradation in Glioma Cells

Colella

Colardo

Iannone

et al. 2020

Cancers

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“…There are also many additional examples of mTORC1 impacting the endocytosis and subsequent intracellular membrane traffic of specific proteins in various cell types and conditions, establishing mTORC1 as a versatile regulator that coordinates endocytic traffic with nutrient availability. For example, mTORC1 controls expression of the endosomal sorting adaptor Hrs, which in turn controls the recycling of transferrin receptor and sphingomyelin . In fruit fly pupal wing epithelial cells, apical endocytosis is controlled by mTORC1 signaling .…”

Section: Mtorc1 Coordinates Endocytic Membrane Traffic With Nutrient mentioning

confidence: 99%

Energetic adaptations: Metabolic control of endocytic membrane traffic

Rahmani

Defferrari

Wakarchuk

et al. 2019

Traffic

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Endocytic membrane traffic controls the access of myriad cell surface proteins to the extracellular milieu, and thus gates nutrient uptake, ion homeostasis, signaling, adhesion and migration. Coordination of the regulation of endocytic membrane traffic with a cell's metabolic needs represents an important facet of maintenance of homeostasis under variable conditions of nutrient availability and metabolic demand. Many studies have revealed intimate regulation of endocytic membrane traffic by metabolic cues, from the specific control of certain receptors or transporters, to broader adaptation or remodeling of the endocytic membrane network. We examine how metabolic sensors such as AMP‐activated protein kinase, mechanistic target of rapamycin complex 1 and hypoxia inducible factor 1 determine sufficiency of various metabolites, and in turn modulate cellular functions that includes control of endocytic membrane traffic. We also examine how certain metabolites can directly control endocytic traffic proteins, such as the regulation of specific protein glycosylation by limiting levels of uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) produced by the hexosamine biosynthetic pathway. From these ideas emerge a growing appreciation that endocytic membrane traffic is orchestrated by many intrinsic signals derived from cell metabolism, allowing alignment of the functions of cell surface proteins with cellular metabolic requirements. Endocytic membrane traffic determines how cells interact with their environment, thus defining many aspects of nutrient uptake and energy consumption. We examine how intrinsic signals that reflect metabolic status of a cell regulate endocytic traffic of specific proteins, and, in some cases, exert broad control of endocytic membrane traffic phenomena. Hence, endocytic traffic is versatile and adaptable and can be modulated to meet the changing metabolic requirements of a cell.

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“…Low mTORC1 activity triggers autophagy (8) and also reroutes cholesterol-rich endosomes, which are normally recycled (9), to lysosomes (10,11). From there, amino acids and membrane components, including cholesterol, can be released for reuse.…”

mentioning

confidence: 99%

mTORC1 activates SREBP-2 by suppressing cholesterol trafficking to lysosomes in mammalian cells

Eid

Dauner

Courtney

et al. 2017

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

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107

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mTORC1 is known to activate sterol regulatory element-binding proteins (SREBPs) including SREBP-2, a master regulator of cholesterol synthesis. Through incompletely understood mechanisms, activated mTORC1 triggers translocation of SREBP-2, an endoplasmic reticulum (ER) resident protein, to the Golgi where SREBP-2 is cleaved to translocate to the nucleus and activate gene expression for cholesterol synthesis. Low ER cholesterol is a well-established trigger for SREBP-2 activation. We thus investigated whether mTORC1 activates SREBP-2 by reducing cholesterol delivery to the ER. We report here that mTORC1 activation is accompanied by low ER cholesterol and an increase of SREBP-2 activation. Conversely, a decrease in mTORC1 activity coincides with a rise in ER cholesterol and a decrease in SERBP-2 activity. This rise in ER cholesterol is of lysosomal origin: blocking the exit of cholesterol from lysosomes by U18666A or NPC1 siRNA prevents ER cholesterol from increasing and, consequently, SREBP-2 is activated without mTORC1 activation. Furthermore, when mTORC1 activity is low, cholesterol is delivered to lysosomes through two membrane trafficking pathways: autophagy and rerouting of endosomes to lysosomes. Indeed, with dual blockade of both pathways by Atg5and dominant-negative rab5, ER cholesterol fails to increase when mTORC1 activity is low, and SREBP-2 is activated. Conversely, overexpressing constitutively active Atg7, which forces autophagy and raises ER cholesterol even when mTORC1 activity is high, suppresses SREBP-2 activation. We conclude that mTORC1 actively suppresses autophagy and maintains endosomal recycling, thereby preventing endosomes and autophagosomes from reaching lysosomes. This results in a reduction of cholesterol in the ER and activation of SREBP-2. mTORC1 | SREBP-2 | cholesterol | autophagy | endosomal recycling

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mTOR complex 1 activity is required to maintain the canonical endocytic recycling pathway against lysosomal delivery

Cited by 26 publications

References 24 publications

mTOR Inhibition Leads to Src-Mediated EGFR Internalisation and Degradation in Glioma Cells

mTOR Inhibition Leads to Src-Mediated EGFR Internalisation and Degradation in Glioma Cells

Energetic adaptations: Metabolic control of endocytic membrane traffic

mTORC1 activates SREBP-2 by suppressing cholesterol trafficking to lysosomes in mammalian cells

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