The Late Endosome is Essential for mTORC1 Signaling

Flinn, Rory; Yan, Ying; Goswami, Sumanta; Parker, Peter J.; Backer, Jonathan M.

doi:10.1091/mbc.e09-09-0756

Cited by 149 publications

(139 citation statements)

References 57 publications

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“…PAO-induced mTORC1 Activation Is Independent of RagRagulator System-Translocation of mTORC1 to lysosomes is a critical step for amino acid-induced mTORC1 activation, where Ragulator (MP1⅐p14⅐p18 complex) plays a crucial role in anchoring Rag small GTPases on the lysosomal membrane (11,12,46). Sancak et al (12) showed that amino acid stimulation failed to induce S6K phosphorylation and mTOR translocation to the lysosome in Ragulator-deficient cells.…”

Section: Mtorc1 But Not Mtorc2 Is Activated By Cysteinementioning

confidence: 99%

Redox Regulates Mammalian Target of Rapamycin Complex 1 (mTORC1) Activity by Modulating the TSC1/TSC2-Rheb GTPase Pathway

Yoshida¹,

Hong²,

Suzuki³

et al. 2011

Journal of Biological Chemistry

131

115

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Mammalian target of rapamycin (mTOR) is a kinase that plays a key role in a wide array of cellular processes and exists in two distinct functional complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Although mTORC2 is primarily activated by growth factors, mTORC1 is regulated by numerous extracellular and intracellular signals such as nutrients, growth factors, and cellular redox. Previous study has shown that cysteine oxidants sufficiently activate mTORC1 activity under amino acid-depleted conditions and that a reducing agent effectively suppresses amino acid-induced mTORC1 activity, thereby raising the possibility that redox-sensitive mechanisms underlie amino acid-dependent mTORC1 regulation. However, the molecular mechanism by which redox regulates mTORC1 activity is not well understood. In this study, we show that the redox-sensitive regulation of mTORC1 occurs via Rheb but not the Rag small GTPase. Enhancing cellular redox potential with cysteine oxidants significantly increases Rheb GTP levels. Importantly, modulation of the cellular redox potential with a cysteine oxidant or reducing agent failed to alter mTORC1 activity in TSC1 ؊/؊ or TSC2 ؊/؊ mouse embryonic fibroblast cells. Furthermore, a cysteine oxidant has little effect on mTOR localization but sufficiently activates mTORC1 activity in both p18 ؊/؊ and control mouse embryonic fibroblast cells, suggesting that the redox-sensitive regulation of mTORC1 occurs independent of the Ragulator⅐Rag complex. Taken together, our results suggest that the TSC complex plays an important role in redox-sensitive mTORC1 regulation and argues for the activation of mTORC1 in places other than the lysosome upon inhibition of the TSC complex.The mammalian target of rapamycin (mTOR) 2 belongs to the family of phosphatidylinositol 3-kinase (PI3K)-related kinases and shares high sequence similarity to PI3K despite possessing protein kinase activity (1). mTOR is an evolutionarily conserved protein kinase that forms two distinct functional complexes termed mTOR complex 1 and mTOR complex 2 (mTORC1 and mTORC2, respectively) (2-4). mTORC1 is known to be a rapamycin-sensitive complex that regulates a wide array of cellular processes such as cell growth and autophagy, whereas mTORC2 is known to be rapamycin-resistant and involved in the regulation of cell survival as well as cytoskeletal reorganization. Although mTORC2 activation is primarily mediated by growth factors, mTORC1 activation can be achieved by multiple inputs such as amino acids, growth factors, glucose, and oxidative stress (5, 6).Recent studies have shown that two small GTPases, Rheb and Rag, play an essential role in the regulation of mTORC1 activation (7-10). Rheb interacts with and activates mTORC1, whereas Rag small GTPases function as essential spatial regulators of mTORC1 localization (8, 11-13). The Rag small GTPases function as heterodimers formed between RagA/B and RagC/D and bind to the MP1⅐p14⅐p18 complex (Ragulator), which is predominantly expressed on the lysosomal membrane (12,14). Upon ...

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Section: Mtorc1 But Not Mtorc2 Is Activated By Cysteinementioning

confidence: 99%

Redox Regulates Mammalian Target of Rapamycin Complex 1 (mTORC1) Activity by Modulating the TSC1/TSC2-Rheb GTPase Pathway

Yoshida¹,

Hong²,

Suzuki³

et al. 2011

Journal of Biological Chemistry

131

115

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“…Kinesin family member (KIF) 2A is one of a handful of kinesins that apparently do not transport cargo, but instead depolymerize microtubules. In HeLa cells, KIF2A was shown to regulate the location of lysosomes in the cytoplasm, which is thought to be essential for mTORC1 activation (15)(16)(17)(18). We find that KIF2A and the closely related kinesin KIF2C (also known as MCAK) also control lysosomal organization in human bronchial epithelial cells.…”

mentioning

confidence: 69%

Ras transformation uncouples the kinesin-coordinated cellular nutrient response

Zaganjor¹,

Weil²,

Gonzales³

et al. 2014

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

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The kinesin family members (KIFs) KIF2A and KIF2C depolymerize microtubules, unlike the majority of other kinesins, which transport cargo along microtubules. KIF2A regulates the localization of lysosomes in the cytoplasm, which assists in activation of the mechanistic target of rapamycin complex 1 (mTORC1) on the lysosomal surface. We find that the closely related kinesin KIF2C also influences lysosomal organization in immortalized human bronchial epithelial cells (HBECs). Expression of KIF2C and, to a lesser extent, KIF2A in untransformed and mutant K-Ras-transformed cells is regulated by ERK1/2. Prolonged inhibition of ERK1/2 activation with PD0325901 mimics nutrient deprivation by disrupting lysosome organization and decreasing mTORC1 activity in HBEC, suggesting a long-term mechanism for optimization of mTORC1 activity by ERK1/2. We tested the hypothesis that up-regulation of KIF2C and KIF2A by ERK1/2 caused aberrant lysosomal positioning and mTORC1 activity in a mutant K-Ras-dependent cancer and cancer model. In Ras-transformed cells, however, mTORC1 activity and lysosome organization appear independent of ERK1/2 and these kinesins although ERK1/2 activity and the kinesins are required for Ras-dependent proliferation and migration. We conclude that mutant K-Ras repurposes these signaling and regulatory proteins to support the transformed phenotype.

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“…Alternatively, like LRS, SH3BP4 could act as a leucine sensor in different cellular compartments. Amino acids were able to affect cellular localization of mTORC1, which depended on vesicle trafficking proteins (Flinn et al, 2010;Hennig et al, 2006;Li et al, 2010;Sancak et al, 2008). The function of SH3BP4 to regulate vesicular trafficking might be important for mTORC1 regulation in response to amino acids.…”

Section: How Sh3bp4 Function Is Regulatedmentioning

confidence: 99%

“…Vam6p binds to Gtr1p and acts as a guanine nucleotide exchange factor (GEF) for Gtr1p (Binda et al, 2009), thus positively regulating amino acid-TORC1 signaling. In HeLa cells, knockdown of hVps39, the mammalian ortholog of Vam6p, suppressed the activation of mTORC1 by amino acids and insulin (Flinn et al, 2010). Whether the suppression is due to inhibition of Rag GTPases needs further investigation.…”

Section: Vam6p Is a Gef For Gtr1 Gtpasementioning

confidence: 99%