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Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity.

Carroll B, Maetzel D, Maddocks OD, Otten G, Ratcliff M, Smith GR, Dunlop EA, Passos JF, Davies OR, Jaenisch R, Tee AR, Sarkar S, Korolchuk VI - Elife (2016)

Bottom Line: Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes.Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling.Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom.

ABSTRACT
The mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that regulates cellular protein homeostasis, growth, and proliferation in health and disease. As a prerequisite for activation of mTORC1 by hormones and mitogens, there first has to be an available pool of intracellular amino acids. Arginine, an amino acid essential during mammalian embryogenesis and early development is one of the key activators of mTORC1. Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine cooperates with growth factor signaling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling. Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling.

No MeSH data available.


Related in: MedlinePlus

A model of amino acid-dependent mTORC1 regulation.Amino acids, most notably leucine activates mTORC1 via Rag GTPases and recruitment of mTOR to lysosomes. Arginine cooperates with growth factors to prevent interaction between TSC and Rheb on lysosomes which allows interaction between Rheb and mTORC1. See text for further details.DOI:http://dx.doi.org/10.7554/eLife.11058.017
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fig6: A model of amino acid-dependent mTORC1 regulation.Amino acids, most notably leucine activates mTORC1 via Rag GTPases and recruitment of mTOR to lysosomes. Arginine cooperates with growth factors to prevent interaction between TSC and Rheb on lysosomes which allows interaction between Rheb and mTORC1. See text for further details.DOI:http://dx.doi.org/10.7554/eLife.11058.017

Mentions: Leucine and arginine represent the major contributors to amino acid-dependent mTORC1 activity. While the role of leucine, together with glutamine, in Rag-dependent activation of mTORC1 has been the subject of intense investigations, the role of arginine in mTORC1 activation has remained relatively understudied. Arginine can contribute to mTORC1 activity via the canonical amino acid sensing, Ragulator/Rag signaling pathway via the recently characterized low-affinity amino acid transporter SLC38A9 (Wang et al., 2015; Rebsamen et al., 2015; Jung et al., 2015). Our data suggest that arginine also works via the parallel, TSC2-Rheb signaling axis upstream of mTORC1 and stimulation of both inputs is required for the maximal activation of this signaling pathway (Figure 6). In particular, we show that arginine cooperates with growth factors and acts as a permissive factor for their activation of mTORC1. Growth factors and arginine interfere with the TSC2-Rheb interaction; while Akt-mediated growth factor signaling phosphorylates TSC2, arginine does not affect phosphorylation of Akt, at least on the sites tested in this study. Instead, arginine appears to act as an intact molecule at a site more proximal to the TSC2-Rheb interaction, whether acting directly or via a putative sensor molecule.10.7554/eLife.11058.017Figure 6.A model of amino acid-dependent mTORC1 regulation.


Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity.

Carroll B, Maetzel D, Maddocks OD, Otten G, Ratcliff M, Smith GR, Dunlop EA, Passos JF, Davies OR, Jaenisch R, Tee AR, Sarkar S, Korolchuk VI - Elife (2016)

A model of amino acid-dependent mTORC1 regulation.Amino acids, most notably leucine activates mTORC1 via Rag GTPases and recruitment of mTOR to lysosomes. Arginine cooperates with growth factors to prevent interaction between TSC and Rheb on lysosomes which allows interaction between Rheb and mTORC1. See text for further details.DOI:http://dx.doi.org/10.7554/eLife.11058.017
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4764560&req=5

fig6: A model of amino acid-dependent mTORC1 regulation.Amino acids, most notably leucine activates mTORC1 via Rag GTPases and recruitment of mTOR to lysosomes. Arginine cooperates with growth factors to prevent interaction between TSC and Rheb on lysosomes which allows interaction between Rheb and mTORC1. See text for further details.DOI:http://dx.doi.org/10.7554/eLife.11058.017
Mentions: Leucine and arginine represent the major contributors to amino acid-dependent mTORC1 activity. While the role of leucine, together with glutamine, in Rag-dependent activation of mTORC1 has been the subject of intense investigations, the role of arginine in mTORC1 activation has remained relatively understudied. Arginine can contribute to mTORC1 activity via the canonical amino acid sensing, Ragulator/Rag signaling pathway via the recently characterized low-affinity amino acid transporter SLC38A9 (Wang et al., 2015; Rebsamen et al., 2015; Jung et al., 2015). Our data suggest that arginine also works via the parallel, TSC2-Rheb signaling axis upstream of mTORC1 and stimulation of both inputs is required for the maximal activation of this signaling pathway (Figure 6). In particular, we show that arginine cooperates with growth factors and acts as a permissive factor for their activation of mTORC1. Growth factors and arginine interfere with the TSC2-Rheb interaction; while Akt-mediated growth factor signaling phosphorylates TSC2, arginine does not affect phosphorylation of Akt, at least on the sites tested in this study. Instead, arginine appears to act as an intact molecule at a site more proximal to the TSC2-Rheb interaction, whether acting directly or via a putative sensor molecule.10.7554/eLife.11058.017Figure 6.A model of amino acid-dependent mTORC1 regulation.

Bottom Line: Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes.Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling.Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom.

ABSTRACT
The mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that regulates cellular protein homeostasis, growth, and proliferation in health and disease. As a prerequisite for activation of mTORC1 by hormones and mitogens, there first has to be an available pool of intracellular amino acids. Arginine, an amino acid essential during mammalian embryogenesis and early development is one of the key activators of mTORC1. Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine cooperates with growth factor signaling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling. Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling.

No MeSH data available.


Related in: MedlinePlus