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Cited by 300PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerMuscle metabolism and nutrition

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The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling

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Yoon, Mee-Sup·2017·Nutrients
DOI 10.3390/nu9111176PMC PMC5707648
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Abstract

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that controls a wide spectrum of cellular processes, including cell growth, differentiation, and metabolism. mTOR forms two distinct multiprotein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are characterized by the presence of raptor and rictor, respectively. mTOR controls insulin signaling by regulating several downstream components such as growth factor receptor-bound protein 10 (Grb10), insulin receptor substrate (IRS-1), F-box/WD repeat-containing protein 8 (Fbw8), and insulin like growth factor 1 receptor/insulin receptor (IGF-IR/IR). In addition, mTORC1 and mTORC2 regulate each other through a feedback loop to control cell growth. This review outlines the current understanding of mTOR regulation in insulin signaling in the context of whole body metabolism.

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Figure 1 mTORC1 and mTORC2. mTOR is a serine/threonine kinase that forms two biochemically and functionally distinct complexes. mTORC1 consists of mTOR, raptor, mLST8 and the two inhibitory subunits, PRAS40 and DEPTOR, whereas mTORC2 consists of mTOR, rictor, mLST8, PRR5, SIN1 and the inhibitory subunit, DEPTOR. mTORC1 senses mitogens, oxygen levels, intracellular energy status, and amino acids to promote cell growth by regulating anabolic and catabolic processes. mTORC2 is activated by mitogen and controls cell survival, metabolism, and cytoskeletal organization. The inhibitory subunits in mTOR complexes are not presented here (PRAS40, DEPTOR). mTOR; mammalian target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; mLST8, mammalian lethal with Sec13 protein 8; PRR5, proline-rich protein 5; SIN1, stress-activated map kinase-interacting protein 1; PRAS40, proline-rich Akt substrate of 40 kDa; DEPTOR, DEP domain-containing mTOR-interacting protein.
Figure 1 mTORC1 and mTORC2. mTOR is a serine/threonine kinase that forms two biochemically and functionally distinct complexes. mTORC1 consists of mTOR, raptor, mLST8 and the two inhibitory subunits, PRAS40 and DEPTOR, whereas mTORC2 consists of mTOR, rictor, mLST8, PRR5, SIN1 and the inhibitory subunit, DEPTOR. mTORC1 senses mitogens, oxygen levels, intracellular energy status, and amino acids to promote cell growth by regulating anabolic and catabolic processes. mTORC2 is activated by mitogen and controls cell survival, metabolism, and cytoskeletal organization. The inhibitory subunits in mTOR complexes are not presented here (PRAS40, DEPTOR). mTOR; mammalian target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; mLST8, mammalian lethal with Sec13 protein 8; PRR5, proline-rich protein 5; SIN1, stress-activated map kinase-interacting protein 1; PRAS40, proline-rich Akt substrate of 40 kDa; DEPTOR, DEP domain-containing mTOR-interacting protein.CC BY · PubMed Central
Figure 2 Negative feedback regulation of insulin receptor substrate (IRS) by rapamycin complex 1 (mTORC1) Activated mTORC1/S6K1 inhibits IRS-1 by phosphorylating serine residues. mTOR phosphorylates mouse (m)S632 (human (h)S636), mS307 (hS312), and mS612 (hS616), and S6K1 phosphorylates mS302 (hS307), mS522 (hS527), mS265 (hS270), and mS1097 (hS1101). mTORC1 phosphorylates and stabilizes Grb10, which inhibits the interaction between IRS and the phosphorylated tyrosine of IR. Akt indirectly activates mTORC1 by phosphorylating tuberous sclerosis complex (TSC) and PRAS40. The gray images are mTORC1 targets in insulin signaling. The red line represents negative regulation. S6K1, ribosomal protein S6 kinase 1; pY, phosphotyrosine; pS, phosphoserine; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol (3,4,5)-triphosphate; PDK1, 3-phosphoinositide-dependent protein kinase 1; pT, phosphothreonine; Akt, protein kinase B (PKB); GRB10, growth factor receptor-bound protein 10; PRAS40, proline-rich AKT substrate of 40 kDa; RHEB, RAS homolog enriched in the brain.
Figure 2 Negative feedback regulation of insulin receptor substrate (IRS) by rapamycin complex 1 (mTORC1) Activated mTORC1/S6K1 inhibits IRS-1 by phosphorylating serine residues. mTOR phosphorylates mouse (m)S632 (human (h)S636), mS307 (hS312), and mS612 (hS616), and S6K1 phosphorylates mS302 (hS307), mS522 (hS527), mS265 (hS270), and mS1097 (hS1101). mTORC1 phosphorylates and stabilizes Grb10, which inhibits the interaction between IRS and the phosphorylated tyrosine of IR. Akt indirectly activates mTORC1 by phosphorylating tuberous sclerosis complex (TSC) and PRAS40. The gray images are mTORC1 targets in insulin signaling. The red line represents negative regulation. S6K1, ribosomal protein S6 kinase 1; pY, phosphotyrosine; pS, phosphoserine; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol (3,4,5)-triphosphate; PDK1, 3-phosphoinositide-dependent protein kinase 1; pT, phosphothreonine; Akt, protein kinase B (PKB); GRB10, growth factor receptor-bound protein 10; PRAS40, proline-rich AKT substrate of 40 kDa; RHEB, RAS homolog enriched in the brain.CC BY · PubMed Central
Figure 3 The role of mTOR in insulin induced metabolic processes. The postprandial increase of insulin activates protein kinase B (PKB, also known as Akt) through PDK1and mTORC2. Akt activates mTORC1 by phosphorylating TSC1/2. Activated mTORC1 phosphorylates IRS-1, leading to negative feedback regulation of block insulin signaling. mTORC1 and mTORC2 promote lipogenesis by regulating SREBP. mTORC1 enhances lipid storage, whereas it inhibits lipolysis, β-oxidation, and ketogenesis. In addition, mTORC2 promotes glycogen synthesis and decreases gluconeogenesis. The blue line represents positive regulation, and the red line represents negative regulation. The detailed regulation is indicated in the text. PDK-1; 3-phosphoinositide-dependent protein kinase 1, SREBP; sterol regulatory element-binding protein.
Figure 3 The role of mTOR in insulin induced metabolic processes. The postprandial increase of insulin activates protein kinase B (PKB, also known as Akt) through PDK1and mTORC2. Akt activates mTORC1 by phosphorylating TSC1/2. Activated mTORC1 phosphorylates IRS-1, leading to negative feedback regulation of block insulin signaling. mTORC1 and mTORC2 promote lipogenesis by regulating SREBP. mTORC1 enhances lipid storage, whereas it inhibits lipolysis, β-oxidation, and ketogenesis. In addition, mTORC2 promotes glycogen synthesis and decreases gluconeogenesis. The blue line represents positive regulation, and the red line represents negative regulation. The detailed regulation is indicated in the text. PDK-1; 3-phosphoinositide-dependent protein kinase 1, SREBP; sterol regulatory element-binding protein.CC BY · PubMed Central

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Metadata

Authors
Yoon, M.-S.
Affiliations
Gachon University (KR)
Corresponding author
Yoon, Mee-Sup
ORCID
Yoon, Mee-Sup
Venue
Nutrients
Publisher
MDPI AG
Published
2017-10-27
Volume
9
Issue
11
Pages
1176
ISSN
2072-6643 (ISSN-L)
DOI
10.3390/nu9111176
PMC
PMC5707648
OpenAlex
W2766921609
Cited by
300
References
142
Citations by year
2026: 17 · 2025: 33 · 2024: 28 · 2023: 30 · 2022: 47 · 2021: 46 · 2020: 43 · 2019: 34 · 2018: 20
FWCI
2.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Nutrients (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2015R1D1A1A01058313)
  • the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (HI17C0426)
  • the Gachon University Gil Medical Center (2015-15)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
Keywords
mTOR, insulin signaling, mTORC1, mTORC2, raptors, Rictor, Grb10, IRS-1, IGF-1 receptor, insulin receptor, cell growth regulation, whole-body metabolism, feedback loops
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Regulatory-Associated Protein of mTOR, Mechanistic Target of Rapamycin Complex 2, Rapamycin-Insensitive Companion of mTOR Protein, Animals, Humans, Insulin, Receptor, Insulin, Signal Transduction, Receptor, IGF Type 1, F-Box Proteins, Cell Proliferation, GRB10 Adaptor Protein, Insulin Receptor Substrate Proteins, TOR Serine-Threonine Kinases

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