mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1)
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SGK1 (serum- and glucocorticoid-induced protein kinase 1) is a member of the AGC (protein kinase A/protein kinase G/protein kinase C) family of protein kinases and is activated by agonists including growth factors. SGK1 regulates diverse effects of extracellular agonists by phosphorylating regulatory proteins that control cellular processes such as ion transport and growth. Like other AGC family kinases, activation of SGK1 is triggered by phosphorylation of a threonine residue within the T-loop of the kinase domain and a serine residue lying within the C-terminal hydrophobic motif (Ser422 in SGK1). PDK1 (phosphoinositide-dependent kinase 1) phosphorylates the T-loop of SGK1. The identity of the hydrophobic motif kinase is unclear. Recent work has established that mTORC1 [mTOR (mammalian target of rapamycin) complex 1] phosphorylates the hydrophobic motif of S6K (S6 kinase), whereas mTORC2 (mTOR complex 2) phosphorylates the hydrophobic motif of Akt (also known as protein kinase B). In the present study we demonstrate that SGK1 hydrophobic motif phosphorylation and activity is ablated in knockout fibroblasts possessing mTORC1 activity, but lacking the mTORC2 subunits rictor (rapamycin-insensitive companion of mTOR), Sin1 (stress-activated-protein-kinase-interacting protein 1) or mLST8 (mammalian lethal with SEC13 protein 8). Furthermore, phosphorylation of NDRG1 (N-myc downstream regulated gene 1), a physiological substrate of SGK1, was also abolished in rictor-, Sin1- or mLST8-deficient fibroblasts. mTORC2 immunoprecipitated from wild-type, but not from mLST8- or rictor-knockout cells, phosphorylated SGK1 at Ser422. Consistent with mTORC1 not regulating SGK1, immunoprecipitated mTORC1 failed to phosphorylate SGK1 at Ser422, under conditions which it phosphorylated the hydrophobic motif of S6K. Moreover, rapamycin treatment of HEK (human embryonic kidney)-293, MCF-7 or HeLa cells suppressed phosphorylation of S6K, without affecting SGK1 phosphorylation or activation. The findings of the present study indicate that mTORC2, but not mTORC1, plays a vital role in controlling the hydrophobic motif phosphorylation and activity of SGK1. Our findings may explain why in previous studies phosphorylation of substrates, such as FOXO (forkhead box O), that could be regulated by SGK, are reduced in mTORC2-deficient cells. The results of the present study indicate that NDRG1 phosphorylation represents an excellent biomarker for mTORC2 activity.
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Activation of SGK1 involves mTORC2 phosphorylating Ser422, followed by PDK1 transferring phosphate to Thr256, which phosphorylates the activation loop and enlarges the ATP-binding site.
“In the activation process of SGK1, extracellular stimuli induce the activation of mTORC2, which phosphorylates Ser422 on SGK1’s hydrophobic motif (Garcia-Martinez and Alessi, 2008). Subsequently, 3-Phosphoinositide-Dependent Protein Kinase-1 (PDK1) is recruited to the phosphorylated Ser, leading to the transfer of a phosphate group to Thr256 within the kinase domain of SGK1 (Biondi et al., 2001),”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Garcia-Martinez and Alessi, 2008
SGK1 activation is a multi-step process involving initial phosphorylation at Ser422 by mTORC2 and subsequent phosphorylation at Thr256 by PDK1.
“SGK1 activation is a multi-step process involving initial phosphorylation at Ser422 by mTORC2 and subsequent phosphorylation at Thr256 by PDK1”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Garcia-Martinez and Alessi, 2008
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- Authors
- García-Martínez, J. M., & Alessi, D. R.
- Affiliations
- MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
- University of Dundee (GB)
- ORCID
- Alessi, Dario R.
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2008-11-26
- Volume
- 416
- Issue
- 3
- Pages
- 375-385
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W1992170852
- Cited by
- 907
- References
- 4
- Citations by year
- 2026: 17 · 2025: 19 · 2024: 24 · 2023: 39 · 2022: 46 · 2021: 40 · 2020: 61 · 2019: 55 · 2018: 54 · 2017: 54 · 2016: 50 · 2015: 64 · 2014: 68 · 2013: 65 · 2012: 76
- FWCI
- 24.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, other-oa)
- 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 › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mTORC2, Rictor, SIN-1, mLST8, NDRG1, mTORC1, AGC kinase family, S6 kinase, Akt, rapamycin, kinase activation, mTOR signaling
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Rapamycin-Insensitive Companion of mTOR Protein, Serum-Glucocorticoid Regulated Kinases, Animals, Antibiotics, Antineoplastic, Carrier Proteins, Cell Line, Fibroblasts, Humans, Phosphorylation, Proteins, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Mice, Knockout, Protein Isoforms, Sirolimus, Amino Acid Motifs, Protein Subunits, Multiprotein Complexes, Mice, TOR Serine-Threonine Kinases
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