The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB
Open accessAbstract
PKB/Akt, S6K1 and SGK are related protein kinases activated in a PI 3-kinase-dependent manner in response to insulin/growth factors signalling. Activation entails phosphorylation of these kinases at two residues, the T-loop and the hydrophobic motif. PDK1 activates S6K, SGK and PKB isoforms by phosphorylating these kinases at their T-loop. We demonstrate that a pocket in the kinase domain of PDK1, termed the 'PIF-binding pocket', plays a key role in mediating the interaction and phosphorylation of S6K1 and SGK1 at their T-loop motif by PDK1. Our data indicate that prior phosphorylation of S6K1 and SGK1 at their hydrophobic motif promotes their interaction with the PIF-binding pocket of PDK1 and their T-loop phosphorylation. Thus, the hydrophobic motif phosphorylation of S6K and SGK converts them into substrates that can be activated by PDK1. In contrast, the PIF-binding pocket of PDK1 is not required for the phosphorylation of PKBalpha by PDK1. The PIF-binding pocket represents a substrate recognition site on a protein kinase that is only required for the phosphorylation of a subset of its physiological substrates.
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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 Biondi et al., 2001
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References 33 · Cited by 377
Research works printed but not linked: 1
- Dennis,P.B., Pullen,N., Pearson,R.B., Kozma,S.C. and Thomas,G. (1998) Phosphorylation sites in the autoinhibitory domain participate in p70(s6k) activation loop phosphorylation. J. Biol. Chem., 273, 14845±14852.
- Authors
- Biondi, R. M., Kieloch, A., Currie, R. A., Deak, M., & Alessi, D. R.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- Biondi, Ricardo M.
- Venue
- The EMBO Journal
- Published
- 2001-08-15
- Volume
- 20
- Issue
- 16
- Pages
- 4380-4390
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC125563
- OpenAlex
- W2142060283
- Cited by
- 377
- References
- 33
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 7 · 2023: 8 · 2022: 9 · 2021: 4 · 2020: 10 · 2019: 16 · 2018: 4 · 2017: 9 · 2016: 11 · 2015: 17 · 2014: 18 · 2013: 13 · 2012: 18
- FWCI
- 7.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- GlaxoSmithKline
- University of Dundee
- Diabetes UK
- Medical Research Council
- 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
- PDK1, S6K1, SGK1, T-loop phosphorylation, substrate recognition, kinase activation, insulin signaling, growth factor signaling, substrate specificity
- MeSH terms
- Serum-Glucocorticoid Regulated Kinases, Alanine, Amino Acid Sequence, Binding Sites, Enzyme Activation, Glutamine, Isoleucine, Lysine, Molecular Sequence Data, Nuclear Proteins, Phosphorylation, Proto-Oncogene Proteins, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Ribosomal Protein S6 Kinases, Amino Acid Motifs, Proto-Oncogene Proteins c-akt, 3-Phosphoinositide-Dependent Protein Kinases
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