Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 (SGK-1)
Open accessAbstract
The serum and glucocorticoid-induced protein kinase gene (sgk-1) encodes a multifunctional kinase that can be phosphorylated and activated through a phosphatidylinositol 3-kinase-dependent signaling pathway. In many cell types, endogenous SGK-1 steady-state protein levels are very low but can be acutely up-regulated after glucocorticoid receptor-mediated transcriptional activation; in breast epithelial and cancer cell lines, this up-regulation is associated with promotion of cell survival. We and others have noted that ectopically introduced full-length SGK-1 is poorly expressed, although SGK-1 lacking the first 60 amino acids (delta60SGK-1) is expressed at much higher-fold protein levels than wild-type SGK-1 in both human embryonic kidney 293T and MCF10A mammary epithelial cells. In this report, we demonstrate for the first time that the low steady-state expression level of SGK-1 is due to polyubiquitination and subsequent degradation by the 26S proteasome. Deletion of the amino-terminal 60 amino acids of SGK-1 results in a mutant SGK-1 protein that is neither efficiently polyubiquitinated nor degraded by the 26S proteasome, accounting for the higher steady-state levels of the truncated protein. We also demonstrate that a subset of SGK-1 localizes to the plasma membrane and that the polyubiquitin-modified SGK-1 localizes to a membrane-associated fraction of the cell. Taken together, these data suggest that a significant fraction of SGK-1 is membrane-associated and ubiquitina…
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In disease states, a deletion mutation in the SGK1 gene causing loss of the first 60 N-terminal amino acids prevents effective ubiquitination and degradation by the 26S proteasome, leading to abnormally high steady-state levels of mutated SGK1 protein.
“However, in disease states, a deletion mutation in the SGK1 gene resulting in the loss of the first 60 amino acids at the N-terminus prevents effective ubiquitination and subsequent degradation by the 26S proteasome. This effect leads to an abnormally high steady-state level of the mutated SGK1 protein”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Brickley et al., 2002
In many cell types, endogenous SGK1 is typically present at very low levels.
“It’s noteworthy that in many cell types, endogenous SGK1 is typically present at very low levels”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Brickley et al., 2002
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(Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms
Lang, F., Böhmer, C., Palmada, M., Seebohm, G., Strutz-Seebohm, N., & Vallon, V. (2006) · Physiological Reviews · doi:10.1152/physrev.00050.2005 · Cited by 689 · see citing works
Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain
Howard, P. G., Zou, P., Zhang, Y., Huang, F., Tesic, V., Wu, C. Y.-C., & Lee, R. H.-C. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114973 · Cited by 13 · see citing works
- Authors
- Brickley, D. R., Mikosz, C. A., Hagan, C. R., & Conzen, S. D.
- Affiliations
- University of Chicago (US)
- Corresponding author
- Conzen, Suzanne D.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-11
- Volume
- 277
- Issue
- 45
- Pages
- 43064-43070
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1984780819
- Cited by
- 94
- References
- 0
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 4 · 2016: 4 · 2014: 4 · 2013: 6 · 2012: 3
- FWCI
- 2.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA14599-25, K08CA090459, P30CA014599)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- SGK1, polyubiquitination, 26S proteasome, protein degradation, membrane localization, Nedd4-2, NHE3, kinase regulation, glucocorticoid receptor
- MeSH terms
- Serum-Glucocorticoid Regulated Kinases, Breast, Breast Neoplasms, Cell Line, Cell Membrane, Cysteine Endopeptidases, Enzyme Induction, Epithelial Cells, Female, Glucocorticoids, Humans, Kinetics, Multienzyme Complexes, Nuclear Proteins, Protein Processing, Post-Translational, Recombinant Proteins, Transfection, Tumor Cells, Cultured, Ubiquitins, Transcriptional Activation, Cysteine Proteinase Inhibitors, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Proteasome Endopeptidase Complex
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