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Constitutive activation of protein kinase B alpha by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells.
Abstract
Phosphatidylinositol 3-kinase (PI 3-kinase) has been implicated in the regulation of numerous cellular processes, including the insulin-induced regulation of glycogen synthase kinase 3 (GSK-3) and glucose transport. The hormonal-induced inactivation of GSK-3 is mediated by protein kinase B (PKB), a downstream target of PI 3-kinase, whose involvement in other insulin-stimulated responses remains poorly defined at present. In this study, we investigated whether the uptake of glucose, system A amino acid transport, and cellular protein synthesis are regulated by PKBalpha in L6 skeletal muscle cells. L6 cells stably overexpressing wild-type PKBalpha (wtPKBalpha) or a constitutively active membrane-targeted PKBalpha (mPKBalpha) showed a 3- and 15-fold increase in PKB activity, respectively. Both wtPKBalpha and mPKBalpha expression led to a significant increase in the basal uptake of glucose and methyl-aminoisobutyric acid (a substrate for the system A amino acid transporter), at least to a level seen in control cells treated with insulin. The stimulation in glucose transport was facilitated, in part, by the increased translocation of GLUT4 to the plasma membrane and also through an increase in the cellular synthesis of GLUT3. In the absence of insulin, only muscle cells expressing the constitutively active PKBalpha showed a significant increase in protein synthesis and an inhibition in GSK-3. Our results indicate that constitutive activation of PKBalpha in skeletal muscle stimulates the uptake of glucose, system A amino acids, and protein synthesis and promotes the inactivation of GSK-3. These observations imply that PKBalpha may have a role in the insulin-regulated control of these processes in skeletal muscle.
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Metadata
- Authors
- Hajduch, E., Alessi, D. R., Hemmings, B. A., & Hundal, H. S.
- Affiliations
- Department of Anatomy and Physiology, University of Dundee, Scotland, UK.
- University of Dundee (GB)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1998-07-01
- Volume
- 47
- Issue
- 7
- Pages
- 1006-1013
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W1972307668
- Cited by
- 335
- References
- 0
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 7 · 2020: 3 · 2019: 5 · 2018: 8 · 2017: 3 · 2016: 12 · 2015: 10 · 2014: 7 · 2013: 7 · 2012: 8
- FWCI
- 10.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Keywords
- constitutive activation, phosphatidylinositol 3-kinase, glycogen synthase kinase-3, glucose transport, system A amino acid transport, protein synthesis, GLUT4 translocation, GLUT3, skeletal muscle, insulin signaling, L6 myoblasts
- MeSH terms
- Amino Acids, Animals, Biological Transport, Cell Differentiation, Cell Division, Cell Line, Cell Membrane, Enzyme Activation, Glucose, Humans, Muscle Proteins, Proto-Oncogene Proteins, Transfection, Gene Expression, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Gene Targeting, Muscle, Skeletal, Glycogen Synthase Kinases, Glycogen Synthase Kinase 3, Proto-Oncogene Proteins c-akt, Rats
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