Cited by 335Metabolism, Diabetes, and CancerPI3K/AKT/mTOR signaling in cancerMuscle metabolism and nutrition

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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.

Hajduch, E, Alessi, D R, Hemmings, B A, Hundal, H S·1998·Diabetes

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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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Crossref · 10.2337/diabetes.47.7.1006

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Background
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Background
GNIP1 E3 ubiquitin ligase is a novel player in regulating glycogen metabolism in skeletal muscle
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Self-citation
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A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration
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Development of whole-body and skeletal muscle insulin resistance after one day of hindlimb suspension
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BackgroundInfluential
Effect of Vanadate and Insulin on Glucose Transport in Isolated Adult Rat Cardiomyocytes
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“For example, stable overexpression of wildtype PKBfi or constitutively active mutants of PKBfi increased glucose transport and translocation of the insulin-sensitive glucose transporter, GLUT4 to levels similar to or greater than those achieved with insulin in rat adipocytes [16], 3T3-L1 adipocytes [17,18], and L6 mus…”
Background
Decreased glycolytic metabolism contributes to but is not the inducer of apoptosis following IL-3-starvation
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“The bone marrow derived IL-3 dependent Baf-3 cells were grown at 378C in Dulbecco's Modified Eagle's medium (DMEM) (Gibco BRL) containing 6% foetal calf serum (Boehringer Mannheim), 2 mM Lglutamine (Gibco BRL) and 5% WEHI 3B cell-conditioned medium as a source of IL-3.”
BackgroundInfluential
The role of system A for neutral amino acid transport in the regulation of cell volume
Bussolati, O., Dall’Asta, V., Franchi‐Gazzola, R., Sala, R., Rotoli, B. M., Visigalli, R., Casado, J. F., López-Fontanals, M., al Pastor-Anglada, M., & Gazzola, G. C. (2001) · Molecular Membrane Biology · doi:10.1080/09687680110033756 · Cited by 38
“…1988 Phorbol esters Decrease LLC-PK1 cells, colon carcinoma cells Dawson and Cook, 1987, Pawlik et al. 2000 PKB activation Increase L6 muscle cells Hajduch et al. 1998 Prostaglandins Decrease MDCK cells Boerner and Saier, 1985b Prostaglandins Increase Synovial cells Le Maire et al. 2000 Sodium…”
Background
3-Phosphoinositide-dependent Protein Kinase 1, an Akt1 Kinase, Is Involved in Dephosphorylation of Thr-308 of Akt1 in Chinese Hamster Ovary Cells
Yamada, T., Katagiri, H., Asano, T., Inukai, K., Tsuru, M., Kodama, T., Kikuchi, M., & Oka, Y. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m005685200 · Cited by 37
The PPARδ agonist, GW501516, promotes fatty acid oxidation but has no direct effect on glucose utilisation or insulin sensitivity in rat L6 skeletal muscle cells
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Self-citation
Enhanced Insulin Sensitivity Associated with Provision of Mono and Polyunsaturated Fatty Acids in Skeletal Muscle Cells Involves Counter Modulation of PP2A
Nardi, F., Lipina, C., Magill, D., Hage Hassan, R., Hajduch, E., Gray, A., & Hundal, H. S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092255 · Cited by 36
Self-citation

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)
ORCID: Alessi, D R
Hundal, H S
Venue: Diabetes
Publisher: American Diabetes Association
Published: 1998-07-01
Volume: 47
Issue: 7
Pages: 1006-1013
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diabetes.47.7.1006
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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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.

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