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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Hyde, R., Hajduch, É., Powell, D. J., Taylor, P. M., & Hundal, H. S. (2004) · The FASEB Journal · doi:10.1096/fj.04-2284fje · Cited by 126
“Transport activities were determined as described previously (11, 31).”
MethodResultSelf-citation
Improvement of insulin sensitivity by antagonism of the renin-angiotensin system
Henriksen, E. J. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00147.2007 · Cited by 127
“Akt is one downstream target of PDK, and this serine/threonine kinase appear to be critical in the regulation of glucose transport (20, 33, 67), although a limited number of studies do not support this concept (32).”
Background
Insulin Resistance With Enhanced Insulin Signaling in High-Salt Diet–Fed Rats
Ogihara, T., Asano, T., Ando, K., Chiba, Y., Sekine, N., Sakoda, H., Anai, M., Onishi, Y., Fujishiro, M., Ono, H., et al. (2001) · Diabetes · doi:10.2337/diabetes.50.3.573 · Cited by 120
“Ser-473 is one of the major phosphorylation sites of Akt (32), which has been linked to glucose transport, based on findings that overexpression of constitutively active Akt leads to enhanced glucose transport in 3T3-l1 adipocyte and L6 myotubes (33,34).”
Background
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Background
Calpain activation causes a proteasome‐dependent increase in protein degradation and inhibits the Akt signalling pathway in rat diaphragm muscle
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“Since this pathway plays a critical role in protein synthesis ( Hajduch et al. 1998; Kimball et al. 1999), these data suggest that calpainmediated inhibition of the Akt signalling pathway may reduce skeletal muscle protein synthesis.”
BackgroundInfluential
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“Numerous proteins can dock on activated IRSs, and among them phosphoinositide-3-kinase (PI3K) and downstream effectors such as serine/threonine kinases protein kinase B (PKB, also known as Akt) and aPKC fk which play a crucial role in glucose homeostasis [9,10].”
BackgroundSelf-citation
Differing Roles of Akt and Serum- and Glucocorticoid-regulated Kinase in Glucose Metabolism, DNA Synthesis, and Oncogenic Activity
Sakoda, H., Gotoh, Y., Katagiri, H., Kurokawa, M., Ono, H., Onishi, Y., Anai, M., Ogihara, T., Fujishiro, M., Fukushima, Y., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301127200 · Cited by 118
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“Preparation of whole cell lysates - Adipocytes were lysed as described previously (23), Whole”
MethodSelf-citation
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“Cells were lysed after experimental manipulation (see figure legends) in an appropriate volume of lysis buffer (27).”
MethodSelf-citation
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“Akt/PKB promotes the uptake of glucose in skeletal muscle by stimulating translocation of Glucose Transporter 4 (GluT4) resulting in an increase in the rate of glucose flux into the tissue, creating a state of decreased circulating glucose and stimulating the its conversion to energy storage molecules such as glycogen…”
Background
Phosphoinositide 3-Kinase-mediated Reduction of Insulin Receptor Substrate-1/2 Protein Expression via Different Mechanisms Contributes to the Insulin-induced Desensitization of Its Signaling Pathways in L6 Muscle Cells
Pirola, L., Bonnafous, S., Johnston, A., Chaussade, C., Portis, F., & OBBERGHEN, E. V. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208984200 · Cited by 110
Targeting of PKCζ and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide
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Self-citation
Insulin Promotes the Cell Surface Recruitment of the SAT2/ATA2 System A Amino Acid Transporter from an Endosomal Compartment in Skeletal Muscle Cells
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Self-citation
Dietary Cod Protein Restores Insulin-Induced Activation of Phosphatidylinositol 3-Kinase/Akt and GLUT4 Translocation to the T-Tubules in Skeletal Muscle of High-Fat-Fed Obese Rats
Tremblay, F., Lavigne, C., Jacques, H., & Marette, A. (2003) · Diabetes · doi:10.2337/diabetes.52.1.29 · Cited by 109
Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1
DeAngelis, A. M., Heinrich, G., Dai, T., Bowman, T. A., Patel, P. R., Lee, S. J., Hong, E., Jung, D. Y., Aßmann, A., Kulkarni, R. N., et al. (2008) · Diabetes · doi:10.2337/db08-0379 · Cited by 106
Osmotic Shock Inhibits Insulin Signaling by Maintaining Akt/Protein Kinase B in an Inactive Dephosphorylated State
Chen, D., Fucini, R. V., Olson, A. L., Hemmings, B. A., & Pessin, J. E. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.7.4684 · Cited by 104
“Although an essential role for PKB in the insulin-stimulated translocation of GLUT4 has recently become controversial (30, 35), stable or inducible expression of a constitutively active membrane-bound form of PKB results in increased glucose transport activity and the persistent plasma membrane localization of GLUT4 (…”
BackgroundSelf-citation
The PD-1/PD-L1 axis contributes to immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia
Qorraj, M., Bruns, H., Böttcher, M., Weigand, L., Saul, D., Mackensen, A., Jitschin, R., & Mougiakakos, D. (2016) · Leukemia · doi:10.1038/leu.2016.214 · Cited by 108
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Akt Is a Molecular Target for Signal Transduction Therapy in Brain Ischemic Insult
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Muscle glycogen content affects insulin-stimulated glucose transport and protein kinase B activity
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“The majority of recent papers support the notion of a functional link between PKB activation and glucose transport stimulation in muscle (15, 23, 25, 26, 42), whereas others do not (27, 39).”
Background
Functional Studies of Akt Isoform Specificity in Skeletal Muscle in Vivo; Maintained Insulin Sensitivity Despite Reduced Insulin Receptor Substrate-1 Expression
Cleasby, M. E., Reinten, T. A., Cooney, G. J., James, D. E., & Kraegen, E. W. (2006) · Molecular Endocrinology · doi:10.1210/me.2006-0154 · Cited by 101
“Transverse sections from ca-Akt-1, ca-Akt-2, and control muscles were also immunostained for slow myosin heavy chain to determine whether Akt overexpression resulted in altered muscle fiber type distribu216 Mol Endocrinol, January 2007, 21(1):215–228 Cleasby et al.”
BackgroundInfluential
Defining the Contribution of AMP-activated Protein Kinase (AMPK) and Protein Kinase C (PKC) in Regulation of Glucose Uptake by Metformin in Skeletal Muscle Cells
Turban, S., Stretton, C., Drouin, O., Green, C., Watson, M., Gray, A., Ross, F. A., Lantier, L., Viollet, B., Hardie, D. G., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.330746 · Cited by 105
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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