Cited by 854Metabolism, Diabetes, and CancerAdipokines, Inflammation, and Metabolic DiseasesPI3K/AKT/mTOR signaling in cancer

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Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance

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Virkamäki, Antti, Ueki, Kohjiro, Kahn, C. Ronald·1999·Journal of Clinical Investigation

DOI 10.1172/jci6609PMC PMC408269

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Abstract

Perspective Figure 1 Schematic illustration of major signaling pathways of insulin action.The phosphorylated insulin receptor binds and phosphorylates IRS proteins and Shc, which bind differentially to various downstream signaling proteins.PI3-kinase is critical for metabolic actions of insulin, such as glucose transport, glycogen synthesis, and protein synthesis, whereas Grb-2/SOS complex, which activates the MAP kinase cascade, is critical in mitogenic response.PI3-kinase probably modulates the mitogenic response as well.This series continues from the March 1999, no.6, issue.

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Choi, D. H., Lee, Y. J., Kim, J. S., Kang, D. G., & Lee, H. S. (2011) · Immunopharmacology and Immunotoxicology · doi:10.3109/08923973.2011.569889 · Cited by 35
“Furthermore, a fat- and cholesterol-enriched diet in rat and mouse models induces endothelial dysfunction associated with reduced signaling through IRS-1/ PI3-kinase/Akt pathway.((32,33)) Recent report supposed that IRS-1/PI-3 kinase/Akt/eNOS signal pathways may play a mechanistic role in endothelial dysfunction and i…”
Background
Impact of Differential P450c17 Phosphorylation by cAMP Stimulation and by Starvation Conditions on Enzyme Activities and Androgen Production in NCI-H295R Cells
Kempná, P., Hirsch, A., Hofer, G., Mullis, P. E., & Flück, C. E. (2010) · Endocrinology · doi:10.1210/en.2010-0093 · Cited by 35
“Several pathways are stimulated after activating the insulin or other IGF receptors, including the phosphatidylinositol kinase/PKB pathway and/or the MAPK/MAPK kinase/ERK pathway (34, 35).”
Background
The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma
Rose, P. P., Carroll, J. M., Carroll, P. A., DeFilippis, V. R., Lagunoff, M., Moses, A. V., Roberts, C. T., & Früh, K. (2006) · Oncogene · doi:10.1038/sj.onc.1210006 · Cited by 35
“Shc is an IR adaptor substrate that is activated upon phosphorylation of IR ultimately leading to the activation of the Ras/MAPK pathway and concomitant stimulation of mitgogenic signaling pathways (Virkamaki et al., 1999; Leibiger et al., 2001).”
Background
The effect of hyperglycaemia on glucose disposal and insulin signal transduction in skeletal muscle
Zierath, J. R., & Kawano, Y. (2003) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/s1521-690x(03)00040-x · Cited by 35
Another Role for the Celebrity
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Eccentric Exercise Leads to Performance Decrease and Insulin Signaling Impairment
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“The regulation of IRS-1 serine phosphorylation is directly related to the molecular mechanism responsible by the impairment of insulin signaling pathway (20,43).”
Background
Chronic treatment with growth hormone stimulates adiponectin gene expression in 3T3‐L1 adipocytes
Xu, A., Wong, L. C., Wang, Y., Xu, J. Y., Cooper, G. J. S., & Lam, K. S. L. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.07.020 · Cited by 34
Signal Integration and the Specificity of Insulin Action
Kanzaki, M., & Pessin, J. E. (2001) · Cell Biochemistry and Biophysics · doi:10.1385/cbb:35:2:191 · Cited by 33
“The tyrosine phosphorylation of these proximal targets creates multisite docking proteins and include family members of the insulin receptor substrate (IRS1–4), Gab1, p53/58, APS, Cbl, Shc, and SIRP proteins (30,35).”
Background
GRK2 Negatively Regulates Glycogen Synthesis in Mouse Liver FL83B Cells
Shahid, G., & Hussain, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700744200 · Cited by 34
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“These interactions are essential tools for the transmission and compartmentalization of the insulin signal from the receptor to the final cellular events such as stimulating glucose uptake, activating glycogen or protein synthesis, and initiating specific gene transcription (Virkamaki et al. 1999).”
Background
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Defferrari, M. S., da Silva, S. R., Orchard, I., & Lange, A. B. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00745 · Cited by 35
“However, while the PI3K/Akt pathway regulates processes involving glucose uptake and metabolism (56), the IR-dependent MAPK pathway is involved in mediating mitogenic and cell cycle responses in mammals (11), among other functions.”
Background
New amino acid substitutions in the IRS-2 gene in Finnish and Chinese subjects with late-onset type 2 diabetes.
Wang, H., Rissanen, J., Miettinen, R., Kärkkäinen, P., Kekäläinen, P., Kuusisto, J., Mykkänen, L., Karhapää, P., & Laakso, M. (2001) · Diabetes · doi:10.2337/diabetes.50.8.1949 · Cited by 37
“Insulin receptor substrates (IRSs) represent the key proteins that transmit the insulin signal from the insulin receptor to downstream molecules (1,2).”
BackgroundInfluential
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“ylation of the insulin receptor (IR) and phosphorylation of the IR substrate (IRS) 1–4 proteins (8) that act as docking proteins for a number of downstream effector molecules”
Background
Molecular Determinants of Grb14-Mediated Inhibition of Insulin Signaling
Goenaga, D., Hampe, C., Carré, N., Cailliau, K., Browaeys‐Poly, E., Perdereau, D., Holt, L. J., Daly, R. J., Girard, J. R., Broutin, I., et al. (2009) · Molecular Endocrinology · doi:10.1210/me.2008-0360 · Cited by 33
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“In response to growth factor stimulation of cells, such as by insulin or insulin-like growth factor-1 (IGF-1), clustering of receptor tyrosine kinases results in transphosphorylation of the intracellular portions of the receptors [ 41 ].”
Background
Addition of Pulses, Cooking Oils, and Vegetables Enhances Resistant Starch and Lowers the Glycemic Index of Rice (Oryza sativa L.)
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“In the feeding state, elevated blood insulin levels promptly stimulate de novo lipogenesis and triglyceride synthesis using carbons from amino acids, glycerol, or the spillover of glucose in the liver (27, 28).”
Background
Sex-dependent differences in rat hepatic lipid accumulation and insulin sensitivity in response to diet-induced obesity
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“In insulin-resistant conditions and T2DM, increased phosphorylation of IRS-1 is a common ﬁ nding 44 .”
Background
m6A mRNA methylation in brown fat regulates systemic insulin sensitivity via an inter-organ prostaglandin signaling axis independent of UCP1
Xiao, L., Jesus, D. F. D., Ju, C., Wei, J. B., Hu, J. Y., DiStefano-Forti, A., Tsuji, T., Cero, C., Männistö, V., Manninen, S. M., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.08.006 · Cited by 32
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“Although less potent, LY 294002 exhibits better selectively for PI 3-kinase and is a preferred alternative (Vlahos et al., 1994; Sarbassov and Peterson, 1998).”
Background
Excessive training impairs the insulin signal transduction in mice skeletal muscles
Pereira, B. C., da Rocha, A. L., Pinto, A. P., Pauli, J. R., de Moura, L. P., Mekary, R. A., de Freitas, E. C., & da Silva, A. S. R. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0063 · Cited by 31
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“PI 3-kinase plays an essential role in mediating insulin-stimulated glucose transport in skeletal muscle and adipose tissue [13].”
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Reinehr, R., Sommerfeld, A., & Häussinger, D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.125781 · Cited by 30
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“The Akt pathway mediates a “metabolic” effect (20), and the MAPK pathway mediates “mitogenic” responses of insulin (22).”
Background
AICAR, an activator of AMP-activated protein kinase, down-regulates the insulin receptor expression in HepG2 cells
Nakamaru, K., Matsumoto, K., Taguchi, T., Suefuji, M., Murata, Y., Igata, M., Kawashima, J., Kondo, T., Motoshima, H., Tsuruzoe, K., et al. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.01.004 · Cited by 30

Authors: Virkamäki, A., Ueki, K., & Kahn, C. R.
Affiliations: Joslin Diabetes Center (US)
Corresponding author: Kahn, C. Ronald
ORCID: Ueki, Kohjiro
Kahn, C. Ronald
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1999-04-01
Volume: 103
Issue: 7
Pages: 931-943
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci6609
PMC: PMC408269
OpenAlex: W2095252238
Cited by: 854
References: 176
Citations by year: 2026: 4 · 2025: 4 · 2024: 15 · 2023: 8 · 2022: 15 · 2021: 12 · 2020: 13 · 2019: 16 · 2018: 13 · 2017: 21 · 2016: 22 · 2015: 26 · 2014: 24 · 2013: 27 · 2012: 31
FWCI: 4.88
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: European Foundation for the Study of Diabetes
National Institutes of Health (DK31036)
National Institute of Diabetes and Digestive and Kidney Diseases (R37DK031036, DK 33201, R01DK031036, DK45935, DK31036, R01DK045935, R01DK033201)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: insulin signaling, insulin resistance, protein-protein interaction, insulin receptor, Shc, PI3-kinase, MAP kinase cascade, glucose transport, glycogen synthesis, mitogen response
MeSH terms: Animals, Humans, Insulin, Insulin Resistance, Phosphorylation, Protein Binding, Receptor, Insulin, Signal Transduction, Gene Targeting, src Homology Domains, Phosphatidylinositol 3-Kinases

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Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance

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