Skip to content

Research at St Andrews

Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance

Research output: Contribution to journalArticlepeer-review

DOI

Standard

Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. / Bayascas, Jose R.; Wullschleger, Stephan; Sakamoto, Kei; Garcia-Martinez, Juan M.; Clacher, Carol; Komander, David; van Aalten, Daan M. F.; Boini, Krishna M.; Lang, Florian; Lipina, Christopher; Logie, Lisa; Sutherland, Calum; Chudek, John A.; van Diepen, Janna A.; Voshol, Peter J.; Lucocq, John Milton; Alessi, Dario R.

In: Molecular and Cellular Biology, Vol. 28, No. 10, 05.2008, p. 3258-3272.

Research output: Contribution to journalArticlepeer-review

Harvard

Bayascas, JR, Wullschleger, S, Sakamoto, K, Garcia-Martinez, JM, Clacher, C, Komander, D, van Aalten, DMF, Boini, KM, Lang, F, Lipina, C, Logie, L, Sutherland, C, Chudek, JA, van Diepen, JA, Voshol, PJ, Lucocq, JM & Alessi, DR 2008, 'Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance', Molecular and Cellular Biology, vol. 28, no. 10, pp. 3258-3272. https://doi.org/10.1128/MCB.02032-07

APA

Bayascas, J. R., Wullschleger, S., Sakamoto, K., Garcia-Martinez, J. M., Clacher, C., Komander, D., van Aalten, D. M. F., Boini, K. M., Lang, F., Lipina, C., Logie, L., Sutherland, C., Chudek, J. A., van Diepen, J. A., Voshol, P. J., Lucocq, J. M., & Alessi, D. R. (2008). Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. Molecular and Cellular Biology, 28(10), 3258-3272. https://doi.org/10.1128/MCB.02032-07

Vancouver

Bayascas JR, Wullschleger S, Sakamoto K, Garcia-Martinez JM, Clacher C, Komander D et al. Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. Molecular and Cellular Biology. 2008 May;28(10):3258-3272. https://doi.org/10.1128/MCB.02032-07

Author

Bayascas, Jose R. ; Wullschleger, Stephan ; Sakamoto, Kei ; Garcia-Martinez, Juan M. ; Clacher, Carol ; Komander, David ; van Aalten, Daan M. F. ; Boini, Krishna M. ; Lang, Florian ; Lipina, Christopher ; Logie, Lisa ; Sutherland, Calum ; Chudek, John A. ; van Diepen, Janna A. ; Voshol, Peter J. ; Lucocq, John Milton ; Alessi, Dario R. / Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 10. pp. 3258-3272.

Bibtex - Download

@article{4dffea86ccc149099bc382a8e44804c9,
title = "Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance",
abstract = "PDK1 activates a group of kinases, including. protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. PDK1 interacts with phosphoinositides through a pleckstrin homology (PH) domain. To study the role of this interaction, we generated knock-in mice expressing a mutant of PDK1 incapable of binding phosphoinositides. The knock-in mice are significantly small, insulin resistant, and hyperinsulinemic. Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. This results in the inhibition of the downstream mTOR complex 1 and S6K1 signaling pathways. In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance.",
keywords = "Amino Acid Substitution, Animals, Body Size, Female, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Models, Molecular, Mutagenesis, Site-Directed, Mutation, Phenotype, Prediabetic State, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt",
author = "Bayascas, {Jose R.} and Stephan Wullschleger and Kei Sakamoto and Garcia-Martinez, {Juan M.} and Carol Clacher and David Komander and {van Aalten}, {Daan M. F.} and Boini, {Krishna M.} and Florian Lang and Christopher Lipina and Lisa Logie and Calum Sutherland and Chudek, {John A.} and {van Diepen}, {Janna A.} and Voshol, {Peter J.} and Lucocq, {John Milton} and Alessi, {Dario R.}",
year = "2008",
month = may,
doi = "10.1128/MCB.02032-07",
language = "English",
volume = "28",
pages = "3258--3272",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "AMER SOC MICROBIOLOGY",
number = "10",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance

AU - Bayascas, Jose R.

AU - Wullschleger, Stephan

AU - Sakamoto, Kei

AU - Garcia-Martinez, Juan M.

AU - Clacher, Carol

AU - Komander, David

AU - van Aalten, Daan M. F.

AU - Boini, Krishna M.

AU - Lang, Florian

AU - Lipina, Christopher

AU - Logie, Lisa

AU - Sutherland, Calum

AU - Chudek, John A.

AU - van Diepen, Janna A.

AU - Voshol, Peter J.

AU - Lucocq, John Milton

AU - Alessi, Dario R.

PY - 2008/5

Y1 - 2008/5

N2 - PDK1 activates a group of kinases, including. protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. PDK1 interacts with phosphoinositides through a pleckstrin homology (PH) domain. To study the role of this interaction, we generated knock-in mice expressing a mutant of PDK1 incapable of binding phosphoinositides. The knock-in mice are significantly small, insulin resistant, and hyperinsulinemic. Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. This results in the inhibition of the downstream mTOR complex 1 and S6K1 signaling pathways. In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance.

AB - PDK1 activates a group of kinases, including. protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. PDK1 interacts with phosphoinositides through a pleckstrin homology (PH) domain. To study the role of this interaction, we generated knock-in mice expressing a mutant of PDK1 incapable of binding phosphoinositides. The knock-in mice are significantly small, insulin resistant, and hyperinsulinemic. Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. This results in the inhibition of the downstream mTOR complex 1 and S6K1 signaling pathways. In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance.

KW - Amino Acid Substitution

KW - Animals

KW - Body Size

KW - Female

KW - Insulin Resistance

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Mutant Strains

KW - Models, Molecular

KW - Mutagenesis, Site-Directed

KW - Mutation

KW - Phenotype

KW - Prediabetic State

KW - Protein Structure, Tertiary

KW - Protein-Serine-Threonine Kinases

KW - Proto-Oncogene Proteins c-akt

U2 - 10.1128/MCB.02032-07

DO - 10.1128/MCB.02032-07

M3 - Article

C2 - 18347057

VL - 28

SP - 3258

EP - 3272

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 10

ER -

Related by author

  1. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

    Autophagy Group & Lucocq, J. M., 2021, In: Autophagy. 17, 1, p. 1-382 382 p.

    Research output: Contribution to journalReview articlepeer-review

  2. Developing electron microscopy tools for profiling plasma lipoproteins using methyl cellulose embedment, machine learning and immunodetection of apolipoprotein B and apolipoprotein(a)

    Giesecke, Y., Soete, S., MacKinnon, K., Tsiaras, T., Ward, M., Althobaiti, M., Suveges, T., Lucocq, J. E., McKenna, S. J. & Lucocq, J. M., 2 Sep 2020, In: International Journal of Molecular Sciences. 21, 17, 25 p., 6373.

    Research output: Contribution to journalArticlepeer-review

  3. The invasive cell coat at the microsporidian Trachipleistophora hominis-host cell interface contains secreted hexokinases

    Ferguson, S. & Lucocq, J., Apr 2019, In: Microbiology Open. 8, 4, 19 p., e00696.

    Research output: Contribution to journalArticlepeer-review

  4. Enhanced imaging of lipid rich nanoparticles embedded in methylcellulose films for transmission electron microscopy using mixtures of heavy metals

    Asadi, J., Ferguson, S., Raja, H., Hacker, C., Marius, P., Ward, R., Pliotas, C., Naismith, J. H. & Lucocq, J., Aug 2017, In: Micron. 99, p. 40-48 9 p.

    Research output: Contribution to journalArticlepeer-review

  5. Quantifying Golgi structure using EM: combining volume-SEM and stereology for higher throughput

    Ferguson, S., Steyer, A. M., Mayhew, T. M., Schwab, Y. & Lucocq, J. M., Jun 2017, In: Histochemistry and Cell Biology. 147, 6, p. 653-669 17 p.

    Research output: Contribution to journalReview articlepeer-review

Related by journal

  1. Site-specific release of nascent chains from ribosomes at a sense codon

    Doronina, VA., Wu, C., De Felipe, P., Sachs, MS., Ryan, M. D. & Brown, JD., Jul 2008, In: Molecular and Cellular Biology. 28, 13, p. 4227-4239 13 p.

    Research output: Contribution to journalArticlepeer-review

  2. ABIN-3: a molecular basis for species divergence in interleukin-10-induced anti-inflammatory actions

    Weaver, B. K., Bohn, E., Judd, B. A., Gil, M. P. & Schreiber, R. D., Jul 2007, In: Molecular and Cellular Biology. 27, 13, p. 4603-4616 14 p.

    Research output: Contribution to journalArticlepeer-review

  3. Histone tails and the H3 alpha N helix regulate nucleosome mobility and stability

    Ferreira, H., Somers, J., Webster, R., Flaus, A. & Owen-Hughes, T., Jun 2007, In: Molecular and Cellular Biology. 27, 11, p. 4037-4048 12 p.

    Research output: Contribution to journalArticlepeer-review

  4. Dynamic regulation of histone modifications in Xenopus oocytes through histone exchange.

    Stewart, MD., Sommerville, J. & Wong, J., Sep 2006, In: Molecular and Cellular Biology. 26, 18, p. 6890-6901 12 p.

    Research output: Contribution to journalArticlepeer-review

ID: 23164880

Top