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

Research output: Contribution to journal › Journal article › Research › peer-review

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; García-Martínez, 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 M.; Alessi, Dario R.

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

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Bayascas, JR, Wullschleger, S, Sakamoto, K, García-Martínez, 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., García-Martínez, 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, García-Martínez 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 ; García-Martínez, 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 M. ; 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

@article{615db828b75841f8bbaf65e96993cd5b,
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.",
author = "Bayascas, {Jose R.} and Stephan Wullschleger and Kei Sakamoto and Garc{\'i}a-Mart{\'i}nez, {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 M.} 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 = "American Society for Microbiology",
number = "10",

}

RIS

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 - García-Martínez, 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 M.

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.

UR - http://www.scopus.com/inward/record.url?scp=43249093752&partnerID=8YFLogxK

U2 - 10.1128/MCB.02032-07

DO - 10.1128/MCB.02032-07

M3 - Journal article

AN - SCOPUS:43249093752

VL - 28

SP - 3258

EP - 3272

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 10

ER -

ID: 239574275