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.
authors.affiliation: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Bayascas
authors.forename: Stephan
authors.initials: S
authors.lastname: Wullschleger
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Juan M
authors.initials: JM
authors.lastname: García-Martínez
authors.forename: Carol
authors.initials: C
authors.lastname: Clacher
authors.forename: David
authors.initials: D
authors.lastname: Komander
authors.forename: Daan M F
authors.initials: DM
authors.lastname: van Aalten
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Boini
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Christopher
authors.initials: C
authors.lastname: Lipina
authors.forename: Lisa
authors.initials: L
authors.lastname: Logie
authors.forename: Calum
authors.initials: C
authors.lastname: Sutherland
authors.forename: John A
authors.initials: JA
authors.lastname: Chudek
authors.forename: Janna A
authors.initials: JA
authors.lastname: van Diepen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Voshol
authors.forename: John M
authors.initials: JM
authors.lastname: Lucocq
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D049628:Body Size / Q000235:genetics* / Q000502:physiology; D005260:Female; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D011236:Prediabetic State / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt