title: Inactivation of the enzyme GSK3α by the kinase IKKi promotes AKT-mTOR signaling pathway that mediates interleukin-1-induced Th17 cell maintenance.
abstract: Interleukin-1 (IL-1)-induced activation of the mTOR kinase pathway has major influences on Th17 cell survival, proliferation, and effector function. Via biochemical and genetic approaches, the kinases IKKi and GSK3α were identified as the critical intermediate signaling components for IL-1-induced AKT activation, which in turn activated mTOR. Although insulin-induced AKT activation is known to phosphorylate and inactivate GSK3α and GSK3β, we found that GSK3α but not GSK3β formed a constitutive complex to phosphorylate and suppress AKT activation, showing that a reverse action from GSK to AKT can take place. Upon IL-1 stimulation, IKKi was activated to mediate GSK3α phosphorylation at S21, thereby inactivating GSK3α to promote IL-1-induced AKT-mTOR activation. Thus, IKKi has a critical role in Th17 cell maintenance and/or proliferation through the GSK-AKT-mTOR pathway, implicating the potential of IKKi as a therapeutic target.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Muhammet F
authors.initials: MF
authors.lastname: Gulen
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bulek
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.forename: Minjia
authors.initials: M
authors.lastname: Yu
authors.forename: Ji
authors.initials: J
authors.lastname: Gao
authors.forename: Lillian
authors.initials: L
authors.lastname: Sun
authors.forename: Eleonore
authors.initials: E
authors.lastname: Beurel
authors.forename: Oksana
authors.initials: O
authors.lastname: Kaidanovich-Beilin
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
authors.forename: Paul E
authors.initials: PE
authors.lastname: DiCorleto
authors.forename: Jian-an
authors.initials: JA
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: David N
authors.initials: DN
authors.lastname: Wald
authors.forename: James R
authors.initials: JR
authors.lastname: Woodgett
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
authors.forename: Julie
authors.initials: J
authors.lastname: Carman
authors.forename: Ashok
authors.initials: A
authors.lastname: Dongre
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000276:immunology / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051550:I-kappa B Kinase / Q000378:metabolism*; D007328:Insulin / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*
chemical_list: D007328:Insulin; D007375:Interleukin-1; C546843:mTOR protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha