Glycogen synthase kinase-3 beta regulates NF-kappa B1/p105 stability.
A number of different kinases have been implicated in NF-kappa B regulation and survival function. Here we investigated the molecular cross-talk between glycogen synthase kinase-3 beta (GSK-3 beta) and the p105 precursor of the NF-kappa B p50 subunit. GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. In addition, the p105 phosphorylation level is reduced in fibroblasts lacking GSK-3 beta as compared with wild-type cells. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. Moreover, p105 degradation in response to TNF-alpha is prevented in GSK-3 beta-/- fibroblasts and by a Ser to Ala point mutation on p105 at positions 903 or 907. Interestingly, the increased sensitiveness to TNF-alpha-induced death occurring in GSK-3 beta-/- fibroblasts, which is coupled to a perturbation of p50/105 ratio, can be reproduced by p105 silencing in wild-type fibroblasts.
Demarchi
Francesca
F
L.N.C.I.B. Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie AREA Science Park, Padriciano 99 34012 Trieste, Italy.
Bertoli
Cosetta
C
Sandy
Peter
P
Schneider
Claudio
C
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D004355:Drug Stability; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D014162:Transfection
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors; D011994:Recombinant Proteins; D012694:Serine; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3