PMID- 10022904
OWN - NLM
STAT- MEDLINE
DCOM- 19990325
LR  - 20190508
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 19
IP  - 3
DP  - 1999 Mar
TI  - Activation of IkappaB kinase beta by protein kinase C isoforms.
PG  - 2180-8
AB  - The atypical protein kinase C (PKC) isotypes (lambda/iotaPKC and zetaPKC) have
      been shown to be critically involved in important cell functions such as
      proliferation and survival. Previous studies have demonstrated that the atypical 
      PKCs are stimulated by tumor necrosis factor alpha (TNF-alpha) and are required
      for the activation of NF-kappaB by this cytokine through a mechanism that most
      probably involves the phosphorylation of IkappaB. The inability of these PKC
      isotypes to directly phosphorylate IkappaB led to the hypothesis that zetaPKC may
      use a putative IkappaB kinase to functionally inactivate IkappaB. Recently
      several groups have molecularly characterized and cloned two IkappaB kinases
      (IKKalpha and IKKbeta) which phosphorylate the residues in the IkappaB molecule
      that serve to target it for ubiquitination and degradation. In this study we have
      addressed the possibility that different PKCs may control NF-kappaB through the
      activation of the IKKs. We report here that alphaPKC as well as the atypical PKCs
      bind to the IKKs in vitro and in vivo. In addition, overexpression of zetaPKC
      positively modulates IKKbeta activity but not that of IKKalpha, whereas the
      transfection of a zetaPKC dominant negative mutant severely impairs the
      activation of IKKbeta but not IKKalpha in TNF-alpha-stimulated cells. We also
      show that cell stimulation with phorbol 12-myristate 13-acetate activates
      IKKbeta, which is entirely dependent on the activity of alphaPKC but not that of 
      the atypical isoforms. In contrast, the inhibition of alphaPKC does not affect
      the activation of IKKbeta by TNF-alpha. Interestingly, recombinant active zetaPKC
      and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that 
      of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC
      directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181.
      Collectively, these results demonstrate a critical role for the PKC isoforms in
      the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation.
FAU - Lallena, M J
AU  - Lallena MJ
AD  - Laboratorio Glaxo Wellcome-CSIC de Biologia Molecular y Celular, Centro de
      Biologia Molecular "Severo Ochoa" (Consejo Superior de Investigaciones
      Cientificas-Universidad Autonoma de Madrid), Universidad Autonoma, 28049 Madrid, 
      Spain.
FAU - Diaz-Meco, M T
AU  - Diaz-Meco MT
FAU - Bren, G
AU  - Bren G
FAU - Paya, C V
AU  - Paya CV
FAU - Moscat, J
AU  - Moscat J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Isoenzymes)
RN  - 0 (Mitogens)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (protein kinase C zeta)
RN  - EC 2.7.11.10 (CHUK protein, human)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - EC 2.7.11.10 (IKBKB protein, human)
RN  - EC 2.7.11.10 (IKBKE protein, human)
RN  - EC 2.7.11.13 (PRKCA protein, human)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.13 (Protein Kinase C-alpha)
RN  - EC 2.7.11.13 (protein kinase C lambda)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - Cell Line, Transformed
MH  - Enzyme Activation
MH  - Gene Expression Regulation
MH  - Humans
MH  - I-kappa B Kinase
MH  - Isoenzymes/genetics/metabolism
MH  - Mitogens/pharmacology
MH  - Promoter Regions, Genetic
MH  - Protein Kinase C/genetics/*metabolism
MH  - Protein Kinase C-alpha
MH  - Protein-Serine-Threonine Kinases/genetics/*metabolism
MH  - Recombinant Fusion Proteins/genetics
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - Tumor Necrosis Factor-alpha/metabolism/pharmacology
PMC - PMC84010
EDAT- 1999/02/18 00:00
MHDA- 1999/02/18 00:01
CRDT- 1999/02/18 00:00
PHST- 1999/02/18 00:00 [pubmed]
PHST- 1999/02/18 00:01 [medline]
PHST- 1999/02/18 00:00 [entrez]
AID - 10.1128/mcb.19.3.2180 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1999 Mar;19(3):2180-8. doi: 10.1128/mcb.19.3.2180.