Phorbol esters and cytokines regulate the expression of the NEMO-related protein, a molecule involved in a NF-kappa B-independent pathway.
The NF-kappaB signaling pathway plays a crucial role in the immune, inflammatory, and apoptotic responses. Recently, we identified the NF-kappaB Essential Modulator (NEMO) as an essential component of this pathway. NEMO is a structural and regulatory subunit of the high molecular kinase complex (IKK) responsible for the phosphorylation of NF-kappaB inhibitors. Data base searching led to the isolation of a cDNA encoding a protein we called NRP (NEMO-related protein), which shows a strong homology to NEMO. Here we show that NRP is present in a novel high molecular weight complex, that contains none of the known members of the IKK complex. Consistently, we could not observe any effect of NRP on NF-kappaB signaling. Nonetheless, we could demonstrate that treatment with phorbol esters induces NRP phosphorylation and decreases its half-life. This phosphorylation event could only be inhibited by K-252a and stauroporin. We also show that de novo expression of NRP can be induced by interferon and tumor necrosis factor alpha and that these two stimuli have a synergistic effect on NRP expression. In addition, we observed that endogenous NRP is associated with the Golgi apparatus. Analogous to NEMO, we find that NRP is associated in a complex with two kinases, suggesting that NRP could play a similar role in another signaling pathway.
Schwamborn
K
K
Unité de Biologie Moléculaire de l'Expression Génique, URA 1773 Centre National de la Recherche Scientifique, Institut Pasteur, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
Weil
R
R
Courtois
G
G
Whiteside
S T
ST
Israël
A
A
D000595:Amino Acid Sequence; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D026121:Indole Alkaloids; D007372:Interferons / Q000494:pharmacology*; D026901:Membrane Transport Proteins; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D017386:Sequence Homology, Amino Acid; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D035582:Transcription Factor TFIIIA; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002227:Carbazoles; D018797:Cell Cycle Proteins; D026121:Indole Alkaloids; D026901:Membrane Transport Proteins; D016328:NF-kappa B; C409460:OPTN protein, human; D010750:Phosphoproteins; D035582:Transcription Factor TFIIIA; D014409:Tumor Necrosis Factor-alpha; D007372:Interferons; C049985:staurosporine aglycone; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate