Inositol 1,3,4-Trisphosphate 5/6-Kinase Is a Protein Kinase That Phosphorylates the Transcription Factors c-Jun and ATF-2

Abstract

Phosphorylation of inositol 1,3,4-trisphosphate by inositol 1,3,4-trisphosphate 5/6-kinase is the first committed step in the formation of higher phosphorylated forms of inositol. We have shown that the eight proteins called the COP9 signalosome complex copurify with calf brain 5/6-kinase. Because the complex has been shown to phosphorylate c-Jun in vitro, we tested both the complex and 5/6-kinase and found that both are able to phosphorylate c-Jun and ATF-2 on serine/threonine residues. These findings establish a link between two major signal transduction systems: the inositol phosphates and the stress response system.

Inositol 1,3,4-Trisphosphate 5/6-Kinase Inhibits Tumor Necrosis Factor-induced Apoptosis

“…The COP9 signalosome has been implicated in regulation of the cell cycle, proteolysis in the proteasome, and plant development (11)(12)(13). We have shown that 5/6-kinase associates with the CSN1 subunit of the COP9 signalosome and phosphorylates I B␣ and c-Jun (9,10). I B␣ phosphorylation is an important regulatory mechanism for TNF␣ 1 -induced NF-B activation.…”

“…In addition, 5/6-kinase has been reported to phosphorylate inositol 3,4,5,6-tetrakisphosphate to inositol 1,3,4,5,6-pentakisphosphate (8). Recently, we have reported that 5/6-kinase also exhibits protein kinase activity and associates with the COP9 signalosome complex (9,10). The COP9 signalosome has been implicated in regulation of the cell cycle, proteolysis in the proteasome, and plant development (11)(12)(13).…”

CSN1 inhibits c-Jun phosphorylation and down-regulates ectopic expression of JNK1

“…The CSN complex associates with multiple protein kinases capable of phosphorylating c-Jun (Uhle et al, 2003;Wilson et al, 2001). CSN2 and CSN5 promote (Claret et al, 1996;Naumann et al, 1999;Pollmann et al, 2001), while CSN1 inhibits AP-1 activation (Tsuge et al, 2001; this study).…”

“…We showed that CSN1 can repress UV and serum induced expression of c-fos-lacZ chimeric gene in mouse fibroblast cells (Tsuge et al, 2001). In addition, CSN1 was shown to mediate interaction of CSN complex with 5/6-kinase, which can phosphorylate c-Jun and ATF-2 (Wilson et al 2001;Sun et al 2002). Moreover, ectopic expression of CSN1 was shown to inhibit the CSN-associated 5/6-kinase activity (Sun et al, 2002).…”

“…CSN has an intrinsic isopeptidase activity that deconjugates the ubiquitin-like protein Nedd8/Rub1 from cullin ubiquitin ligases (deneddylation) (Cope and Deshaies 2003). In addition, the complex can associate with protein kinases such as protein kinase CK2 (CK2, formerly casein kinase II), protein kinase D (PKD), and inositol 1,3,4-triphosphate 5/6-kinase (5/6-kinase), which have been shown to phosphorylate c-Jun (Wilson et al, 2001;Uhle et al, 2003). One of CSN subunits, CSN5, also known as Jab1 (c-Jun activation domain binding protein 1), has been identified as a transcription co-activator that enhances transcription activity of c-Jun (Claret et al, 1996) and Myc (Adler et al, 2006).…”