cRel-TD kinase: a serine/threonine kinase binding in vivo and in vitro c-Rel and phosphorylating its transactivation domain

Abstract

The activity of transcription factors is often modulated by signal responsive protein kinases. Rel/NF-kB transcription factors are regulated by IkB inhibitors, the phosphorylation of which causes ubiquitination and degradation, resulting in nuclear translocation of NFkB and activation of target genes. Here we report pulldown and immunoprecipitation experiments showing that a mammalian 66 kDa protein kinase binds murine c-Rel, both in vitro and in vivo. This kinase appears to have at least two binding sites on c-Rel, a proline-directed serine/ threonine substrate speci®city similar to MAP kinases and to speci®cally phosphorylate the C-terminal domain of murine c-Rel at an ERK consensus site. Oncogene (2000) 19, 2224 ± 2232.

Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway

“…In addition, IKKe has also been shown to phosphorylate the c-Rel transactivation domain at unknown sites and stimulate its nuclear accumulation (Harris et al, 2006). Mouse c-Rel is phosphorylated in vitro at an ERK kinase consensus site in its transactivation domain (Ser-451) (Fognani et al, 2000) but, although otherwise conserved, this exact site is not present in the human or chimpanzee forms of the protein (Starczynowski et al, 2005). c-Rel, in common with RelA and p105, is also inducibly tyrosine phosphorylated at unknown sites (Neumann et al, 1992;Druker et al, 1994;Liu and Beller, 2002;Kang et al, 2003;Pellegatta et al, 2003).…”

Regulation if NF-κB Transcriptional Activity

“…Ser451 in the C-terminal part of cRel was suggested to be the target of this kinase which has not been further characterized up until now. Mutation of Ser451 or deletion of the surrounding consensus sequence inhibited transcriptional activity of c-Rel (Fognani et at., 2000). In the case of RelB, phosphorylation has not been found to alter its transcriptional activity.…”

Mutation of an IKK phosphorylation site within the transactivation domain of REL in two patients with B-cell lymphoma enhances REL's in vitro transforming activity

“…The C-terminal half of REL (aa 296-587) contains a transactivation domain, which is comprised of at least two subdomains: subdomain I (aa 422-497) and subdomain II (aa 518-587) (Martin et al, 2001;Starczynowski et al, 2003). The REL C-terminal transactivation domain can also be regulated by phosphorylation of specific serine (Ser) residues (Fognani et al, 2000;Martin and Fresno, 2000;Martin et al, 2001;Yu et al, 2004;Lawrence et al, 2005;Harris et al, 2006). Recently, IkB kinase (IKK)-associated kinases have been found to phosphorylate C-terminal residues of REL in an immune complex kinase assay (Lawrence et al, 2005;Harris et al, 2006).…”