Constitutive phosphorylation of I kappa B alpha by casein kinase II.

Abstract

The NF-acB/Rel proteins are sequestered in the cytoplasm in association with the phosphorylated form of IKBa. Upon induction with a wide variety of agents, the activity of NF-KcB/Ret proteins is preceded by the rapid degradation of IucBa protein. We report the identification and partial purification of a cellular kinase from unstimulated or stimulated murine cells, which specifically phosphorylates the C terminus of IKBa. There are several consensus sites for casein kinase II (CKII) In the C-terminal region of I#cB&.Additionally, the activity of the cellular kinase is blocked by antibodies against the a subunit of CKII. No phosphorylation of the C-terminal region of IicBa can be detected if the five possible serine and threonine residues that can be phosphorylated by CKII are mutated to alanine. A two-dimensional tryptic phosphopeptide map of IecBa from unstimulated cells was identical to that obtained by in vitro phosphorylation of I#cBa with the partially purified cellular kinase. We propose that constitutive phosphorylation of I#cBa is carried out by CKII.The NF-KB/Rel family of transcription factors are key regulators of a variety of genes involved in the immune and inflammatory responses, growth, differentiation, and development (reviewed in refs.

Casein kinase II phosphorylates Ser468 in the PEST domain of the Drosophila IκB homologue cactus

“…PEST sequences have not yet been identified with a particular pathway of proteolysis, so it is possible that CKII phosphorylation can affect either the ubiquitin-or trypsin-mediated forms of degradation [21]. As noted above, specific phosphorylation of cactus by CKII is consistent with reports that mammalian ΙκΒα is a substrate for this enzyme [8]. It appears that CKII phosphorylation has been conserved in evolution, further indicating that it has a functional significance.…”

“…Fax: (44) (1223) 333345. E-mail: njgll@mole.bio.cam.ac.uk Recently, it has been shown that IKBOC is phosphorylated constitutively by casein kinase II (CKII) at 4 sites in the PEST protein stability sequences (Ser 283 , Ser 289 , Ser 293 and Thr 291 ) [8][9][10][11]. These phosphorylation sites are conserved in the equivalent sequences of cactus and may be required for signal-induced dissociation of the heterotrimeric dorsal/cactus complexes.…”

NF‐κB as a potential molecular target for cancer therapy

“…The third signaling pathway is classified as atypical because it is independent of IKK, and is activated by UV and doxorubicin, both of which cause DNA damage [105]. UV radiation induces IκBα degradation via the proteasome, but the targeted serine residues are located within a C-terminal cluster, which is recognized by the p38-activated casein kinase 2 [8,68,83]. Oxidative stress also leads to NF-κB activation via IκBα tyrosine phosphorylation [55].…”

Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation

“…The phosphorylation-defective mutants IKK-1 SS/AA and IKK-2 SS/AA (Mercurio et al, 1997), and the pMT2T-IkB-a and pMT2T-RelA (Brown et al, 1995) are as described. The dominant-negative (dm) IkB-a 3C/2N-IkBa, SS/AA, and RR/LL have been described elsewhere (Barroga et al, 1995;DiDonato et al, 1996). The dn TAK1-K63W (Yamaguchi et al, 1995) was a kind gift of Dr Sakurai (Tanabe Seiaku Co., Osaka, Japan).…”