Disease relevance of CHUK

• Thus, IKK complex constitutes the main intracellular target for LPS-induced NF-kappaB signaling to the nucleus in human monocytic cells to activate genes responsible for septic shock [1].
• In this report, the investigators show that LPS derived from different gram-negative bacteria activates cytokine-responsive IkappaB kinases containing catalytic subunits termed IKKalpha (IKK1) and IKKbeta (IKK2) [1].
• Immunoreactive IKK protein was found to be abundant in both RA and osteoarthritis FLS by Western blot analysis [2].
• We measured COX-2, NF-kappa B and I kappa B kinase alpha (IKK alpha) protein expression in matched colonic biopsy samples comprising both nontumour and adjacent tumour tissue from 32 colorectal cancer patients using immunohistochemistry [3].
• FLS were infected with adenovirus constructs encoding either wild-type (wt) IKK1 or IKK2, the dominant negative (dn) mutant of both kinases, or a control construct encoding green fluorescence protein [4].

Psychiatry related information on CHUK

• This crosstalk constitutes a decision-making process that determines the consequences of NF-kappaB and IKK activation and, ultimately, cell fate [5].

High impact information on CHUK

• Our genetic evidence confirms that p100 is required and sufficient as a fourth IkappaB protein for noncanonical NF-kappaB signaling downstream of NIK and IKK1 [6].
• CHUK specifically phosphorylates IkappaB-alpha on both serine 32 and serine 36, modifications that are required for targeted degradation of IkappaB-alpha via the ubiquitin-proteasome pathway [7].
• Overexpression of CHUK activates a NF-kappaB-dependent reporter gene [7].
• Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression [8].
• We find that IKK is composed of similar amounts of IKK-alpha, IKK-beta and two other polypeptides, for which we obtained partial sequences [9].

Chemical compound and disease context of CHUK

• Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells [10].

Biological context of CHUK

• The nucleotide sequence of a near full-length murine CHUK cDNA clone revealed an encoded polypeptide specifying: a carboxyl-terminal H-L-H domain, an amino terminal serine-threonine kinase catalytic domain, and a leucine zipper-like amphipathic alpha-helix juxtaposed in between the H-L-H and kinase domains [11].
• CHUK may provide new insights into the regulated transmission of cytoplasmic signals to specific nuclear factors manifesting rapid alterations in patterns of cellular gene expression [11].
• Taken together, our results not only reveal the IKK-mediated phosphorylation of SRC-3 to be a regulated event that plays an important role but also substantiate the role of SRC-3 in multiple signaling pathways [12].
• However, the precise molecular mechanisms by which IKK may contribute to the development of insulin resistance are not well understood [13].
• In addition to modulation of IKK activity, the NF-kappa B pathway is also regulated by other processes, including the nucleocytoplasmic shuttling of various components of this pathway and the post-translational modification of factors bound to NF-kappa B-dependent promoters [14].

Anatomical context of CHUK

• CHUK is highly conserved in evolution and ubiquitously expressed in diverse types of established cell lines, whereas it is differentially expressed in normal murine tissues [11].
• IKK beta overexpression in a Jurkat cell line resulted in the formation of a constitutively active IKK complex, which was CD3/CD28 inducible [15].
• There was none or very little expression of COX-2, NF-kappa B and IKK alpha in non-neoplastic colon epithelial cells, while the expression of all three of these proteins was significantly increased (P<0.05, Wilcoxon's signed rank test) in adjacent cancerous cells [3].
• In the present study, C-terminal truncated forms of IKK gamma--Delta C-IKK gamma 306 and Delta C-IKK gamma 261--were stably expressed in the myeloid cell line U937 by retroviral-mediated gene transfer [16].
• Tumor necrosis factor alpha triggers proliferation of adult neural stem cells via IKK/NF-kappaB signaling [17].

Associations of CHUK with chemical compounds

• Geldanamycin (GA), an antitumor agent that disrupts the formation of this heterocomplex, prevents TNF-induced activation of IKK and NF-kappaB [18].
• IKK activity was stimulated by both TNF-alpha and TPA, and these effects were inhibited by staurosporine or herbimycin [19].
• Prolonged incubation in the presence of LMB also leads to nuclear accumulation of IKK1, which was dependent on a lysine residue at position 44, which is also essential for kinase activity [20].
• We describe a small molecule, selective inhibitor of IKK-2, SC-514, which does not inhibit other IKK isoforms or other serine-threonine and tyrosine kinases [21].
• Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells [22].

Physical interactions of CHUK

• In this study, we explored the role of the nucleocytoplasmic shuttling of components of the IKK complex in the regulation of the NF-kappa B pathway [14].
• Immunoprecipitation analysis revealed that PKR interacts with the IKK complex [23].
• The phosphorylation of IkappaBalpha on Ser(32) and Ser(36) is initiated by an IkappaB kinase (IKK) complex that includes a catalytic heterodimer composed of IkappaB kinase 1 (IKK-1) and IkappaB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator [24].
• This suggests that the IKK-2 catalytic subunit provides nearly all of the catalytic activity of the msIKK complex with the IKK-1 subunit providing little contribution to catalysis [25].
• By co-immunoprecipitation studies, we found that Hsp27 interacts with IKK-alpha and IKK-beta, and this association was increased in SAP-treated conditioned epithelial cells [26].

Enzymatic interactions of CHUK

• In addition, we showed that SRC-3 was phosphorylated by the IKK complex in vitro [12].
• A mutant form of IKK-alpha containing alanine at residue 176 cannot be phosphorylated or activated by NIK and acts as a dominant negative inhibitor of interleukin 1- and tumor necrosis factor-induced NF-kappaB activation [27].

Regulatory relationships of CHUK

• NIK cannot phosphorylate IkappaB-alpha directly, but it appears to be a functionally important subunit, because mutated NIK inhibited stimulus-induced kappaB-dependent transcription more effectively than mutated IKK-alpha or -beta [28].
• Our laboratory has delineated that the phosphatidylinositol 3' kinase (PI3K)/AKT/I kappa B kinase (IKK) pathway positively regulates NF kappa B and beta-catenin, both important transcriptional regulators in colorectal cancer (CRC) [29].
• IKK activity was stimulated by either IL-1beta or TPA, and these effects were inhibited by Ro 31-8220 or tyrphostin 23 [30].
• Finally, we show that IKK-alpha is present in the MEKK1-inducible, high molecular weight IkappaB kinase complex and treatment of this complex with MEKK1 induces phosphorylation of IKK-alpha in vitro [31].
• Nonetheless, dibutyryl-cAMP or forskolin did not affect the IKK activation induced by IL-1 [32].
• These results indicate that FAF1 inhibits IKK activation and its downstream signaling by interrupting the IKK complex assembly through physical interaction with IKKbeta [33].

Other interactions of CHUK

• The IKK complex, containing two catalytic subunits IKKalpha and IKKbeta and a regulatory subunit NEMO, plays central roles in signal-dependent activation of NF-kappaB [18].
• We identify Cdc37 and Hsp90 as two additional components of the IKK complex [18].
• Canonical activation of NF-kappa B is mediated via phosphorylation of the inhibitory I kappa B proteins by the I kappa B kinase complex (IKK) [34].
• The TANK binding domain within NEMO/IKK gamma is required for proper functioning of this IKK subunit [34].
• In a yeast two-hybrid screen for NIK-interacting proteins, we have identified a protein kinase previously known as CHUK [7].

Analytical, diagnostic and therapeutic context of CHUK

• We observed interactions between endogenous IRS-1 and IKK in intact cells using a co-immunoprecipitation approach [13].
• Northern blot analysis showed that IKK-1 and IKK-2 genes were constitutively expressed in all FLS lines [2].
• IKKalpha, a subunit of IkBalpha kinase (IKK) complex, has an important role in the activation of nuclear factor-kB (NF-kB), a key regulator of normal and tumor cell proliferation, apoptosis, and response to chemotherapy [35].
• In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators [36].
• Using immunoblotting, we have shown that HT augments phosphorylation of IKK-beta and IKK-alpha (up to an 8-fold increase at 28 degrees C and a 3.6-fold increase at 32 degrees C vs. 37 degrees C) [37].

References