CHUK

Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α) also known as IKK1 or conserved helix-loop-helix ubiquitous kinase (CHUK) is a is_associated_with::protein kinase that in humans is encoded by the CHUK is_associated_with::gene. IKK-α is part of the is_associated_with::IκB kinase complex that plays an important role in regulating the is_associated_with::NF-κB transcription factor. However, IKK-α has many additional cellular targets, and is thought to function independently of the NF-κB pathway to regulate epidermal differentiation.

NF-κB response
IKK-α is a member of the serine/threonine protein kinase family and forms a complex in the cell with IKK-β and NEMO. is_associated_with::NF-κB transcription factors are normally held in an inactive state by the inhibitory proteins IκBs. IKK-α and IKK-β phosphorylate the IκB proteins, marking them for degradation via is_associated_with::ubiquitination and allowing NF-κB transcription factors to go into the nucleus.

Once activated, NF-κB transcription factors regulate genes that are implicated in many important cellular processes, including immune response, inflammation, cell death, and cell proliferation.

Epidermal differentiation
IKK-α has been shown to function in epidermal differentiation independently of the NF-κB pathway. In the mouse, IKK-α is required for cell cycle exit and differentiation of the embryonic is_associated_with::keratinocytes. IKK-α null mice have a truncated snout and limbs, shiny skin, and die shortly after birth due to dehydration. Their epidermis retains a proliferative precursor cell population and lacks the outer two most differentiated cell layers. This function of IKK-α has been shown to be independent of the protein's kinase activity and of the NF-κB pathway. Instead it is thought that IKK-α regulates skin differentiation by acting as a cofactor in the TGF-β / Smad2/3 signaling pathway.

The zebrafish homolog of IKK-α has also been shown to play a role in the differentiation of the embryonic epithelium. Zebrafish embryos born from mothers that are mutant in IKK-α do not produce a differentiated outer epithelial monolayer. Instead, the outermost cells in these embryos are hyperproliferative and fail to turn on critical epidermal genes. Different domains of the protein are required for this function of IKK-α in zebrafish than in mice, but in neither case does the NF-κB pathway seem to be implicated.

Other cellular targets
IKK-α has also been reported to regulate the cell cycle protein is_associated_with::cyclin D1 in an NF-κB-independent manner.

Clinical significance
Inhibition of is_associated_with::IκB kinase (IKK) and IKK-related kinases, is_associated_with::IKBKE (IKKε) and is_associated_with::TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.

Mutations in IKK-α in humans have been linked to lethal fetal malformations. The phenotype of these mutant fetuses is similar to the mouse IKK-α null phenotype, and is characterized by shiny, thickened skin and truncated limbs.

Decreased IKK-α activity has been reported in a large percentage of human squamous cell carcinomas, and restoring IKK-α in mouse models of skin cancer has been shown to have an anti-tumorigenic effect.

Interactions
IKK-α has been shown to interact with:


 * is_associated_with::AKT1,
 * is_associated_with::AKT2,
 * CTNNB1,
 * is_associated_with::FANCA,
 * is_associated_with::IKBKG
 * is_associated_with::IKK2,
 * is_associated_with::IRAK1,
 * is_associated_with::MAP3K14,
 * is_associated_with::MAP3K7,
 * is_associated_with::MAP3K8,
 * NFKBIA,
 * NCOA3,
 * is_associated_with::PPM1B,
 * PRKDC, and
 * is_associated_with::TRAF2.