CHUK Proteins

CHUK Background

Conserved helix-loop-helix ubiquitous kinase, abbreviated for CHUK, is also called inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α/IKKA) or IKK1 ^[1]. IKK-α, a serine⁄threonine kinase, belongs to the catalytic component of the inhibitor of the NF-kappa B Kinase(IKK) complex that plays a central role in regulating the NF-κB transcription factor ^[2]. Under homeostatic conditions, NF-κ B is weakly active due to cytoplasmic sequestration via noncovalent binding to IκB (inhibitor of NF-κB) proteins ^[3]. An NF-κB-inducing kinase (NIK), a central signaling component of the noncanonical NF-κB pathway, is targeted for continuous degradation by a tumor necrosis factor (TNF) receptor-associated factor-3 (TRAF3)-dependent E3 ubiquitin ligase ^[4]. Stimulated by non-canonical signals, NIK is stabilized from proteolysis to the extent that it becomes capable of recruiting and inducing the kinase activity of IKK-α ^[5] Subsequently, IKK-α and NIK phosphorylate three serines of NF-κB2/β100 within its C-terminal IκBδ segment, leading to the processing of NF-κB2 precursor protein p100 to p52. Phosphorylation-dependent ubiquitylation and proteasomal degradation of the IκB proteins lead to the release of active NF-κB dimers ^[6]. In turn, free NF-κB is translocated into the nucleus and activates the transcription of multiple genes involved in immune response, growth control, or protection against apoptosis. Since weak IKK- α activity has been reported in a large percentage of human squamous cell carcinomas, Lahtela J et al. found that normalizing IKK-α in mouse models of skin cancer exhibited an anti-tumorigenic effect ^[7]. IKK-α mutations in humans have been associated with lethal fetal malformations, which are characterized by shiny, thickened skin and truncated limbs in appearance ^[8].

[1] Mock BA, Connelly MA, et al. CHUK, a conserved helix-loop-helix ubiquitous kinase, maps to human chromosome 10 and mouse chromosome 19 [J]. Genomics. 1995, 27 (2): 348-51.
[2] Häcker H, Karin M. Regulation and function of IKK and IKK-related kinases [J]. Sci. STKE. 2006 (357): re13.
[3] Hinz M, Scheidereit C The IκB kinase complex in NF-κB regulation and beyond [J]. EMBO Rep. 2014 Jan; 15(1):46-61.
[4] Qing G, Qu Z, Xiao G Stabilization of basally translated NF-kappaB-inducing kinase (NIK) protein functions as a molecular switch of processing of NF-kappaB2 p100 [J]. J Biol Chem. 2005 Dec 9; 280 (49):40578-82.
[5] Vallabhapurapu S, Matsuzawa A, et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling [J]. Nat Immunol. 2008 Dec; 9(12):1364-70.
[6] Hayden MS, Ghosh S Shared principles in NF-kappaB signaling [J]. Cell. 2008 Feb 8; 132(3):344-62.
[7] Liu B, Park E, et al. A critical role for IκB kinase α in the development of human and mouse squamous cell carcinomas [J]. Proc. Natl. Acad. Sci. U.S.A. 2006, 103 (46): 17202-7.
[8] Lahtela J, Nousiainen HO, et al.Mutant CHUK and severe fetal encasement malformation [J]. New England Journal of Medicine. 2010, 363 (17): 1631-1637.