Abstract
NF-κB-inducing kinase (NIK), the essential upstream kinase, which regulates activation of the noncanonical NF-κB pathway, has important roles in regulating immunity and inflammation. In addition, NIK is vital for maintaining cellular health through its control of fundamental cellular processes, including differentiation, growth, and cell survival. As such aberrant expression or regulation of NIK is associated with several disease states. For example, loss of NIK leads to severe immune defects, while the overexpression of NIK is observed in inflammatory diseases, metabolic disorders, and the development and progression of cancer. This review discusses recent studies investigating the therapeutic potential of NIK inhibitors in various diseases.
Highlights
The canonical NF-κB pathway is well characterized for having an inhibitor of kappa B kinase (IKK) complex consisting of IKKα, IKKβ, and IKKγ [4]
NF-κB-inducing kinase (NIK) was found to play a cell-intrinsic role in regulating intestinal homeostasis, promoting mucosal immunity against pathogens, as well as promoting chronic inflammation associated with inflammatory bowel disease (IBD) [33]
As NIK has a crucial role in hematopoiesis, its dysregulation has been well studied in leukemias and lymphomas
Summary
Nuclear factor-kappa light chain enhancer of activated B cells (NF-κB) refers to a family of evolutionarily conserved transcription factors that regulate a wide range of biological processes, including cell growth and survival to immunity and inflammation [1]. The canonical NF-κB pathway is well characterized for having an inhibitor of kappa B kinase (IKK) complex consisting of IKKα, IKKβ, and IKKγ ( known as NEMO) [4]. Activated IKKβ phosphorylates and induces the proteasomal degradation of IκBα (inhibitory kappa B alpha), which sequesters RelA-p50. NNuucclleeaarrffaaccttoorr--kkaappppaalliigghhtt cchhaaiinn eennhhaanncceerr ooff aaccttiivvaatteedd BB cceellllss ((NNFF--κκBB)) ppaatthhwwaayyss. [T1h1,o1u2g].hThinoiutigahllyiniitdiaelnlytifiideedntbifyieidtsbyabitislitaybitloityatcotiavcattievattheethceancaonnoicnailcaNl NF-Fκ-BκBppatahthwwaay,y,lolossss ooff NNIIKK ddiidd nnoott iimmppaaiirr TTNNFF--iinndduucceedd aaccttiivvaattiioonn ooff IIKKKKββ//pp6655//pp5500,, aanndd NNIIKK wwaass ssuubbsseeqquueennttllyy sshhoowwnn ttoo bbee eesssseennttiiaall ffoorr aaccttiivvaattiioonn ooff nnoonnccaannoonniiccaall NNFF--κκBB ssiiggnnaalliinngg [[1133,,1144]]. RReegguullaattiioonn ooff NNIIKK aaccttiivviittyy ooccccuurrss primarily at the post-translational level This serine/threonine kinase has four domains including a. N-terminal region for TRAF3 binding, a negative regulatory domain (NRD), a core kinase domain, Int. J. This serine/threonine kinase has four domains inclu3dofin19g a N-terminal region for TRAF3 binding, a negative regulatory domain (NRD), a core kinase domain, andanadCa-tCe-rtmerimnainl dalodmoaminairnesrpeosnpsoinbsliebfloerfboirnbdiinndginwgitwh ipthropteriontseisnuschsuacshIKasKIαKaKnαd apn1d00p(1F0ig0u(rFeig2u)r[e152,)16]. It plays criNticIaKl rioslbesesint kbnotohwthnefdoreviteslorpegmuelnattioofnlyomf pthheoidmomrguannes,saysswteemll adsetvheelofupnmcteinont aonf difufenrecntitoinm. mItupnleays critcieclalsl,rionlcelsuidninbgotBh-ctehlels,dTe-vceellolsp,mmeancrtoopfhlyagmeps,hdoeinddorrigtiacncse,llass, awnedllhaesmtahteopfuoniecttiicosnteomf dcieffllesre(HntSiCms)m. une cells, including B-cells, T-cells, macrophages, dendritic cells, and hematopoietic stem cells (HSCs)
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