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Rangwala, A.; Mingione, V.; , .; Seeliger, M. Kinases on Double Duty. Encyclopedia. Available online: https://encyclopedia.pub/entry/23368 (accessed on 15 April 2024).
Rangwala A, Mingione V,  , Seeliger M. Kinases on Double Duty. Encyclopedia. Available at: https://encyclopedia.pub/entry/23368. Accessed April 15, 2024.
Rangwala, Aziz, Victoria Mingione,  , Markus Seeliger. "Kinases on Double Duty" Encyclopedia, https://encyclopedia.pub/entry/23368 (accessed April 15, 2024).
Rangwala, A., Mingione, V., , ., & Seeliger, M. (2022, May 25). Kinases on Double Duty. In Encyclopedia. https://encyclopedia.pub/entry/23368
Rangwala, Aziz, et al. "Kinases on Double Duty." Encyclopedia. Web. 25 May, 2022.
Kinases on Double Duty
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Phosphorylation facilitates the regulation of all fundamental biological processes, which has triggered extensive research of protein kinases and their roles in human health and disease. In addition to their phosphotransferase activity, certain kinases have evolved to adopt additional catalytic functions, while others have completely lost all catalytic activity.

kinase signal transduction

1. Introduction

Protein phosphorylation regulates prokaryotic and eukaryotic cellular processes and signal transduction [1]. In humans, protein phosphorylation is mediated by 538 protein kinases, which comprise 3% of the human genome [2][3]. Protein kinases control metabolism, transcription, translation, cell cycle progression, cytoskeletal rearrangement, apoptosis, differentiation, intracellular communication, and homeostasis; thus, their dysregulation drives many human diseases. Development of small molecule kinase inhibitors has yielded 71 FDA-approved compounds used in the treatment of various cancers and inflammatory diseases [4][5].
Most FDA-approved kinase inhibitors bind to the highly conserved adenosine triphosphate (ATP)-binding pocket and prevent binding of substrate ATP. Surprisingly, some kinase targets have been found to retain or even increase their downstream signaling despite binding to ATP-competitive inhibitors. For example, certain BRAF inhibitors and kinase-dead BRAF mutants paradoxically activate downstream MEK phosphorylation by inducing dimerization and activation of uninhibited BRAF and CRAF [6][7][8]. The RAF family kinases exemplify the many noncatalytic functions of kinases, which extend to scaffolding, allosteric regulation, protein-DNA interactions, subcellular targeting, and beyond [9][10].
Protein kinases can exhibit catalytic activities other than phosphotransfer. For example, Ire1α is an evolutionarily conserved member of the unfolded protein response pathway (UPR) and contains both a protein kinase domain and an endoribonuclease domain. The UPR is a stress response pathway that responds to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by producing molecular chaperones and halting translation. Misfolded proteins induce Ire1α dimerization, which subsequently activates the ribonuclease domain (RNase) domain to splice transcription factor XBP1 and upregulate UPR response genes. Feldman and coworkers explored the allosteric relationship between Ire1α’s kinase and RNase domains by screening commercially available ATP-competitive kinase inhibitors and imidazopyrazine-based kinase-inhibiting RNase attenuators (KIRAs) [11]. Inhibitors of Ire1α kinase were found to bind and stabilize specific kinase domain conformations. Some kinase inhibitors promoted dimerization and activated the enzyme’s RNase activity, whereas the KIRAs stabilized monomeric Ire1α and inhibited both kinase and RNase activity. This work provides a proof-of-concept that ATP-competitive inhibitors can influence the non-phosphotransferase functions of their target kinases.
Bifunctional kinases such as Ire1α have the potential to reveal unique modes of allosteric regulation between different protein domains, as well as provide mechanistic insights into the functional benefits of having two signaling activities within the same enzyme. This knowledge can be further employed to guide drug discovery or drug repurposing campaigns toward finding unique strategies for specific and effective kinase inhibition. There may also be functional benefits to having two signaling activities on one enzyme, as is seen in other multi-domain enzyme complexes like fatty acid synthase.

2. Regulation of Phosphoinositide Signaling Pathways

2.1. Phosphatidylinositol 3-Kinases (PI3K)

PI3Ks are ubiquitously expressed intracellular lipid kinases that phosphorylate the 3′ hydroxyl groups of phosphatidylinositol and also harbor Ser/Thr protein kinase activity. These proteins regulate several critical cellular functions including cell survival, proliferation, motility, and vesicle trafficking [12][13]. PI3Ks are divided into three classes (class I, II, and III) based on their primary structure and substrate specificity. Class-I PI3Ks are further separated into subclasses IA (PI3Kα, PI3Kβ, PI3Kδ) and IB (PI3Kγ) based on their regulatory proteins and signaling pathway involvement.
PI3Ks function as heterodimers, consisting of a regulatory subunit and a catalytic subunit that converts the phosphatidylinositol second messenger PI(3,4)P2 (PIP2) to PI(3,4,5)P3 (PIP3) in response to extracellular stimuli on the activation of upstream receptor tyrosine kinases (RTKs) and G-protein coupled receptors (GPCRs) [14][15]. Conversion of PIP2 to PIP3 promotes the activation of downstream proteins AKT and mTOR [16]. PI3K activity is antagonized by the PTEN phosphatase, which hydrolyzes PIP3 to PIP2 [17]. As PIP3 plays a critical role in cell growth and replication, aberrant lipid kinase activity can promote oncogenic signaling. Class-I proteins have been recognized as promising drug targets due to their involvement in cancer and immune disease pathogenesis via the PI3K/mTOR pathway. The structural conservation of the ATP-binding pocket has complicated the development of isoform-specific inhibitors. Pan-PI3K inhibitors are active against all class-I isoforms and result in off-target toxicity and side effects. To date, there are five FDA-approved PI3K inhibitors (alpelisib, copanlisib, duvelisib, idelalisib, and umbralisib). While PI3K kinase inhibitors have been successfully applied to certain malignancies, their use and development has been hindered by poor drug tolerance and toxicity [18].

2.2. PI3Kα (PIK3CA)

PIK3CA encodes the phosphatidylinositol 3-kinase catalytic subunit alpha (PI3Kα), also known as p110α. PI3Kα is the predominant catalytic isoform for regulation of glucose homeostasis and is commonly mutated and amplified in a variety of cancers [19]. The catalytic p110α subunit is composed of five domains, including an adaptor binding domain (ABD) that binds to the Class-IA regulatory domains, a Ras binding domain (RBD), a C2 domain that binds to cell membranes, a helical domain with unknown function, and a catalytic kinase domain. PI3Kα activation is mediated by receptor tyrosine kinases (RTKs), Ras proteins, and additional small molecules including calmodulin [20][21].
The catalytic p110α subunit can couple to regulatory subunit p85α, the SH2 domain of which contains high-affinity binding sites to the phosphorylated tyrosine motif (pYXXM) found in the C-terminus of RTKs [22]. The RTK pYXXM motif disrupts interactions between the catalytic p110α subunit and regulatory p85α subunit and activates PI3Kα by releasing the inhibitory p85α SH2 domains from the catalytic p110α subunit. This release triggers a conformational change in PI3Kα that exposes the kinase domain and permits membrane binding [23]. It has been shown that p110α phosphorylates Ser608 of the p85α regulatory subunit and decreases catalytic activity in vitro [24]. Mutation of Ser608 to Ala or Glu reduced lipid kinase activity, as well as the interactions between the p110α catalytic subunit and p85α regulatory subunit. Thus, phosphorylation of Ser608 may reveal a mechanism for regulating activity by stabilizing the autoinhibited state.
Mutations in PI3Kα are frequently found in brain, breast, head and neck, endometrial, cervical, and gastric cancers [16][25][26]. Most mutations cause gain-of-function (GOF) and are found within the helical or kinase domains. It has been reported that GOF mutations in the helical domain require interactions with Ras-GTP, whereas kinase domain mutations require interactions with the p85 regulatory subunit [27]. Co-existing mutations in both domains have been found to synergistically increase the catalytic function and tumorigenic activity [28]. In addition, deletions in the C2 domain have been found to activate PI3K signaling while also increasing the sensitivity to PI3Kα inhibitors, suggesting that residues within the C2 domain are critical for for PI3Kα function [29]. There are several hotspot mutations in p110α that confer a gain of function, including helical domain mutations E545K and E542K and the catalytic domain mutation H1047R. Helical domain mutations E545K and E542K have been shown to suppress inhibition of p110α by the p85 regulatory subunit, which results in mutation-driven signaling that promotes glucose metabolism and cervical cancer cell proliferation [30]. Catalytic domain mutation H1047R has been shown to enhance interactions between p110α and the lipid membrane, thereby enhancing its lipid kinase activity and downstream signaling.
The importance of PI3Kα in disease has been well-established; in May 2019, alpelisib (Piqray™, Novartis, Morris County, NJ, USA) was the first PI3Kα inhibitor approved by the FDA for the treatment of breast cancer [31]. Alpelisib has specific activity for PI3Kα over other isoforms, despite their nearly identical active sites, and potently inhibits common mutations such as E545K and H1047R.

2.3. PI3Kγ (PIK3CG)

PIK3CG encodes for the phosphatidylinositol 3-kinase catalytic subunit gamma (PI3Kγ), also known as p110γ. PI3Kγ belongs to class-IB PI3Ks and has both lipid and Ser/Thr protein kinase activity. It regulates immune stimulation and suppression in inflammation and cancer [32]. The PI3Kγ catalytic subunit has five domains, consisting of a putative uncharacterized adaptor binding domain (ABD), a Ras-binding domain (RBD), a C2 domain for binding cell membranes, an α-helical domain, and a catalytic kinase domain [33][34]. PI3Kγ activation is primarily regulated through interactions with GPCRs, which occur through association of the PI3Kγ regulatory subunit with the G-protein βγ subunits [35][36]. It can also be activated through interaction between the PI3Kγ RBD domain and Ras GTPases [37]. In the absence of lipid membrane binding, PI3Kγ maintains an inactive conformation [38].
In contrast to PI3Kα, PI3Kγ is commonly upregulated or overexpressed in cancer rather than mutated; however, mutations have been identified in cancer patients [39][40]. Loss-of-function mutations in PI3Kγ cause severe immunodeficiency, highlighting PI3Kγ’s critical role in promoting appropriate adaptive immune responses [41]. PI3Kγ is also a driver of inflammatory and metabolic disorders including rheumatoid arthritis, atherosclerosis, lupus, obesity, and pulmonary fibrosis [42].

2.4. PIKfyve (PIKFYVE)

PIKfyve is a bifunctional lipid kinase with Ser/Thr protein kinase activity. PIKfyve and its enzymatic products regulate cellular processes including membrane trafficking, ion channel activity, cytoskeletal dynamics, nuclear transport, stress- and hormone-induced signaling, transcription, and cell cycle progression [43][44].
As a lipid kinase, it synthesizes phosphoinositides (PIs) PtdIns(3,5)P2 from PtdIns3P and PtdIns5P from PtdIns. Synthesis of PtdIns(3,5)P2 by PIKfyve is negatively regulated by the formation of a multi-protein complex with scaffolding regulator ArPIKfyve and phosphatase Sac3 [45]. The cryo-EM structure revealed that formation of this complex sterically hinders PIKfyve from accessing membrane-associated PIs [44]. Serine residue autophosphorylation of PIKfyve represses its own lipid kinase activity and simultaneously activates Sac3 lipid phosphatase activity to downregulate lipid product synthesis [44]. Sac3 is also a serine phosphatase that acts on PIKfyve to increase the lipid kinase activity [44]. PIKfyve kinase activity is required for Sac3 lipid phosphatase activity [44], meaning that its dual function is critical for maintaining the delicate balance of lipid homeostasis. However, given the presence of multiple phospho-sites on PIKfyve and its role as a target in multiple signaling pathways, how the delicate balance between the dual activities of PIKfyve and Sac3 is maintained remains unknown.
PIKfyve has four structured domains including a FYVE finger domain, which targets the protein to PtdIns3P-enriched endosome membranes, and a DEP domain with unknown function. The middle of the protein interacts with several binding partners and contains two domains, a Cpn60-TCP1 domain, which has sequence similarity to chaperonins, and a CHK homology region containing the conserved Cys, His, and Lys residues found in all PIKfyve orthologs. The PIKfyve catalytic domain controls all three of its catalytic functions (PtdIns(3,5)P2/PtdIns5P synthesis and protein phosphorylation) and contains a single ATP-binding site. Mutation of the catalytic Lys-1831 abrogates all three kinase activities [46]. Mutations in PIKfyve cause functional defects in endosomal sorting, leading to Francois-Neetens fleck corneal dystrophy [47].

3. Regulation of Transcription and Translation

3.1. Ire1α (ERN1)

Ire1α is a ubiquitously expressed transmembrane ER stress sensor that functions as a Ser/Thr protein kinase and endoribonuclease. It is the best-studied branch of the unfolded protein response (UPR), an integrated intracellular signal transduction pathway that is activated in response to the accumulation of unfolded proteins in the ER [48]. The UPR initially responds to ER stress by blocking translation and upregulating molecular chaperones and folding enzymes. Prolonged cell stress causes a switch to pro-apoptotic and pro-inflammatory signaling cascades. The UPR has become an attractive pathway for drug discovery efforts due to its involvement in cancer, inflammation, neurological disorders, diabetes, and ischemia-reperfusion injury [49].
Ire1α contains an N-terminal ER luminal domain bound to cytoplasmic Ser/Thr kinase and endoribonuclease domains through a transmembrane linker [50]. The accumulation of misfolded protein causes Ire1α to dimerize in a “back-to-back” orientation [51], resulting in the formation of high-order oligomers and release of the ER Hsp70 chaperone BiP from the inactive Ire1α monomer. Thus, Ire1α activation is facilitated by luminal domain dimerization and trans-autophosphorylation of the cytosolic kinase domains [52][53]. Phosphorylation of the Ire1α activation segment stabilizes the RNase domain, which excises a 26-nucleotide intron from XBP1 [51][54]. The two spliced exons are then ligated by RNA ligase RtcB to form XBP1s [55], which encode an essential transcription factor for downstream activation of UPR response genes [56][57].

3.2. Ire1β (ERN2)

Ire1β is a close paralog of Ire1α. It has dual Ser/Thr protein kinase and endoribonuclease activities and induces the unfolded protein response (UPR) through transcription factor XBP1 [54][57], albeit less effectively than Ire1α [58]. Like Ire1α, it contains separate kinase and endoribonuclease domains. Ire1β serves as a direct and dominant-negative suppressor of Ire1α, dampening the UPR and ER stress response in epithelial cells of the intestine and other mucosal surfaces [52][59].

3.3. Protein Kinase R (EIF2AK2)

The eukaryotic translation initiation factor 2α kinase 2 (EIF2AK2), also known as protein kinase R (PKR) and interferon-induced double-stranded RNA-activated protein kinase, is a dual-specificity Ser/Thr and Tyr protein kinase. It contains two dsRNA binding motifs (dsRBD) and a kinase domain. PKR has been extensively studied as a regulator of the integrated stress response to RNA and DNA viruses, working as both a translational repressor through phosphorylation of Ser-51 on EIF2α and as a transcriptional upregulator of innate immune pathway proteins including Iκβ and NF-κβ [60][61][62]. On DNA damage, PKR halts the G2-M cell cycle transition by phosphorylating Tyr-4 of CDK1, causing its ubiquitination and proteasomal degradation [63]. PKR is a critical signaling mediator of cell proliferation and apoptosis through its interactions with p38 MAP kinase, NF-κβ, and the insulin signaling pathways [62][64][65][66]. It is ubiquitously expressed in vertebrates [67] and is implicated in cancer, neurodegeneration, inflammation, aging, and metabolic disorders [68][69].
The most widely used PKR inhibitor is C16, an imidazo-oxindole inhibitor with an in vitro IC50 of 210 nM; however, less potent inhibitors including 2-aminopurine have also been developed [69]. As an ATP-competitive inhibitor, C16 inhibits both the Ser/Thr and Tyr kinase functions of PKR and has been investigated for use in memory enhancement [70], neurodegeneration [71], inflammation [72], and metabolic disorders [73].

3.4. RIOK1 (RIOK1)

RIOK1 is a Ser/Thr protein kinase and ATPase in the Rio (right open reading frame) family of atypical protein kinases. In humans, there are three Rio subfamilies: Rio1 and Rio2 are conserved across all kingdoms of life, while Rio3 is only found in multicellular eukaryotes [74]. Specifically, RIOK1 functions in processes essential for cell proliferation, cell cycle progression, and chromosome maintenance. Yeast and human RIOK1 kinases are essential for the biogenesis of small ribosomal subunits, and depletion of this enzyme causes cell cycle arrest in yeast. Although RIOK1 is classified as a Ser/Thr kinase [75], it predominantly acts as an ATPase and regulates pre-40S ribosomal subunit association [76].
The RIO kinase domain adopts the conserved bilobal kinase domain structure but lacks an activation loop and substrate recognition sites. It instead contains a C-terminal RIO-kinase specific αR helix and a flexible loop between β3 and helix αC, which together allow it to accommodate a phospho-Asp substrate and serve as an ATPase [77]. At this time, there are no specific RIOK1 inhibitors. However, RNAi-mediated knockdown of RIOK1 reduced cell proliferation in RAS-driven cancer cell lines [78], making it an alluring target for drug discovery efforts.

3.5. TATA-Box Binding Protein Associated Factor 1/Transcription Initiation Factor TFIID Subunit 1 (TAF1)

TATA-box binding protein associated factor 1 (TAF1) is a Ser/Thr protein kinase and histone acetyltransferase with ubiquitin-activation and -conjugation activities [79]. TAF1 is the largest subunit of TFIID and binds core promoter sequences and transcriptional regulators. TFIID, which initiates RNA-polymerase II-dependent transcription, is the core scaffold for the TFIID basal transcription factor complex [80][81]. TFIID is comprised of the evolutionarily conserved TATA binding protein (TBP) and multiple TBP-associated factors (TAFs).
TAF1 is a bipartite kinase composed of N- and C-terminal kinase domains (NTK and CTK) and a centrally located histone acetyltransferase domain (HAT) [82]. Between the HAT and CTK domains are two bromodomains that selectively bind to multiply acetylated histone H4 peptides [83]. TAF1 acetylates histones H3 and H4 [84], and TAF1-mediated acetylation of H3 is required for Sp1 activation of cyclin D1 transcription and G1 to S-phase cell cycle progression [85]. Both TAF1 kinase domains are necessary for Ser phosphorylation of the TFIIF subunit transcription factor RAP74 and initiation of the RNA polymerase II transcription complex assembly [82][86]. TAF1 also phosphorylates tumor suppressor p53 on Thr-55, resulting in Mdm2-mediated p53 degradation and progression through G1 of the cell cycle [87]. Interaction between retinoblastoma protein Rb and TAF1 inhibits its kinase activity, which suggests that TAF1 may play a role in tumor suppression [88]. Mutations to the TAF1 gene cause X-linked dystonia parkinsonism and X-linked syndromic intellectual development disorder-33 [89][90]; however, the specific mechanisms by which TAF1 mutations drive these diseases are unknown.

3.6. MHC Class II Transactivator (CIITA)

MHC class-II transactivator (CIITA) is a Ser/Thr protein kinase and histone acetyltransferase that functions as a transcriptional coactivator and as the master regulator of major histone compatibility complex (MHC) class-II gene expression [91]. CIITA is a functional homolog of TAF1 and uses multiple mechanisms to activate transcription initiation and elongation [92][93]. CIITA phosphorylates the C-terminal of TAF7, a component of the TFIID promoter complex, and Ser-36 of histone H2B [94]. Its acetyltransferase domain is required for de novo transcription of MHC class-II genes and enhanced transcription of MHC class-I genes [95]. Autophosphorylation of CIITA markedly increases its acetyltransferase activity, which suggests that the acetyltransferase domain is regulated by CIITA’s intrinsic kinase activity [94].
CIITA is the only documented transcription factor in the nucleotide-binding oligomerization (NOD) family and contains a conserved tripartite structure consisting of a variable N-terminal effector-binding domain (EBD), a central NOD domain, and a C-terminal region with a variable number of leucine-rich repeats [92]. Its N-terminal acidic domain for transcriptional transactivation contains its histone acetyltransferase domain (HAT), followed by a proline-, serine-, and threonine-rich domain (P/S/T domain) with multiple phosphorylation sites [96]. The central nucleotide-binding domain (NACHT domain) acts as a kinase domain, and in conjunction with the C-terminal leucine-rich repeats, it affects self-association and nuclear import [97][98]. Mutations in the CIITA gene cause severe immunodeficiency syndrome, also known as bare lymphocyte syndrome [99].

3.7. p53-Related Protein Kinase (TP53RK)

The p53-related protein kinase (PRPK) and its homologs Bud32/Kae1 are Ser/Thr protein kinases and ATPases present in eukaryotes including yeast, humans, and pathogenic fungi including Candida albicans, Coccidioides immitis, and Cryptococcus neoformans. PRPK is one component of the highly conserved EKC/KEOPS complex (endopeptidase-like and kinase associated to transcribed chromatin/kinase, endopeptidase, and other proteins of small size). The EKC/KEOPS complex is required for the universal threonyl carbamoyl adenosine (t6a) tRNA modification, which is found in all tRNAs that pair with ANN codons where N is any of the four bases [100]. The EKC/KEOPS complex and t6a modification are critical for life, with remarkable sequence conservation from archaea to mammals [101][102].
PRPK maintains the conserved human kinase domain architecture including the regulatory and catalytic spines, a DFG motif, and a salt bridge between the invariant lysine in β3 and the invariant glutamate in helix αC [103]. There is high functional conservation between PRPK and its yeast homolog Bud32 [104]. Bud32′s regulatory partner Kae1 (OSGEP in humans) switches its intrinsic kinase activity to ATPase activity, which is required for EKC/KEOPS complex function [105]. Kae1 binds to the C-terminal lobe of Bud32 while Cgi121 (TPRKB in humans) binds to the N-terminal lobe, with the catalytic residues Lys-52, Asp-161, and Asp-182 interacting between the two lobes [106]. Based on the similarity between Bud32 and the Rio2 atypical kinase, it is hypothesized that its ATPase activity is required for the dissociation of tRNA from the complex.
Mutations in PRPK and the EKC/KEOPS complex cause Galloway-Mowat syndrome, an autosomal recessive disease characterized by a combination of early-onset nephrotic syndrome and microcephaly with brain anomalies [107]. PRPK is phosphorylated at Ser-250 by AKT [108] and is a promising therapeutic target in colon adenocarcinomas, cutaneous squamous carcinomas [107], and multiple myeloma [109].

References

  1. Endicott, J.A.; Noble, M.E.; Johnson, L.N. The structural basis for control of eukaryotic protein kinases. Annu. Rev. Biochem. 2012, 81, 587–613.
  2. Manning, G.; Whyte, D.B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science 2002, 298, 1912–1934.
  3. Fabbro, D.; Cowan-Jacob, S.W.; Moebitz, H. Ten things you should know about protein kinases: IUPHAR Review 14. Br. J. Pharmacol. 2015, 172, 2675–2700.
  4. Roskoski, R., Jr. Properties of FDA-approved small molecule protein kinase inhibitors: A 2022 update. Pharmacol. Res. 2022, 175, 106037.
  5. Attwood, M.M.; Fabbro, D.; Sokolov, A.V.; Knapp, S.; Schioth, H.B. Trends in kinase drug discovery: Targets, indications and inhibitor design. Nat. Rev. Drug Discov. 2021, 20, 839–861.
  6. Hatzivassiliou, G.; Song, K.; Yen, I.; Brandhuber, B.J.; Anderson, D.J.; Alvarado, R.; Ludlam, M.J.; Stokoe, D.; Gloor, S.L.; Vigers, G.; et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010, 464, 431–435.
  7. Heidorn, S.J.; Milagre, C.; Whittaker, S.; Nourry, A.; Niculescu-Duvas, I.; Dhomen, N.; Hussain, J.; Reis-Filho, J.S.; Springer, C.J.; Pritchard, C.; et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010, 140, 209–221.
  8. Poulikakos, P.I.; Zhang, C.; Bollag, G.; Shokat, K.M.; Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010, 464, 427–430.
  9. Kung, J.E.; Jura, N. Structural Basis for the Non-catalytic Functions of Protein Kinases. Structure 2016, 24, 7–24.
  10. Rauch, J.; Volinsky, N.; Romano, D.; Kolch, W. The secret life of kinases: Functions beyond catalysis. Cell Commun. Signal. 2011, 9, 23.
  11. Feldman, H.C.; Tong, M.; Wang, L.; Meza-Acevedo, R.; Gobillot, T.A.; Lebedev, I.; Gliedt, M.J.; Hari, S.B.; Mitra, A.K.; Backes, B.J.; et al. Structural and Functional Analysis of the Allosteric Inhibition of IRE1alpha with ATP-Competitive Ligands. ACS Chem. Biol. 2016, 11, 2195–2205.
  12. Cantley, L.C. The phosphoinositide 3-kinase pathway. Science 2002, 296, 1655–1657.
  13. Vivanco, I.; Sawyers, C.L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2002, 2, 489–501.
  14. Locke, M.N.; Thorner, J. Regulation of TORC2 function and localization by Rab5 GTPases in Saccharomyces cerevisiae. Cell Cycle 2019, 18, 1084–1094.
  15. Martinez Marshall, M.N.; Emmerstorfer-Augustin, A.; Leskoske, K.L.; Zhang, L.H.; Li, B.; Thorner, J. Analysis of the roles of phosphatidylinositol-4,5-bisphosphate and individual subunits in assembly, localization, and function of Saccharomyces cerevisiae target of rapamycin complex 2. Mol. Biol. Cell 2019, 30, 1555–1574.
  16. Cheng, H.; Orr, S.T.M.; Bailey, S.; Brooun, A.; Chen, P.; Deal, J.G.; Deng, Y.L.; Edwards, M.P.; Gallego, G.M.; Grodsky, N.; et al. Structure-Based Drug Design and Synthesis of PI3Kalpha-Selective Inhibitor (PF-06843195). J. Med. Chem. 2021, 64, 644–661.
  17. Maehama, T.; Dixon, J.E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 1998, 273, 13375–13378.
  18. Hanker, A.B.; Kaklamani, V.; Arteaga, C.L. Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors. Cancer Discov. 2019, 9, 482–491.
  19. Molinaro, A.; Becattini, B.; Mazzoli, A.; Bleve, A.; Radici, L.; Maxvall, I.; Sopasakis, V.R.; Molinaro, A.; Backhed, F.; Solinas, G. Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kalpha and PI3Kbeta Activities and Is Promoted by RAS. Cell Metab. 2019, 29, 1400–1409.E5.
  20. Fruman, D.A.; Rommel, C. PI3K and cancer: Lessons, challenges and opportunities. Nat. Rev. Drug Discov. 2014, 13, 140–156.
  21. Zhang, M.; Jang, H.; Gaponenko, V.; Nussinov, R. Phosphorylated Calmodulin Promotes PI3K Activation by Binding to the SH2 Domains. Biophys. J. 2017, 113, 1956–1967.
  22. Nolte, R.T.; Eck, M.J.; Schlessinger, J.; Shoelson, S.E.; Harrison, S.C. Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes. Nat. Struct. Biol. 1996, 3, 364–374.
  23. Zhang, M.; Jang, H.; Nussinov, R. The mechanism of PI3Kalpha activation at the atomic level. Chem. Sci. 2019, 10, 3671–3680.
  24. Foukas, L.C.; Beeton, C.A.; Jensen, J.; Phillips, W.A.; Shepherd, P.R. Regulation of phosphoinositide 3-kinase by its intrinsic serine kinase activity in vivo. Mol. Cell. Biol. 2004, 24, 966–975.
  25. Fruman, D.A.; Chiu, H.; Hopkins, B.D.; Bagrodia, S.; Cantley, L.C.; Abraham, R.T. The PI3K Pathway in Human Disease. Cell 2017, 170, 605–635.
  26. Samuels, Y.; Wang, Z.; Bardelli, A.; Silliman, N.; Ptak, J.; Szabo, S.; Yan, H.; Gazdar, A.; Powell, S.M.; Riggins, G.J.; et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004, 304, 554.
  27. Zhao, L.; Vogt, P.K. Hot-spot mutations in p110alpha of phosphatidylinositol 3-kinase (pI3K): Differential interactions with the regulatory subunit p85 and with RAS. Cell Cycle 2010, 9, 596–600.
  28. Zhao, L.; Vogt, P.K. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl. Acad. Sci. USA 2008, 105, 2652–2657.
  29. Croessmann, S.; Sheehan, J.H.; Lee, K.M.; Sliwoski, G.; He, J.; Nagy, R.; Riddle, D.; Mayer, I.A.; Balko, J.M.; Lanman, R.; et al. PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3Kalpha Inhibitors. Clin. Cancer Res. 2018, 24, 1426–1435.
  30. Jiang, W.; He, T.; Liu, S.; Zheng, Y.; Xiang, L.; Pei, X.; Wang, Z.; Yang, H. The PIK3CA E542K and E545K mutations promote glycolysis and proliferation via induction of the beta-catenin/SIRT3 signaling pathway in cervical cancer. J. Hematol. Oncol. 2018, 11, 139.
  31. Markham, A. Alpelisib: First Global Approval. Drugs 2019, 79, 1249–1253.
  32. Kaneda, M.M.; Messer, K.S.; Ralainirina, N.; Li, H.; Leem, C.J.; Gorjestani, S.; Woo, G.; Nguyen, A.V.; Figueiredo, C.C.; Foubert, P.; et al. PI3Kgamma is a molecular switch that controls immune suppression. Nature 2016, 539, 437–442.
  33. Zhu, J.; Li, K.; Yu, L.; Chen, Y.; Cai, Y.; Jin, J.; Hou, T. Targeting phosphatidylinositol 3-kinase gamma (PI3Kgamma): Discovery and development of its selective inhibitors. Med. Res. Rev. 2021, 41, 1599–1621.
  34. Walker, E.H.; Perisic, O.; Ried, C.; Stephens, L.; Williams, R.L. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 1999, 402, 313–320.
  35. Deladeriere, A.; Gambardella, L.; Pan, D.; Anderson, K.E.; Hawkins, P.T.; Stephens, L.R. The regulatory subunits of PI3Kgamma control distinct neutrophil responses. Sci. Signal. 2015, 8, ra8.
  36. Rynkiewicz, N.K.; Anderson, K.E.; Suire, S.; Collins, D.M.; Karanasios, E.; Vadas, O.; Williams, R.; Oxley, D.; Clark, J.; Stephens, L.R.; et al. Gbetagamma is a direct regulator of endogenous p101/p110gamma and p84/p110gamma PI3Kgamma complexes in mouse neutrophils. Sci. Signal. 2020, 13, eaaz4003.
  37. Pacold, M.E.; Suire, S.; Perisic, O.; Lara-Gonzalez, S.; Davis, C.T.; Walker, E.H.; Hawkins, P.T.; Stephens, L.; Eccleston, J.F.; Williams, R.L. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 2000, 103, 931–943.
  38. Gangadhara, G.; Dahl, G.; Bohnacker, T.; Rae, R.; Gunnarsson, J.; Blaho, S.; Oster, L.; Lindmark, H.; Karabelas, K.; Pemberton, N.; et al. A class of highly selective inhibitors bind to an active state of PI3Kgamma. Nat. Chem. Biol. 2019, 15, 348–357.
  39. Kang, S.; Denley, A.; Vanhaesebroeck, B.; Vogt, P.K. Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. USA 2006, 103, 1289–1294.
  40. Thorpe, L.M.; Yuzugullu, H.; Zhao, J.J. PI3K in cancer: Divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer 2015, 15, 7–24.
  41. Takeda, A.J.; Maher, T.J.; Zhang, Y.; Lanahan, S.M.; Bucklin, M.L.; Compton, S.R.; Tyler, P.M.; Comrie, W.A.; Matsuda, M.; Olivier, K.N.; et al. Human PI3Kgamma deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology. Nat. Commun. 2019, 10, 4364.
  42. Rathinaswamy, M.K.; Dalwadi, U.; Fleming, K.D.; Adams, C.; Stariha, J.T.B.; Pardon, E.; Baek, M.; Vadas, O.; DiMaio, F.; Steyaert, J.; et al. Structure of the phosphoinositide 3-kinase (PI3K) p110gamma-p101 complex reveals molecular mechanism of GPCR activation. Sci. Adv. 2021, 7, eabj4282.
  43. Shisheva, A. PIKfyve and its Lipid products in health and in sickness. Curr. Top. Microbiol. Immunol. 2012, 362, 127–162.
  44. Lees, J.A.; Li, P.; Kumar, N.; Weisman, L.S.; Reinisch, K.M. Insights into Lysosomal PI(3,5)P2 Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex. Mol. Cell 2020, 80, 736–743.E4.
  45. Sbrissa, D.; Ikonomov, O.C.; Fu, Z.; Ijuin, T.; Gruenberg, J.; Takenawa, T.; Shisheva, A. Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex. J. Biol. Chem. 2007, 282, 23878–23891.
  46. Ikonomov, O.C.; Sbrissa, D.; Shisheva, A. Mammalian cell morphology and endocytic membrane homeostasis require enzymatically active phosphoinositide 5-kinase PIKfyve. J. Biol. Chem. 2001, 276, 26141–26147.
  47. Li, S.; Tiab, L.; Jiao, X.; Munier, F.L.; Zografos, L.; Frueh, B.E.; Sergeev, Y.; Smith, J.; Rubin, B.; Meallet, M.A.; et al. Mutations in PIP5K3 are associated with Francois-Neetens mouchetee fleck corneal dystrophy. Am. J. Hum. Genet. 2005, 77, 54–63.
  48. Walter, P.; Ron, D. The unfolded protein response: From stress pathway to homeostatic regulation. Science 2011, 334, 1081–1086.
  49. Hetz, C.; Chevet, E.; Harding, H.P. Targeting the unfolded protein response in disease. Nat. Rev. Drug Discov. 2013, 12, 703–719.
  50. Tirasophon, W.; Welihinda, A.A.; Kaufman, R.J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 1998, 12, 1812–1824.
  51. Korennykh, A.V.; Egea, P.F.; Korostelev, A.A.; Finer-Moore, J.; Zhang, C.; Shokat, K.M.; Stroud, R.M.; Walter, P. The unfolded protein response signals through high-order assembly of Ire1. Nature 2009, 457, 687–693.
  52. Bertolotti, A.; Zhang, Y.; Hendershot, L.M.; Harding, H.P.; Ron, D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat. Cell Biol. 2000, 2, 326–332.
  53. Ali, M.M.; Bagratuni, T.; Davenport, E.L.; Nowak, P.R.; Silva-Santisteban, M.C.; Hardcastle, A.; McAndrews, C.; Rowlands, M.G.; Morgan, G.J.; Aherne, W.; et al. Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response. EMBO J. 2011, 30, 894–905.
  54. Calfon, M.; Zeng, H.; Urano, F.; Till, J.H.; Hubbard, S.R.; Harding, H.P.; Clark, S.G.; Ron, D. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 2002, 415, 92–96.
  55. Lu, Y.; Liang, F.X.; Wang, X. A synthetic biology approach identifies the mammalian UPR RNA ligase RtcB. Mol. Cell 2014, 55, 758–770.
  56. Lee, A.H.; Iwakoshi, N.N.; Glimcher, L.H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 2003, 23, 7448–7459.
  57. Yoshida, H.; Matsui, T.; Yamamoto, A.; Okada, T.; Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001, 107, 881–891.
  58. Imagawa, Y.; Hosoda, A.; Sasaka, S.; Tsuru, A.; Kohno, K. RNase domains determine the functional difference between IRE1alpha and IRE1beta. FEBS Lett. 2008, 582, 656–660.
  59. Grey, M.J.; Cloots, E.; Simpson, M.S.; LeDuc, N.; Serebrenik, Y.V.; De Luca, H.; De Sutter, D.; Luong, P.; Thiagarajah, J.R.; Paton, A.W.; et al. IRE1beta negatively regulates IRE1alpha signaling in response to endoplasmic reticulum stress. J. Cell Biol. 2020, 219, e201904048.
  60. McAllister, C.S.; Taghavi, N.; Samuel, C.E. Protein kinase PKR amplification of interferon beta induction occurs through initiation factor eIF-2alpha-mediated translational control. J. Biol. Chem. 2012, 287, 36384–36392.
  61. Garcia, M.A.; Gil, J.; Ventoso, I.; Guerra, S.; Domingo, E.; Rivas, C.; Esteban, M. Impact of protein kinase PKR in cell biology: From antiviral to antiproliferative action. Microbiol. Mol. Biol. Rev. 2006, 70, 1032–1060.
  62. Bonnet, M.C.; Weil, R.; Dam, E.; Hovanessian, A.G.; Meurs, E.F. PKR stimulates NF-kappaB irrespective of its kinase function by interacting with the IkappaB kinase complex. Mol. Cell. Biol. 2000, 20, 4532–4542.
  63. Yoon, C.H.; Miah, M.A.; Kim, K.P.; Bae, Y.S. New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers Cdc2 polyubiquitination and G2 arrest under genotoxic stresses. EMBO Rep. 2010, 11, 393–399.
  64. Gil, J.; Garcia, M.A.; Gomez-Puertas, P.; Guerra, S.; Rullas, J.; Nakano, H.; Alcami, J.; Esteban, M. TRAF family proteins link PKR with NF-kappa B activation. Mol. Cell. Biol. 2004, 24, 4502–4512.
  65. Silva, A.M.; Whitmore, M.; Xu, Z.; Jiang, Z.; Li, X.; Williams, B.R. Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation. J. Biol. Chem. 2004, 279, 37670–37676.
  66. Yang, X.; Nath, A.; Opperman, M.J.; Chan, C. The double-stranded RNA-dependent protein kinase differentially regulates insulin receptor substrates 1 and 2 in HepG2 cells. Mol. Biol. Cell 2010, 21, 3449–3458.
  67. Taniuchi, S.; Miyake, M.; Tsugawa, K.; Oyadomari, M.; Oyadomari, S. Integrated stress response of vertebrates is regulated by four eIF2alpha kinases. Sci. Rep. 2016, 6, 32886.
  68. Garcia-Ortega, M.B.; Lopez, G.J.; Jimenez, G.; Garcia-Garcia, J.A.; Conde, V.; Boulaiz, H.; Carrillo, E.; Peran, M.; Marchal, J.A.; Garcia, M.A. Clinical and therapeutic potential of protein kinase PKR in cancer and metabolism. Expert Rev. Mol. Med. 2017, 19, E9.
  69. Gal-Ben-Ari, S.; Barrera, I.; Ehrlich, M.; Rosenblum, K. PKR: A Kinase to Remember. Front. Mol. Neurosci. 2018, 11, 480.
  70. Stern, E.; Chinnakkaruppan, A.; David, O.; Sonenberg, N.; Rosenblum, K. Blocking the eIF2alpha kinase (PKR) enhances positive and negative forms of cortex-dependent taste memory. J. Neurosci. 2013, 33, 2517–2525.
  71. Couturier, J.; Paccalin, M.; Lafay-Chebassier, C.; Chalon, S.; Ingrand, I.; Pinguet, J.; Pontcharraud, R.; Guillard, O.; Fauconneau, B.; Page, G. Pharmacological inhibition of PKR in APPswePS1dE9 mice transiently prevents inflammation at 12 months of age but increases Abeta42 levels in the late stages of the Alzheimer’s disease. Curr. Alzheimer Res. 2012, 9, 344–360.
  72. Wang, W.J.; Yin, S.J.; Rong, R.Q. PKR and HMGB1 expression and function in rheumatoid arthritis. Genet. Mol. Res. 2015, 14, 17864–17870.
  73. Udumula, M.P.; Babu, M.S.; Bhat, A.; Dhar, I.; Sriram, D.; Dhar, A. High glucose impairs insulin signaling via activation of PKR pathway in L6 muscle cells. Biochem. Biophys. Res. Commun. 2017, 486, 645–651.
  74. LaRonde, N.A. The ancient microbial RIO kinases. J. Biol. Chem. 2014, 289, 9488–9492.
  75. Angermayr, M.; Bandlow, W. RIO1, an extraordinary novel protein kinase. FEBS Lett. 2002, 524, 31–36.
  76. Widmann, B.; Wandrey, F.; Badertscher, L.; Wyler, E.; Pfannstiel, J.; Zemp, I.; Kutay, U. The kinase activity of human Rio1 is required for final steps of cytoplasmic maturation of 40S subunits. Mol. Biol. Cell 2012, 23, 22–35.
  77. Ferreira-Cerca, S.; Kiburu, I.; Thomson, E.; LaRonde, N.; Hurt, E. Dominant Rio1 kinase/ATPase catalytic mutant induces trapping of late pre-40S biogenesis factors in 80S-like ribosomes. Nucleic Acids Res. 2014, 42, 8635–8647.
  78. Weinberg, F.; Reischmann, N.; Fauth, L.; Taromi, S.; Mastroianni, J.; Kohler, M.; Halbach, S.; Becker, A.C.; Deng, N.; Schmitz, T.; et al. The Atypical Kinase RIOK1 Promotes Tumor Growth and Invasive Behavior. EBioMedicine 2017, 20, 79–97.
  79. Kloet, S.L.; Whiting, J.L.; Gafken, P.; Ranish, J.; Wang, E.H. Phosphorylation-dependent regulation of cyclin D1 and cyclin A gene transcription by TFIID subunits TAF1 and TAF7. Mol. Cell. Biol. 2012, 32, 3358–3369.
  80. Wang, H.; Curran, E.C.; Hinds, T.R.; Wang, E.H.; Zheng, N. Crystal structure of a TAF1-TAF7 complex in human transcription factor IID reveals a promoter binding module. Cell Res. 2014, 24, 1433–1444.
  81. Louder, R.K.; He, Y.; Lopez-Blanco, J.R.; Fang, J.; Chacon, P.; Nogales, E. Structure of promoter-bound TFIID and model of human pre-initiation complex assembly. Nature 2016, 531, 604–609.
  82. Dikstein, R.; Ruppert, S.; Tjian, R. TAFII250 is a bipartite protein kinase that phosphorylates the base transcription factor RAP74. Cell 1996, 84, 781–790.
  83. Jacobson, R.H.; Ladurner, A.G.; King, D.S.; Tjian, R. Structure and function of a human TAFII250 double bromodomain module. Science 2000, 288, 1422–1425.
  84. Mizzen, C.A.; Yang, X.J.; Kokubo, T.; Brownell, J.E.; Bannister, A.J.; Owen-Hughes, T.; Workman, J.; Wang, L.; Berger, S.L.; Kouzarides, T.; et al. The TAF(II)250 subunit of TFIID has histone acetyltransferase activity. Cell 1996, 87, 1261–1270.
  85. Hilton, T.L.; Li, Y.; Dunphy, E.L.; Wang, E.H. TAF1 histone acetyltransferase activity in Sp1 activation of the cyclin D1 promoter. Mol. Cell. Biol. 2005, 25, 4321–4332.
  86. O’Brien, T.; Tjian, R. Functional analysis of the human TAFII250 N-terminal kinase domain. Mol. Cell 1998, 1, 905–911.
  87. Li, H.H.; Li, A.G.; Sheppard, H.M.; Liu, X. Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: A role for TAF1 in cell G1 progression. Mol. Cell 2004, 13, 867–878.
  88. Siegert, J.L.; Robbins, P.D. Rb inhibits the intrinsic kinase activity of TATA-binding protein-associated factor TAFII250. Mol. Cell. Biol. 1999, 19, 846–854.
  89. Makino, S.; Kaji, R.; Ando, S.; Tomizawa, M.; Yasuno, K.; Goto, S.; Matsumoto, S.; Tabuena, M.D.; Maranon, E.; Dantes, M.; et al. Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am. J. Hum. Genet. 2007, 80, 393–406.
  90. O’Rawe, J.A.; Wu, Y.; Dorfel, M.J.; Rope, A.F.; Au, P.Y.; Parboosingh, J.S.; Moon, S.; Kousi, M.; Kosma, K.; Smith, C.S.; et al. TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations. Am. J. Hum. Genet. 2015, 97, 922–932.
  91. Devaiah, B.N.; Singer, D.S. CIITA and Its Dual Roles in MHC Gene Transcription. Front. Immunol. 2013, 4, 476.
  92. Reith, W.; LeibundGut-Landmann, S.; Waldburger, J.M. Regulation of MHC class II gene expression by the class II transactivator. Nat. Rev. Immunol. 2005, 5, 793–806.
  93. Choi, N.M.; Majumder, P.; Boss, J.M. Regulation of major histocompatibility complex class II genes. Curr. Opin. Immunol. 2011, 23, 81–87.
  94. Soe, K.C.; Devaiah, B.N.; Singer, D.S. Transcriptional coactivator CIITA, a functional homolog of TAF1, has kinase activity. Biochim. Biophys. Acta 2013, 1829, 1184–1190.
  95. Raval, A.; Howcroft, T.K.; Weissman, J.D.; Kirshner, S.; Zhu, X.S.; Yokoyama, K.; Ting, J.; Singer, D.S. Transcriptional coactivator, CIITA, is an acetyltransferase that bypasses a promoter requirement for TAF(II)250. Mol. Cell 2001, 7, 105–115.
  96. Fontes, J.D.; Kanazawa, S.; Jean, D.; Peterlin, B.M. Interactions between the class II transactivator and CREB binding protein increase transcription of major histocompatibility complex class II genes. Mol. Cell. Biol. 1999, 19, 941–947.
  97. Kretsovali, A.; Spilianakis, C.; Dimakopoulos, A.; Makatounakis, T.; Papamatheakis, J. Self-association of class II transactivator correlates with its intracellular localization and transactivation. J. Biol. Chem. 2001, 276, 32191–32197.
  98. Ting, J.P.; Trowsdale, J. Genetic control of MHC class II expression. Cell 2002, 109 (Suppl. 1), S21–S33.
  99. Steimle, V.; Otten, L.A.; Zufferey, M.; Mach, B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 1993, 75, 135–146.
  100. Srinivasan, M.; Mehta, P.; Yu, Y.; Prugar, E.; Koonin, E.V.; Karzai, A.W.; Sternglanz, R. The highly conserved KEOPS/EKC complex is essential for a universal tRNA modification, t6A. EMBO J. 2011, 30, 873–881.
  101. Downey, M.; Houlsworth, R.; Maringele, L.; Rollie, A.; Brehme, M.; Galicia, S.; Guillard, S.; Partington, M.; Zubko, M.K.; Krogan, N.J.; et al. A genome-wide screen identifies the evolutionarily conserved KEOPS complex as a telomere regulator. Cell 2006, 124, 1155–1168.
  102. Kisseleva-Romanova, E.; Lopreiato, R.; Baudin-Baillieu, A.; Rousselle, J.C.; Ilan, L.; Hofmann, K.; Namane, A.; Mann, C.; Libri, D. Yeast homolog of a cancer-testis antigen defines a new transcription complex. EMBO J. 2006, 25, 3576–3585.
  103. Li, J.; Ma, X.; Banerjee, S.; Chen, H.; Ma, W.; Bode, A.M.; Dong, Z. Crystal structure of the human PRPK-TPRKB complex. Commun. Biol. 2021, 4, 167.
  104. Facchin, S.; Lopreiato, R.; Ruzzene, M.; Marin, O.; Sartori, G.; Gotz, C.; Montenarh, M.; Carignani, G.; Pinna, L.A. Functional homology between yeast piD261/Bud32 and human PRPK: Both phosphorylate p53 and PRPK partially complements piD261/Bud32 deficiency. FEBS Lett. 2003, 549, 63–66.
  105. Perrochia, L.; Guetta, D.; Hecker, A.; Forterre, P.; Basta, T. Functional assignment of KEOPS/EKC complex subunits in the biosynthesis of the universal t6A tRNA modification. Nucleic Acids Res. 2013, 41, 9484–9499.
  106. Zhang, W.; Collinet, B.; Graille, M.; Daugeron, M.C.; Lazar, N.; Libri, D.; Durand, D.; van Tilbeurgh, H. Crystal structures of the Gon7/Pcc1 and Bud32/Cgi121 complexes provide a model for the complete yeast KEOPS complex. Nucleic Acids Res. 2015, 43, 3358–3372.
  107. Braun, D.A.; Rao, J.; Mollet, G.; Schapiro, D.; Daugeron, M.C.; Tan, W.; Gribouval, O.; Boyer, O.; Revy, P.; Jobst-Schwan, T.; et al. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. Nat. Genet. 2017, 49, 1529–1538.
  108. Facchin, S.; Ruzzene, M.; Peggion, C.; Sartori, G.; Carignani, G.; Marin, O.; Brustolon, F.; Lopreiato, R.; Pinna, L.A. Phosphorylation and activation of the atypical kinase p53-related protein kinase (PRPK) by Akt/PKB. Cell. Mol. Life Sci. 2007, 64, 2680–2689.
  109. Hideshima, T.; Cottini, F.; Nozawa, Y.; Seo, H.S.; Ohguchi, H.; Samur, M.K.; Cirstea, D.; Mimura, N.; Iwasawa, Y.; Richardson, P.G.; et al. p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma. Blood 2017, 129, 1308–1319.
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