Prospects for pharmacological targeting of pseudokinases

Nature Reviews Drug Discovery, Journal Year: 2019, Volume and Issue: unknown

Published: March 8, 2019

Language: Английский

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Aurora A regulation by reversible cysteine oxidation reveals evolutionarily conserved redox control of Ser/Thr protein kinase activity

Science Signaling, Journal Year: 2020, Volume and Issue: 13(639)

Published: July 7, 2020

Reactive oxygen species (ROS) are physiological mediators of cellular signaling and play potentially damaging roles in human diseases. In this study, we found that the catalytic activity Ser/Thr kinase Aurora A was inhibited by oxidation a conserved cysteine residue (Cys

Language: Английский

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Emerging concepts in pseudoenzyme classification, evolution, and signaling

Science Signaling, Journal Year: 2019, Volume and Issue: 12(594)

Published: Aug. 13, 2019

A roadmap for identifying and analyzing pseudoenzymes is proposed this rapidly expanding field.

Language: Английский

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There’s more to death than life: Noncatalytic functions in kinase and pseudokinase signaling

Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 296, P. 100705 - 100705

Published: Jan. 1, 2021

Protein kinases are present in all domains of life and play diverse roles cellular signaling. Whereas the impact substrate phosphorylation by protein has long been appreciated, it is becoming increasingly clear that also other, noncatalytic, functions. Here, we review recent developments understanding noncatalytic functions kinases. Many activities best exemplified devoid enzymatic activity altogether—known as pseudokinases. These dead proteins illustrate that, beyond conventional notions kinase function, catalytic can be dispensable for biological function. Through key examples mechanisms activity: allosteric modulators; protein-based switches; scaffolds complex assembly; competitive inhibitors signaling pathways. In common, these exploit nature fold a versatile protein–protein interaction module. intrinsically linked to ability switch between multiple states, function shared with Finally, consider contemporary landscape small molecules modulate kinases, which, although challenging, significant potential given scope health disease. quintessential proteins. Their posttranslationally modify amino acid side chains phosphoryl group underlies broad swath eukaryotic biology (1Hardman G. Perkins S. Brownridge P.J. Clarke C.J. Byrne D.P. Campbell A.E. Kalyuzhnyy A. Myall Eyers P.A. Jones A.R. C.E. Strong anion exchange-mediated phosphoproteomics reveals extensive human non-canonical phosphorylation.EMBO J. 2019; 38e100847Crossref PubMed Scopus (31) Google Scholar) regulates addition catalyzing transfer, roles, interacting other modifying their activity. A proportion even take extreme—lacking phosphoryl-transfer completely—and known pseudokinases (2Manning Whyte D.B. Martinez R. Hunter T. Sudarsanam The complement genome.Science. 2002; 298: 1912-1934Crossref (5717) Scholar, 3Zeqiraj E. van Aalten D.M.F. Pseudokinases-remnants evolution or regulators?.Curr. Opin. Struct. Biol. 2010; 20: 772-781Crossref (102) 4Eyers Murphy J.M. Dawn dead: signal new adventures cell biology.Biochem. Soc. Trans. 2013; 41: 969-974Crossref (60) Scholar). Originally thought evolutionary remnants, have since revealed remarkably pathways (5Jacobsen A.V. secret kinases: Insights into non-catalytic signalling from pseudokinases.Biochem. 2017; 45: 665-681Crossref (41) Importantly, zombie provide window often unheralded, nonenzymatic performed alive enzyme counterparts. Catalytically competent diverse, but means folds similar core elements show little variation (Fig. 1A). catalysis bind ATP, coordinate Mg2+, catalyze transfer. generally consist of: lysine residue within VAIK motif N-terminal lobe, glycine rich loop (Gly-loop), which features enabling ATP binding; an aspartate DFG-motif activation coordinates magnesium alongside ATP; HRD contributed C-terminal acts base during transfer 1B; 6Hanks S.K. Quinn A.M. family: Conserved deduced phylogeny domains.Science. 1988; 241: 42-52Crossref Scholar)). Any, multiple, lost (7Kung J.E. Jura N. Prospects pharmacological targeting pseudokinases.Nat. Rev. Drug Discov. 18: 501-526Crossref (28) 8Kwon Scott Taujale Yeung W. Kochut K.J. Kannan Tracing origin across tree life.Sci. Signal. 12eaav3810Crossref 9Murphy Zhang Q. Young S.N. Reese M.L. Bailey F.P. Ungureanu D. Hammarén H. Silvennoinen O. Varghese L.N. Chen K. Tripaydonis Fukuda Qin et al.A robust methodology subclassify based on nucleotide-binding properties.Biochem. 2014; 457: 323-334Crossref (0) Depending what lost, may unable nucleotides (Class I), not cations II), only III), both cations, still carry out IV) 1C) (9Murphy Analyses coding genes archaea, bacteria, eukaryotes identified pseudokinases, (8Kwon This focuses fold, predicted low abundance archaea bacteria (10Childers W.S. Shapiro L. pseudokinase couples enable asymmetric division bacterium.Microb. Cell. 2: 29-32Crossref 11Gee C.L. Papavinasasundaram K.G. Blair S.R. Baer Falick King D.S. Griffin Venghatakrishnan Zukauskas Wei J.-R. Dhiman R.K. Crick D.C. Rubin E.J. Sassetti C.M. Alber phosphorylated controls wall synthesis mycobacteria.Sci. 2012; 5ra7Crossref Scholar), our more broadly prokaryotes emerging (12Kannan Taylor S.S. Zhai Y. Venter J.C. Manning Structural functional diversity microbial kinome.PLoS 2007; 5e17Crossref (195) 13Pérez Castañeda-García Jenke-Kodama Müller Muñoz-Dorado Eukaryotic-like myxobacterial kinome.Proc. Natl. Acad. Sci. U. 2008; 105: 15950-15955Crossref (83) proteome contain approximately 550 10% retained vertebrates, ∼10% kinomes designated 14Caenepeel Charydczak mouse kinome: Discovery comparative genomics kinases.Proc. 2004; 101: 11707-11712Crossref (237) More broadly, some species expanded complements. For instance, plants frequently comprise up ∼17% half kinase-like selected protists (Toxoplasma gondii Giardia lamblia) lack essential residues Such expansion concentrated specific classes example, undergone massive likely due important role innate immunity (15Jubic L.M. Saile Furzer O.J. El Kasmi F. Dangl J.L. Help wanted: Helper NLRs plant immune responses.Curr. Plant 50: 82-94Crossref (53) scale current analyses most classification sequence-based rather than experimentally verified. While computational approaches enlightening, several pertinent demonstrate need couple experimental characterization. seemingly degraded sequences nonetheless retain phosphorylate biomolecules (16Beraki Hu X. Broncel M. O'Shaughnessy W.J. Borek Treeck Divergent membrane ultrastructure Toxoplasma parasitophorous vacuole.Proc. 116: 6361-6370Crossref 17Zhu Venzke Walimbe A.S. Anderson M.E. Fu Kinch Wang Grishin N.V. Huang Yu Dixon K.P. Xiao Structure O-mannose unique active site architecture.Elife. 2016; 5e22238Crossref (19) 18Yoshida-Moriguchi Willer Muntoni Lee Nelson S.F. SGK196 glycosylation-specific required dystroglycan function.Science. 341: 896-899Crossref (139) 19Lopez V.A. Park B.C. Nowak Sreelatha Zembek P. Fernandez Servage K.A. Gradowski Hennig Tomchick D.R. Pawłowski Krzymowska Tagliabracci V.S. bacterial effector mimics host HSP90 client undermine immunity.Cell. 179: 205-218.e21Abstract Full Text PDF completely unanticipated distinct (20Black M.H. Osinski Bacterial catalyzes polyglutamylation inhibit SidE-family ubiquitin ligases.Science. 364: 787-792Crossref 21Sulpizio Minelli Wan Burrowes P.D. Wu Sanford Shin J.-H. Williams Goldberg Smolka M.B. Mao catalyzed calmodulin-dependent SidJ.Elife. 8e51162Crossref 22Bhogaraju Bonn Mukherjee Adams Pfleiderer M.M. Galej W.P. Matkovic V. Lopez-Mosqueda Kalayil Dikic I. Inhibition ligases SidJ-calmodulin catalysed glutamylation.Nature. 572: 382-386Crossref (34) 23Sreelatha Yee Lopez Pilch Jiou Karasiewicz-Urbańska Łobocka Orth Kucharczyk al.Protein AMPylation evolutionarily conserved pseudokinase.Cell. 2018; 175: 809-821.e19Abstract (54) Nonetheless, coupled bioinformatic will continued insight played throughout evolution. Pseudokinases led realization catalytically inactive enzymes (pseudoenzymes) almost facets (24Ribeiro A.J.M. Das Dawson Zaru Orchard Thornton Orengo C. Zeqiraj Emerging concepts pseudoenzyme classification, evolution, signaling.Sci. 12eaat9797Crossref (32) Across families kingdoms life, regulate processes through number different 25Murphy Mace Live let die: structure.Curr. 47: 95-104Crossref 26Murphy Farhan Bio-zombie: rise pseudoenzymes 537-544Crossref (47) Pseudoenzymes include pseudo-phosphatases, pseudoproteases, pseudoGTPases, among others. Broadly speaking, as: activators, inhibitors, assembly complexes, switches 2; (25Murphy Examples each categories regulatory surfaces evolved repurposed toward alternative versions same eschewed evolve Thus, while this does mean they nonfunctional. It note pseudogenes. Pseudogenes refer incomplete DNA lacking elements, whereas translated encoded genes. focus illustrative at molecular level. Because definition many clearest regulation pseudoenzymes. Noncatalytic particularly switches, because architecture domain encodes on- off-states. conformations though elements. activity, simultaneously scaffolds, activators. when freed constraints retaining elaborate develop novel enzymes. Accordingly, offer exemplars additional, unrecognized might conventional, enzymes—in keeping idea least case enzymes, there death life. One best-characterized modulation cognate either promoting attenuating binding partners. arisen gene duplication events, pathway partners owing common expression patterns subcellular localization, noted previously (26Murphy 27Adrain Freeman New lives old: Evolution illustrated iRhoms.Nat. Mol. Cell 13: 489-498Crossref 28Pils B. Schultz Inactive enzyme-homologues find processes.J. 340: 399-404Crossref (109) duplications bring enormous liberty; redundancy arises duplication, no necessity maintain geometry mediate striking Janus Kinase (JAK) family, where (termed JH2) occurs tandem, tyrosine JH1) attenuates its trans receptor-scaffolded dimers (29Brooks A.J. Dai O'Mara Abankwa Chhabra Pelekanos R.A. Gardon Tunny Blucher K.M. Morton Parker M.W. Sierecki Gambin Gomez G.A. Alexandrov al.Mechanism JAK2 growth hormone receptor.Science. 344: 1249783Crossref (231) 30Varghese Liau N.P.D. Laktyushin Lucet I.S. Nicola N.A. Babon J.J. Mechanistic insights SOCS3-mediated inhibition myeloproliferative neoplasm-associated mutants biochemical structural analyses.Biochem. 458: 395-405Crossref 31Babon activation.Biochem. 462: 1-13Crossref (143) mechanism debated (31Babon was clearly discovery activating mutations (32James Ugo Le Couédic J.-P. Staerk Delhommeau Lacout Garçon Raslova Berger Bennaceur-Griscelli Villeval Constantinescu Casadevall Vainchenker clonal mutation leading constitutive causes polycythaemia vera.Nature. 2005; 434: 1144-1148Crossref (2692) promote induce hematopoietic malignancies. ancestors, pseudoactive sites do nucleotide, diminish loops, adopt discordant Any modifications allosterically. Via intermolecular interactions, able position element, αC helix N-lobe partner kinase. Several modes dimerization reported influence helix, illuminated detailed studies, highlight versatility 3; (33Lavoie Li Thevakumaran Therrien Sicheri Dimerization-induced allostery regulation.Trends Biochem. 39: 475-486Abstract 34Oliver M.R. Horne C.R. Shrestha Keown J.R. Liang L.-Y. Sandow Webb A.I. Goldstone Metcalf Granulovirus PK-1 relies side-to-side mode centered helix.Nat. Commun. 2021; 12: 1002Crossref (1) 35Horne whom bell tolls: structure kinase, IRAK3.Structure. 29: 197-199Abstract domain, including: back-to-back (as observed Ire1 RNase L homodimers (36Lee K.P.K. Dey Neculai Cao Dever T.E. dual basis nonconventional RNA splicing.Cell. 132: 89-100Abstract (238) 37Huang Dong Jha B.K. Duffy N.M. Orlicky Talukdar Pillon M.C. Ceccarelli D.F. L.C.K. Juang Y.-C. D.Y.L. Gaughan Brinton M.A. al.Dimeric bound 2-5A interferon-induced antiviral activity.Mol. 53: 221-234Abstract head-to-tail EGFR family proteins, such HER3 pseudokinase:EGFR (38Littlefield Liu Mysore Shan Shaw D.E. analysis EGFR/HER3 heterodimer mutations.Sci. 7ra114Crossref Scholar)), head-to-head found IRAK3 proposed pseudokinase:IRAK4 pairs (39Lange S.M. Nelen M.I. Cohen Kulathu Dimeric suggests negative regulation.Structure. 238-251.e4Abstract antiparallel (exemplified RAF:RAF KSR pseudokinase:RAF heterodimers (40Hu Stites E.C. Germino E.A. Meharena H.S. Stork P.J.S. Kornev A.P. Allosteric functionally RAF dimers.Cell. 154: 1036-1046Abstract (162) 41Hatzivassiliou Song Yen Brandhuber B.J. D.J. Alvarado Ludlam M.J.C. Stokoe Gloor S.L. Vigers Morales Aliagas Sideris Hoeflich al.RAF prime wild-type activate MAPK enhance growth.Nature. 464: 431-435Crossref (1177) 42Rajakulendran Sahmi Lefrançois dimerization-dependent drives activation.Nature. 2009; 461: 542-545Crossref Scholar)) modes. studies raise possibility exert those exerted recently parallel homodimerization granuloviral (34Oliver yet pseudokinase:kinase pairs, occupying synonymous Furthermore, currently poorly understood, allosterically nonkinase VRK3 to, of, VHR phosphatase (43Scheeff E.D. Eswaran Bunkóczi Knapp site, highly putative site.Structure. 17: 128-138Abstract (127) 44Kang T.-H. Kim K.-T. Negative ERK VRK3-mediated phosphatase.Nat. 2006; 8: 863-869Crossref (64) Overall, findings breadth mediated suggest underappreciated generally. Deducing precise remains major challenge. rely elegant chemical knockin approaches, deletion knockdown, reveal Over past 30 years, crystal structures captured N- C-lobes loop, pillars hydrophobic networks spines) continuum conformations, illustrating intrinsic dynamicity (45Kornev Dynamics-driven kinases.Trends 2015; 40: 628-647Abstract (136) 46Taylor dynamic proteins.Trends 2011; 36: 65-77Abstract (517) 47Modi Dunbrack Jr., R.L. Defining nomenclature 6818-6827Crossref flexibility associated Basally, apoenzyme exist uncommitted state until binding, galvanizes protein's internal poises catalysis. effectors oligomerization adoption conformation signified intact (R)-spine Glu engaged salt bridge β3-strand Lys However, if, range accessible reflect propensity serve switches? Recent via interactions. Consequently, attractive hypothesis interactions could governed pseudokinase, additionally, regulated posttranslational modifications. concept being employed Mixed Lineage domain-Like (MLKL) pseudokinase. Unlike solely thus interpretation conformational effects confounded additional MLKL terminal necroptosis pathway, lytic modality unlike cousin apoptosis, proteolytic Caspases (reviewed (48Samson A.L. Garnish S.E. Hildebrand Location, location, location: compartmentalized view TNF-induced necroptotic 14eabc6178Crossref (3) Instead, following insult, inflammatory receptor pathogen sensors, leads receptor-interacting kinase-3 (RIPK3) autophosphorylation (49Meng Czabotar P.E. post-translational modifications.Cell Death Differ. 28: 861-883Crossref (2) Activated RIPK3 then substrate, MLKL, ac

Language: Английский

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The role of tribbles homolog 2 in cell proliferation

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 6, 2025

Language: Английский

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Covalent Aurora A regulation by the metabolic integrator coenzyme A

Redox Biology, Journal Year: 2019, Volume and Issue: 28, P. 101318 - 101318

Published: Sept. 5, 2019

Aurora A kinase is a master mitotic regulator whose functions are controlled by several regulatory interactions and post-translational modifications. It frequently dysregulated in cancer, making inhibition very attractive antitumor target. However, recently uncovered links between A, cellular metabolism redox regulation not well understood. In this study, we report novel mechanism of the response to oxidative stress through CoAlation. combination biochemical, biophysical, crystallographic cell biology approaches revealed new and, our knowledge, unique mode CoA, involving selective binding ADP moiety CoA ATP pocket covalent modification Cys290 activation loop thiol group pantetheine tail. We provide evidence that (CoAlation) specific, it can be induced human cells. Oxidising agents, such as diamide, hydrogen peroxide menadione were found induce Thr 288 phosphorylation DTT-dependent dimerization A. Moreover, microinjection into fertilized mouse embryos disrupts bipolar spindle formation alignment chromosomes, consistent with inhibition. Altogether, data reveal new, rather selective, inhibitor which locks an inactive state via "dual anchor" might also operate stress. Finally most importantly, believe these findings rationale for developing effective irreversible inhibitors perhaps other protein kinases containing appropriately conserved Cys residues.

Language: Английский

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Cataloguing the dead: breathing new life into pseudokinase research

FEBS Journal, Journal Year: 2020, Volume and Issue: 287(19), P. 4150 - 4169

Published: Feb. 13, 2020

Pseudoenzymes are present within many, but not all, known enzyme families and lack one or more conserved canonical amino acids that help define their catalytically active counterparts. Recent findings in the pseudokinase field confirm evolutionary repurposing of structurally defined bilobal protein kinase fold permits distinct biological functions to emerge, many which rely on conformational switching, as opposed catalysis. In this analysis, we evaluate progress evaluating several members ‘dark’ pseudokinome pertinent drive expanding field. Initially, discuss how adaptions erythropoietin‐producing hepatocellular carcinoma (Eph) receptor tyrosine domains resulted two vertebrate pseudokinases, EphA10 EphB6, co‐evolving sequences generate new motifs likely be important for both nucleotide binding catalysis‐independent signalling. Secondly, conformationally flexible Tribbles have radiated complex vertebrates, control fundamental aspects cell signalling may targetable with covalent small molecules. Finally, show species‐level duplicated serine histone (PSKH)1 sequence led appearance PSKH2, whose physiological role remains mysterious. conclusion, patterns discover selectively specific when they modelled alongside closely related kinases, found located functionally regions fold. Interrogation these will useful future evaluation these, other, unstudied human kinome.

Language: Английский

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TRIB2 safeguards naive T cell homeostasis during aging

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112195 - 112195

Published: March 1, 2023

Naive CD4+ T cells are more resistant to age-related loss than naive CD8+ cells, suggesting mechanisms that preferentially protect during aging. Here, we show TRIB2 is abundant in and counteracts quiescence exit by suppressing AKT activation. deficiency increases activity accelerates proliferation differentiation response interleukin-7 (IL-7) humans lymphopenia mice. transcription controlled the lineage-determining factors ThPOK RUNX3. Ablation of Zbtb7b (encoding ThPOK) Cbfb (obligatory RUNT cofactor) attenuates difference lymphopenia-induced between cells. In older adults, expression wanes causing naivety. These findings assign a key role regulating cell homeostasis provide model explain lesser resilience undergo changes with age.

Language: Английский

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Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1

Science Signaling, Journal Year: 2018, Volume and Issue: 11(549)

Published: Sept. 25, 2018

Allosteric regulation of the pseudokinase TRIB1 reveals therapeutic potential kinase inhibitors.

Language: Английский

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Pseudokinases: a tribble‐edged sword

FEBS Journal, Journal Year: 2019, Volume and Issue: 287(19), P. 4170 - 4182

Published: Oct. 17, 2019

Advances in the understanding of Tribbles family pseudokinases (TRIB1, TRIB2 and TRIB3) reveal these proteins as potentially valuable biomarkers disease diagnosis, prognosis, prediction clinical strategy. In their role signalling mediators scaffolding proteins, TRIBs lead to changes protein stability activity, which impact on diverse cellular processes such proliferation, differentiation, cell cycle death. We review TRIB promising therapeutic targets, with an emphasis cancer, biomarkers, potential application across pathological processes.

Language: Английский

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