| Structural highlights
Function
AURKA_HUMAN Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and stabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity. Necessary for proper cilia disassembly prior to mitosis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]
Publication Abstract from PubMed
Selective orthosteric inhibition of kinases has been challenging due to the conserved active site architecture of kinases and emergence of resistance mutants. Simultaneous inhibition of distant orthosteric and allosteric sites, which we refer to as "double-drugging", has recently been shown to be effective in overcoming drug resistance. However, detailed biophysical characterization of the cooperative nature between orthosteric and allosteric modulators has not been undertaken. Here, we provide a quantitative framework for double-drugging of kinases employing isothermal titration calorimetry, Forster resonance energy transfer, coupled-enzyme assays, and X-ray crystallography. We discern positive and negative cooperativity for Aurora A kinase (AurA) and Abelson kinase (Abl) with different combinations of orthosteric and allosteric modulators. We find that a conformational equilibrium shift is the main principle governing cooperativity. Notably, for both kinases, we find a synergistic decrease of the required orthosteric and allosteric drug dosages when used in combination to inhibit kinase activities to clinically relevant inhibition levels. X-ray crystal structures of the double-drugged kinase complexes reveal the molecular principles underlying the cooperative nature of double-drugging AurA and Abl with orthosteric and allosteric inhibitors. Finally, we observe a fully closed conformation of Abl when bound to a pair of positively cooperative orthosteric and allosteric modulators, shedding light on the puzzling abnormality of previously solved closed Abl structures. Collectively, our data provide mechanistic and structural insights into rational design and evaluation of double-drugging strategies.
A biophysical framework for double-drugging kinases.,Kim C, Ludewig H, Hadzipasic A, Kutter S, Nguyen V, Kern D Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2304611120. doi: , 10.1073/pnas.2304611120. Epub 2023 Aug 17. PMID:37590418[22]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Walter AO, Seghezzi W, Korver W, Sheung J, Lees E. The mitotic serine/threonine kinase Aurora2/AIK is regulated by phosphorylation and degradation. Oncogene. 2000 Oct 5;19(42):4906-16. PMID:11039908 doi:10.1038/sj.onc.1203847
- ↑ Katayama H, Zhou H, Li Q, Tatsuka M, Sen S. Interaction and feedback regulation between STK15/BTAK/Aurora-A kinase and protein phosphatase 1 through mitotic cell division cycle. J Biol Chem. 2001 Dec 7;276(49):46219-24. Epub 2001 Sep 10. PMID:11551964 doi:10.1074/jbc.M107540200
- ↑ Marumoto T, Hirota T, Morisaki T, Kunitoku N, Zhang D, Ichikawa Y, Sasayama T, Kuninaka S, Mimori T, Tamaki N, Kimura M, Okano Y, Saya H. Roles of aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes Cells. 2002 Nov;7(11):1173-82. PMID:12390251
- ↑ Hirota T, Kunitoku N, Sasayama T, Marumoto T, Zhang D, Nitta M, Hatakeyama K, Saya H. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell. 2003 Sep 5;114(5):585-98. PMID:13678582
- ↑ Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E, Saya H. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem. 2003 Dec 19;278(51):51786-95. Epub 2003 Oct 1. PMID:14523000 doi:10.1074/jbc.M306275200
- ↑ Toji S, Yabuta N, Hosomi T, Nishihara S, Kobayashi T, Suzuki S, Tamai K, Nojima H. The centrosomal protein Lats2 is a phosphorylation target of Aurora-A kinase. Genes Cells. 2004 May;9(5):383-97. PMID:15147269 doi:10.1111/j.1356-9597.2004.00732.x
- ↑ Ouchi M, Fujiuchi N, Sasai K, Katayama H, Minamishima YA, Ongusaha PP, Deng C, Sen S, Lee SW, Ouchi T. BRCA1 phosphorylation by Aurora-A in the regulation of G2 to M transition. J Biol Chem. 2004 May 7;279(19):19643-8. Epub 2004 Feb 27. PMID:14990569 doi:10.1074/jbc.M311780200
- ↑ Dutertre S, Cazales M, Quaranta M, Froment C, Trabut V, Dozier C, Mirey G, Bouche JP, Theis-Febvre N, Schmitt E, Monsarrat B, Prigent C, Ducommun B. Phosphorylation of CDC25B by Aurora-A at the centrosome contributes to the G2-M transition. J Cell Sci. 2004 May 15;117(Pt 12):2523-31. Epub 2004 May 5. PMID:15128871 doi:10.1242/jcs.01108
- ↑ Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F, Fujii S, Arlinghaus RB, Czerniak BA, Sen S. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet. 2004 Jan;36(1):55-62. Epub 2003 Dec 14. PMID:14702041 doi:10.1038/ng1279
- ↑ Yu CT, Hsu JM, Lee YC, Tsou AP, Chou CK, Huang CY. Phosphorylation and stabilization of HURP by Aurora-A: implication of HURP as a transforming target of Aurora-A. Mol Cell Biol. 2005 Jul;25(14):5789-800. PMID:15987997 doi:10.1128/MCB.25.14.5789-5800.2005
- ↑ Sankaran S, Crone DE, Palazzo RE, Parvin JD. Aurora-A kinase regulates breast cancer associated gene 1 inhibition of centrosome-dependent microtubule nucleation. Cancer Res. 2007 Dec 1;67(23):11186-94. PMID:18056443 doi:10.1158/0008-5472.CAN-07-2578
- ↑ Pugacheva EN, Jablonski SA, Hartman TR, Henske EP, Golemis EA. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell. 2007 Jun 29;129(7):1351-63. PMID:17604723 doi:10.1016/j.cell.2007.04.035
- ↑ Manfredi MG, Ecsedy JA, Meetze KA, Balani SK, Burenkova O, Chen W, Galvin KM, Hoar KM, Huck JJ, LeRoy PJ, Ray ET, Sells TB, Stringer B, Stroud SG, Vos TJ, Weatherhead GS, Wysong DR, Zhang M, Bolen JB, Claiborne CF. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4106-11. Epub 2007 Feb 23. PMID:17360485 doi:10.1073/pnas.0608798104
- ↑ Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, Clouin C, Taylor SS, Yaffe MB, Medema RH. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature. 2008 Sep 4;455(7209):119-23. doi: 10.1038/nature07185. Epub 2008 Jul 9. PMID:18615013 doi:10.1038/nature07185
- ↑ Khazaei MR, Puschel AW. Phosphorylation of the par polarity complex protein Par3 at serine 962 is mediated by aurora a and regulates its function in neuronal polarity. J Biol Chem. 2009 Nov 27;284(48):33571-9. doi: 10.1074/jbc.M109.055897. Epub 2009, Oct 6. PMID:19812038 doi:10.1074/jbc.M109.055897
- ↑ Jang CY, Coppinger JA, Seki A, Yates JR 3rd, Fang G. Plk1 and Aurora A regulate the depolymerase activity and the cellular localization of Kif2a. J Cell Sci. 2009 May 1;122(Pt 9):1334-41. doi: 10.1242/jcs.044321. Epub 2009 Apr , 7. PMID:19351716 doi:10.1242/jcs.044321
- ↑ Mori D, Yamada M, Mimori-Kiyosue Y, Shirai Y, Suzuki A, Ohno S, Saya H, Wynshaw-Boris A, Hirotsune S. An essential role of the aPKC-Aurora A-NDEL1 pathway in neurite elongation by modulation of microtubule dynamics. Nat Cell Biol. 2009 Sep;11(9):1057-68. Epub 2009 Aug 9. PMID:19668197 doi:ncb1919
- ↑ Fu J, Bian M, Liu J, Jiang Q, Zhang C. A single amino acid change converts Aurora-A into Aurora-B-like kinase in terms of partner specificity and cellular function. Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):6939-44. doi:, 10.1073/pnas.0900833106. Epub 2009 Apr 8. PMID:19357306 doi:10.1073/pnas.0900833106
- ↑ Kinzel D, Boldt K, Davis EE, Burtscher I, Trumbach D, Diplas B, Attie-Bitach T, Wurst W, Katsanis N, Ueffing M, Lickert H. Pitchfork regulates primary cilia disassembly and left-right asymmetry. Dev Cell. 2010 Jul 20;19(1):66-77. doi: 10.1016/j.devcel.2010.06.005. PMID:20643351 doi:10.1016/j.devcel.2010.06.005
- ↑ Fancelli D, Moll J, Varasi M, Bravo R, Artico R, Berta D, Bindi S, Cameron A, Candiani I, Cappella P, Carpinelli P, Croci W, Forte B, Giorgini ML, Klapwijk J, Marsiglio A, Pesenti E, Rocchetti M, Roletto F, Severino D, Soncini C, Storici P, Tonani R, Zugnoni P, Vianello P. 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J Med Chem. 2006 Nov 30;49(24):7247-51. PMID:17125279 doi:10.1021/jm060897w
- ↑ Kim C, Ludewig H, Hadzipasic A, Kutter S, Nguyen V, Kern D. A biophysical framework for double-drugging kinases. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2304611120. PMID:37590418 doi:10.1073/pnas.2304611120
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