| 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] CE192_HUMAN Required for mitotic centrosome maturation and bipolar spindle assembly (PubMed:25042804, PubMed:17980596, PubMed:18207742). Appears to be a major regulator of pericentriolar material (PCM) recruitment, centrosome maturation, and centriole duplication (PubMed:25042804, PubMed:17980596, PubMed:18207742). Centrosome-specific activating scaffold for AURKA and PLK1 (PubMed:25042804).[22] [23] [24]
Publication Abstract from PubMed
Aurora kinase A (AURKA) performs critical functions in mitosis. Thus, the activity and subcellular localization of AURKA are tightly regulated and depend on diverse factors including interactions with the multiple binding cofactors. How these different cofactors regulate AURKA to elicit different levels of activity at distinct subcellular locations and times is poorly understood. Here, we identified a conserved region of CEP192, the major cofactor of AURKA, that mediates the interaction with AURKA. Quantitative binding studies were performed to map the interactions of a conserved helix (Helix-1) within CEP192. The crystal structure of Helix-1 bound to AURKA revealed a distinct binding site that is different from other cofactor proteins such as TPX2. Inhibiting the interaction between Helix-1 and AURKA in cells led to the mitotic defects, demonstrating the importance of the interaction. Collectively, we revealed a structural basis for the CEP192-mediated AURKA regulation at the centrosome, which is distinct from TPX2-mediated regulation on the spindle microtubule.
Structural basis for CEP192-mediated regulation of centrosomal AURKA.,Park JG, Jeon H, Shin S, Song C, Lee H, Kim NK, Kim EE, Hwang KY, Lee BJ, Lee IG Sci Adv. 2023 Apr 21;9(16):eadf8582. doi: 10.1126/sciadv.adf8582. Epub 2023 Apr , 21. PMID:37083534[25]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C, Chan CS, Novotny M, Slamon DJ, Plowman GD. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998 Jun 1;17(11):3052-65. PMID:9606188 doi:10.1093/emboj/17.11.3052
- ↑ 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
- ↑ Gomez-Ferreria MA, Rath U, Buster DW, Chanda SK, Caldwell JS, Rines DR, Sharp DJ. Human Cep192 is required for mitotic centrosome and spindle assembly. Curr Biol. 2007 Nov 20;17(22):1960-6. doi: 10.1016/j.cub.2007.10.019. Epub 2007, Nov 1. PMID:17980596 doi:http://dx.doi.org/10.1016/j.cub.2007.10.019
- ↑ Zhu F, Lawo S, Bird A, Pinchev D, Ralph A, Richter C, Muller-Reichert T, Kittler R, Hyman AA, Pelletier L. The mammalian SPD-2 ortholog Cep192 regulates centrosome biogenesis. Curr Biol. 2008 Jan 22;18(2):136-41. doi: 10.1016/j.cub.2007.12.055. PMID:18207742 doi:http://dx.doi.org/10.1016/j.cub.2007.12.055
- ↑ Joukov V, Walter JC, De Nicolo A. The Cep192-organized aurora A-Plk1 cascade is essential for centrosome cycle and bipolar spindle assembly. Mol Cell. 2014 Aug 21;55(4):578-91. doi: 10.1016/j.molcel.2014.06.016. Epub 2014 , Jul 17. PMID:25042804 doi:http://dx.doi.org/10.1016/j.molcel.2014.06.016
- ↑ Park JG, Jeon H, Shin S, Song C, Lee H, Kim NK, Kim EE, Hwang KY, Lee BJ, Lee IG. Structural basis for CEP192-mediated regulation of centrosomal AURKA. Sci Adv. 2023 Apr 21;9(16):eadf8582. PMID:37083534 doi:10.1126/sciadv.adf8582
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