ARD1-mediated Aurora Kinase A Acetylation Promotes Cell Proliferation and Migration

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Sep 17

PMID 28915666

Citations 11

Authors

Tam Thuy Lu Vo

Ji-Hyeon Park

Ji Hae Seo

Eun Ji Lee

Hoon Choi

Sung-Jin Bae

Hoang Le

Sunho An

Hye Shin Lee

Hee-Jun Wee

Kyu-Won Kim

Affiliations

Soon will be listed here.

Abstract

Aurora kinase A (AuA) is a prerequisite for centrosome maturation, separation, and mitotic spindle assembly, thus, it is essential for cell cycle regulation. Overexpression of AuA is implicated in poor prognosis of many types of cancer. However, the regulatory mechanisms underlying the functions of AuA are still not fully understood. Here, we report that AuA colocalizes with arrest defective protein 1 (ARD1) acetyltransferase during cell division and cell migration. Additionally, AuA is acetylated by ARD1 at lysine residues at positions 75 and 125. The double mutations at K75/K125 abolished the kinase activity of AuA. Moreover, the double mutant AuA exhibited diminished ability to promote cell proliferation and cell migration. Mechanistic studies revealed that AuA acetylation at K75/K125 promoted cell proliferation via activation of cyclin E/CDK2 and cyclin B1. In addition, AuA acetylation stimulated cell migration by activating the p38/AKT/MMP-2 pathway. Our findings indicate that ARD1-mediated acetylation of AuA enhances cell proliferation and migration, and probably contributes to cancer development.

Citing Articles

Molecular Mechanisms of ARD1 in Tumors.

Yu C, Lei H, Hou X, Yan S Cancer Med. 2025; 14(5):e70708.

PMID: 40026288 PMC: 11873779. DOI: 10.1002/cam4.70708.

Illuminating the impact of N-terminal acetylation: from protein to physiology.

McTiernan N, Kjosas I, Arnesen T Nat Commun. 2025; 16(1):703.

PMID: 39814713 PMC: 11735805. DOI: 10.1038/s41467-025-55960-5.

The promotion action of AURKA on post-ischemic angiogenesis in diabetes-related limb ischemia.

Bai T, Li M, Liu Y, Qiao Z, Zhang X, Wang Y Mol Med. 2023; 29(1):39.

PMID: 36977984 PMC: 10053687. DOI: 10.1186/s10020-023-00635-4.

PARP10 Mediates Mono-ADP-Ribosylation of Aurora-A Regulating G2/M Transition of the Cell Cycle.

Di Paola S, Matarese M, Barretta M, Dathan N, Colanzi A, Corda D Cancers (Basel). 2022; 14(21).

PMID: 36358629 PMC: 9659153. DOI: 10.3390/cancers14215210.

Biochemical analysis of novel NAA10 variants suggests distinct pathogenic mechanisms involving impaired protein N-terminal acetylation.

McTiernan N, Tranebjaerg L, Bjorheim A, Hogue J, Wilson W, Schmidt B Hum Genet. 2022; 141(8):1355-1369.

PMID: 35039925 PMC: 9304055. DOI: 10.1007/s00439-021-02427-4.

References

Giono L, Manfredi J . The p53 tumor suppressor participates in multiple cell cycle checkpoints. J Cell Physiol. 2006; 209(1):13-20. DOI: 10.1002/jcp.20689. View

Farria A, Li W, Dent S . KATs in cancer: functions and therapies. Oncogene. 2015; 34(38):4901-13. PMC: 4530097. DOI: 10.1038/onc.2014.453. View

Lim J, Park J, Chun Y . Human arrest defective 1 acetylates and activates beta-catenin, promoting lung cancer cell proliferation. Cancer Res. 2006; 66(22):10677-82. DOI: 10.1158/0008-5472.CAN-06-3171. View

Chin Y, Toker A . The actin-bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Mol Cell. 2010; 38(3):333-44. PMC: 2872630. DOI: 10.1016/j.molcel.2010.02.031. View

Bai M, Ni J, Shen S, Wu J, Huang Q, Le Y . Two newly identified sites in the N-terminal regulatory domain of Aurora-A are essential for auto-inhibition. Biotechnol Lett. 2014; 36(8):1595-604. DOI: 10.1007/s10529-014-1516-3. View

Zorba A, Buosi V, Kutter S, Kern N, Pontiggia F, Cho Y . Molecular mechanism of Aurora A kinase autophosphorylation and its allosteric activation by TPX2. Elife. 2014; 3:e02667. PMC: 4032492. DOI: 10.7554/eLife.02667. View

Cheetham G, Knegtel R, Coll J, Renwick S, Swenson L, Weber P . Crystal structure of aurora-2, an oncogenic serine/threonine kinase. J Biol Chem. 2002; 277(45):42419-22. DOI: 10.1074/jbc.C200426200. View

Zhao B, Smallwood A, Yang J, Koretke K, Nurse K, Calamari A . Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2. Protein Sci. 2008; 17(10):1791-7. PMC: 2548374. DOI: 10.1110/ps.036590.108. View

Page-McCaw A, Ewald A, Werb Z . Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007; 8(3):221-33. PMC: 2760082. DOI: 10.1038/nrm2125. View

10.

Arnesen T, Gromyko D, Pendino F, Ryningen A, Varhaug J, Lillehaug J . Induction of apoptosis in human cells by RNAi-mediated knockdown of hARD1 and NATH, components of the protein N-alpha-acetyltransferase complex. Oncogene. 2006; 25(31):4350-60. DOI: 10.1038/sj.onc.1209469. View

11.

Satinover D, Brautigan D, Stukenberg P . Aurora-A kinase and inhibitor-2 regulate the cyclin threshold for mitotic entry in Xenopus early embryonic cell cycles. Cell Cycle. 2006; 5(19):2268-74. DOI: 10.4161/cc.5.19.3316. View

12.

Kufer T, Sillje H, Korner R, Gruss O, Meraldi P, Nigg E . Human TPX2 is required for targeting Aurora-A kinase to the spindle. J Cell Biol. 2002; 158(4):617-23. PMC: 2174010. DOI: 10.1083/jcb.200204155. View

13.

Nigg E . Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol. 2001; 2(1):21-32. DOI: 10.1038/35048096. View

14.

Ohashi S, Sakashita G, Ban R, Nagasawa M, Matsuzaki H, Murata Y . Phospho-regulation of human protein kinase Aurora-A: analysis using anti-phospho-Thr288 monoclonal antibodies. Oncogene. 2006; 25(59):7691-702. DOI: 10.1038/sj.onc.1209754. View

15.

Bayliss R, Sardon T, Vernos I, Conti E . Structural basis of Aurora-A activation by TPX2 at the mitotic spindle. Mol Cell. 2003; 12(4):851-62. DOI: 10.1016/s1097-2765(03)00392-7. View

16.

Hirota T, Kunitoku N, Sasayama T, Marumoto T, Zhang D, Nitta M . Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell. 2003; 114(5):585-98. DOI: 10.1016/s0092-8674(03)00642-1. View

17.

Pines J . Four-dimensional control of the cell cycle. Nat Cell Biol. 1999; 1(3):E73-9. DOI: 10.1038/11041. View

18.

DAssoro A, Liu T, Quatraro C, Amato A, Opyrchal M, Leontovich A . The mitotic kinase Aurora--a promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα(+) breast cancer cells. Oncogene. 2013; 33(5):599-610. PMC: 4058768. DOI: 10.1038/onc.2012.628. View

19.

Zhang Y, Ni J, Huang Q, Ren W, Yu L, Zhao S . Identification of the auto-inhibitory domains of Aurora-A kinase. Biochem Biophys Res Commun. 2007; 357(2):347-52. DOI: 10.1016/j.bbrc.2007.03.129. View

20.

Fu J, Bian M, Jiang Q, Zhang C . Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res. 2007; 5(1):1-10. DOI: 10.1158/1541-7786.MCR-06-0208. View