# AURKA

## Overview
Aurora kinase A (AURKA) is a gene that encodes a serine/threonine kinase protein, known as aurora kinase A, which plays a pivotal role in the regulation of the cell cycle. This kinase is crucial for various cellular processes, particularly during mitosis, where it is involved in centrosome maturation, spindle assembly, and chromosome alignment, ensuring accurate chromosome segregation (Nikonova2012Aurora; Willems2018The). Beyond its mitotic functions, aurora kinase A is also implicated in non-mitotic roles, such as cilia disassembly and cell motility, highlighting its versatility in cellular dynamics (Bertolin2019Insights). The gene's overexpression and genetic alterations are associated with several cancers, making it a significant focus for cancer research and therapeutic targeting (Mou2021Aurora; Nikonova2012Aurora).

## Structure
Aurora kinase A (AURKA) is a serine/threonine kinase involved in cell cycle regulation, particularly in spindle assembly and stability. The protein is composed of 403 amino acids, with its first 3D structure solved in 2002. The primary structure includes a kinase domain and an activation loop, which are crucial for its function (de2020Structural).

The secondary structure of AURKA features an N-terminal lobe predominantly composed of β-sheets and a C-terminal lobe that is mostly α-helical. The kinase domain is divided into these N-lobe and C-lobe regions, with the active site cleft formed between them. A key regulatory structure, the activation loop, resides in the C-lobe and contains the conserved catalytic Asp-Phe-Gly (DFG) motif (Levinson2018The).

The tertiary structure of AURKA includes a regulatory spine and a catalytic spine, which are stabilized by specific residues and interactions. The regulatory spine involves residues like Gln 185 and His 254, while the catalytic spine includes Val 147 and Leu 318. The DFG motif's position is crucial for kinase activity, with active conformations showing specific interactions (de2020Structural).

AURKA undergoes post-translational modifications, such as phosphorylation at threonine residues T287 and T288, which are essential for its activation. The protein also interacts with TPX2, a microtubule-associated protein, which facilitates its activation and localization during mitosis (Janeček2016Allosteric; de2020Structural).

## Function
Aurora kinase A (AURKA) is a serine/threonine kinase that plays a critical role in various cellular processes in healthy human cells. It is primarily known for its involvement in mitosis, where it supports centrosome maturation, spindle assembly, and chromosome alignment, ensuring accurate chromosome segregation during cell division (Nikonova2012Aurora; Willems2018The). AURKA is active at the centrosomes and spindle poles, where it interacts with proteins such as TPX2, Ajuba, and NEDD9 to facilitate its activation and proper localization (Nikonova2012Aurora).

Beyond its mitotic functions, AURKA is involved in non-mitotic roles, including the regulation of cilia disassembly, neurite extension, and cell motility. It plays a part in DNA replication initiation during the G1/S phase transition, where it has a kinase-independent function crucial for replisome assembly (Bertolin2019Insights; Guarino2020A). AURKA also contributes to microtubule dynamics and cell polarity control, interacting with proteins like NDEL1 and TACC3, and is involved in ciliary resorption, which is essential for cellular responses to environmental cues (Nikonova2012Aurora). These diverse roles highlight AURKA's importance in maintaining normal cellular functions and structures.

## Clinical Significance
Aurora kinase A (AURKA) is significantly implicated in various cancers due to its overexpression and genetic alterations. High levels of AURKA are associated with poor prognosis in cancers such as breast, ovarian, lung, and colorectal cancers (Mou2021Aurora; Nikonova2012Aurora). AURKA overexpression is linked to increased tumorigenicity, epithelial-mesenchymal transition, and stem cell formation, contributing to cancer progression (Nikhil2024The). It is often amplified or overexpressed due to gene amplification at the 20q13.2 locus, leading to chromosomal instability and aneuploidy (Nikonova2012Aurora; Goldenson2014The).

AURKA interacts with several proteins, such as p53, leading to its degradation and reduced tumor suppressor activity, which promotes tumorigenesis (Goldenson2014The; Du2021Targeting). It also phosphorylates substrates like KEAP1, resulting in Nrf2 activation and ferroptosis resistance, which are significant in cancer progression (Nikhil2024The). The kinase's interactions with oncogenic pathways, such as PI3K/Akt and mTOR, further underscore its role in cancer (Du2021Targeting). These alterations in AURKA expression and interactions make it a promising target for cancer therapy, with several inhibitors in clinical trials (Du2021Targeting).

## Interactions
Aurora kinase A (AURKA) is involved in various protein interactions that regulate its activity and localization. AURKA interacts with TPX2, which is crucial for its activation and localization to the mitotic spindle. This interaction is essential for AURKA's catalytic activity and is disrupted by the small-molecule inhibitor AurkinA, which binds to the Y-pocket of AURKA, inducing structural changes that inhibit its activity (Janeček2016Allosteric).

AURKA also interacts with centriolar satellites, which regulate its function during primary cilium biogenesis. The interaction with centriolar satellites involves proteins such as PCM1, CEP131, and CEP72. PCM1 is identified as a putative substrate for AURKA, with specific phosphorylation sites that may influence this interaction. The regulation by centriolar satellites affects AURKA's localization, abundance, and activity, particularly during cilium assembly and disassembly (Arslanhan2020Aurora).

In colorectal cancer, AURKA interacts with the Wnt and Ras-MAPK signaling pathways, enhancing their activity. It stabilizes β-catenin levels, activating Wnt signaling, and interacts with the H-RAS/Raf-1 complex to upregulate Ras-MAPK signaling, contributing to cancer progression (Jacobsen2018Aurora).


## References


[1. (Mou2021Aurora) Pui Kei Mou, Eun Ju Yang, Changxiang Shi, Guowen Ren, Shishi Tao, and Joong Sup Shim. Aurora kinase a, a synthetic lethal target for precision cancer medicine. Experimental & Molecular Medicine, 53(5):835–847, May 2021. URL: http://dx.doi.org/10.1038/s12276-021-00635-6, doi:10.1038/s12276-021-00635-6. This article has 65 citations.](https://doi.org/10.1038/s12276-021-00635-6)

[2. (Nikonova2012Aurora) Anna S. Nikonova, Igor Astsaturov, Ilya G. Serebriiskii, Roland L. Dunbrack, and Erica A. Golemis. Aurora a kinase (aurka) in normal and pathological cell division. Cellular and Molecular Life Sciences, 70(4):661–687, August 2012. URL: http://dx.doi.org/10.1007/s00018-012-1073-7, doi:10.1007/s00018-012-1073-7. This article has 339 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-012-1073-7)

[3. (Jacobsen2018Aurora) Annika Jacobsen, Linda J. W. Bosch, Sanne R. Martens-de Kemp, Beatriz Carvalho, Anke H. Sillars-Hardebol, Richard J. Dobson, Emanuele de Rinaldis, Gerrit A. Meijer, Sanne Abeln, Jaap Heringa, Remond J. A. Fijneman, and K. Anton Feenstra. Aurora kinase a (aurka) interaction with wnt and ras-mapk signalling pathways in colorectal cancer. Scientific Reports, May 2018. URL: http://dx.doi.org/10.1038/s41598-018-24982-z, doi:10.1038/s41598-018-24982-z. This article has 33 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s41598-018-24982-z)

[4. (Goldenson2014The) B Goldenson and J D Crispino. The aurora kinases in cell cycle and leukemia. Oncogene, 34(5):537–545, March 2014. URL: http://dx.doi.org/10.1038/onc.2014.14, doi:10.1038/onc.2014.14. This article has 242 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/onc.2014.14)

5. (Arslanhan2020Aurora) Aurora Kinase A proximity interactome reveals centriolar satellites as regulators of its function during primary cilium biogenesis. This article has 1 citations.

[6. (Willems2018The) Estelle Willems, Matthias Dedobbeleer, Marina Digregorio, Arnaud Lombard, Paul Noel Lumapat, and Bernard Rogister. The functional diversity of aurora kinases: a comprehensive review. Cell Division, September 2018. URL: http://dx.doi.org/10.1186/s13008-018-0040-6, doi:10.1186/s13008-018-0040-6. This article has 257 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s13008-018-0040-6)

[7. (Nikhil2024The) Kumar Nikhil and Kavita Shah. The significant others of aurora kinase a in cancer: combination is the key. Biomarker Research, September 2024. URL: http://dx.doi.org/10.1186/s40364-024-00651-4, doi:10.1186/s40364-024-00651-4. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s40364-024-00651-4)

[8. (Bertolin2019Insights) Giulia Bertolin and Marc Tramier. Insights into the non-mitotic functions of aurora kinase a: more than just cell division. Cellular and Molecular Life Sciences, 77(6):1031–1047, September 2019. URL: http://dx.doi.org/10.1007/s00018-019-03310-2, doi:10.1007/s00018-019-03310-2. This article has 52 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-019-03310-2)

[9. (de2020Structural) Valéria Barbosa de Souza and Daniel Fábio Kawano. Structural basis for the design of allosteric inhibitors of the aurora kinase a enzyme in the cancer chemotherapy. Biochimica et Biophysica Acta (BBA) - General Subjects, 1864(1):129448, January 2020. URL: http://dx.doi.org/10.1016/j.bbagen.2019.129448, doi:10.1016/j.bbagen.2019.129448. This article has 16 citations.](https://doi.org/10.1016/j.bbagen.2019.129448)

[10. (Du2021Targeting) Ruijuan Du, Chuntian Huang, Kangdong Liu, Xiang Li, and Zigang Dong. Targeting aurka in cancer: molecular mechanisms and opportunities for cancer therapy. Molecular Cancer, January 2021. URL: http://dx.doi.org/10.1186/s12943-020-01305-3, doi:10.1186/s12943-020-01305-3. This article has 288 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1186/s12943-020-01305-3)

[11. (Levinson2018The) Nicholas Mark Levinson. The multifaceted allosteric regulation of aurora kinase a. Biochemical Journal, 475(12):2025–2042, June 2018. URL: http://dx.doi.org/10.1042/bcj20170771, doi:10.1042/bcj20170771. This article has 45 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1042/bcj20170771)

[12. (Janeček2016Allosteric) Matej Janeček, Maxim Rossmann, Pooja Sharma, Amy Emery, David J. Huggins, Simon R. Stockwell, Jamie E. Stokes, Yaw S. Tan, Estrella Guarino Almeida, Bryn Hardwick, Ana J. Narvaez, Marko Hyvönen, David R. Spring, Grahame J. McKenzie, and Ashok R. Venkitaraman. Allosteric modulation of aurka kinase activity by a small-molecule inhibitor of its protein-protein interaction with tpx2. Scientific Reports, June 2016. URL: http://dx.doi.org/10.1038/srep28528, doi:10.1038/srep28528. This article has 72 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/srep28528)

[13. (Guarino2020A) Estrella Guarino Almeida, Xavier Renaudin, and Ashok R Venkitaraman. A kinase-independent function for aurora-a in replisome assembly during dna replication initiation. Nucleic Acids Research, 48(14):7844–7855, July 2020. URL: http://dx.doi.org/10.1093/nar/gkaa570, doi:10.1093/nar/gkaa570. This article has 16 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkaa570)