Fangmbeng Nana Valerie

11079429

ertyuiopasdfghjklzxcvbnmqwertyuio
AURORA KINASE A
dfghjklzxcvbnmqwertyuiopasdfghjkl
[Type the document subtitle]
vbnmqwertyuiopasdfghjklzxcvbnmq
AUTHORS
[Pick the date]

1. : Introduction
rtyuiopasdfghjklzxcvbnmqwertyuiop
2.BELLA MALOPE (13378733):Structure and post-translational
modifications
3.Functions of the protein and its role in cell signalling

fghjklzxcvbnmqwertyuiopasdfghjklz
4.Its role in disease
5.The effect that small –molecule inhibitors will have (or do have) in
relation to how it will affect the cell cycle and/or induce cell death

bnmqwertyuiopasdfghjklzxcvbnmq
rtyuiopasdfghjklzxcvbnmqwertyuiop
fghjklzxcvbnmqwertyuiopasdfghjklz
bnmqwertyuiopasdfghjklzxcvbnmq
rtyuiopasdfghjklzxcvbnmqwertyuiop
fghjklzxcvbnmqwertyuiopasdfghjklz
bnmqwertyuiopasdfghjklzxcvbnmq
rtyuiopasdfghjklzxcvbnmqwertyuiop
fghjklzxcvbnmrtyuiopasdfghjklzxcvb
INTRODUCTION

INFORMATION ABOUT THE GENES OF AURORA KINAS A

Aurora-A kinase (official gene symbol AURKA) has many aliases, including more commonly Aurora, Aurora-
2, serine/threonine kinase 15 (STK15), serine/threonine kinase 6 (STK6), breast tumor amplified kinase
(BTAK), aurora-related kinase 1 (ARK1), Homo sapiens Aurora/IPL1-related kinase (HsAirk1), Eg2, and Ipl-
and Aurora-related kinase 1 (IAK1). As these names indicate, this protein is a member of Aurora/IPL1-
related kinase family of serine/threonine kinases¹, essential for proper execution of various mitotic events
and are important for maintaining genomic integrity. The three human homologues of Aurora kinases (A,
B and C) share similarity² . AURKA is regulated by phosphorylation in a cell cycle dependent manner³.

controlled activation of the Aurora-A kinase (AURKA) is regulates centrosome maturation, entry into
mitosis, formation and function of the bipolar spindle, and cytokinesis.

The Aurka gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish,
fruit fly, mosquito, C.elegans, M.oryzae, A.thaliana, rice, and frog. By examination of the AURKA cDNA
sequence the threonine at residue 288 in the catalytic domain was found to be highly conserved in all
Aurora family members as well as in various other serine/threonine kinases ⁴.

BRCA1 (BRCA1 and BRCA2 are normally expressed in the cells of breast and other tissue, where they help
repair damaged DNA, or destroy cells if DNA cannot be repaired), MBD3, NME1, P53, TACC1 and TPX2 ⁵.

Serine/threonine kinase identified as key regulator of the mitotic cell division process. Known to be
involved in the regulation of centrosome function, bipolar spindle assembly and chromosome segregation
processes

Two upstream regulators of AURKA, Ajuba and targeting protein for Xklp2 ( TPX2 ) are known. TPX2 is a
MT-binding protein involved in spindle pole formation and is the best characterized RanGTP-dependent
spindle activator. TPX2 is required for AURKA binding to spindle MTs and its binding to AURKA holds the
latter in an active conformation. Ajuba and AURKA interact in mitotic cells and become phosphorylated.
In vitro analyses revealed that Ajuba induces the autophosphorylation and consequent activation of
AURKA. Depletion of Ajuba prevented activation of AURKA at centrosomes in late G2 phase and inhibited
mitotic entry.
STRUCTURE AND POST-TRANSLATIONAL MODIFICATIONS OF AURORA KINASE A

Aurora kinase A is part of the Aurora kinases family⁶. They are characterized by Threonines and Serines in
their amino acid sequence(6). Their amino acid sequence length ranges from 309 to 403⁶. Their structure
consists of N-terminal domain (139-129), a protein kinase domain andC -terminal domain (15-20)⁶. All
Aurora kinases have an ATP binding active site lined by 26 residues and three variants( Leu 215, Thr 217
and R220) are specific to Aurora A⁶. TPX2 is the best known substrate of Aurora A. Its interaction with
Aurora A is responsible for the autophosphorylation of Aurora A at Thr-288/277 activation loop⁷. This
autophosphorylation activates Aurora A⁷. The activity of Aurora A is regulated by two post translational
modifications which are:phosphorylation and dephosphorylation⁶. Phosphorylation leads to the
stimulation of Aurora kinases⁶. Studies identified three phosphorylation sites which are Ser-53, Thr-295
and Ser-349 in Aurora A⁶. Mutations in Thr-295 and Ser-349 decreased Aurora A activity⁶.
Dephosphorylation of Aurora A at T288 by PP1 phosphatase regulates the activity of Aurora A negatively⁶.
Ubiquitination also plays a role⁶. Kei Honda et al illustrated that Aurora A turn-over is by APC-ubiquitin-
proteosome pathway⁶. Degradation is mediated by Cdh1 or Fizzy related recognition of the D-box⁶.

Figure 1. Schematic representation of the domains found in Aurora kinases⁶

FUNCTION OF THE PROTEINS AND ITS ROLE IN CELL SIGNALLING

Aurora A is involved in mitotic entry, separation of centriole pairs, accurate bipolar spindle assembly,
and alignment of metaphase chromosomes and completion of cytokinesis. The activity of Aurora A is
closely related to centrosomes. It plays a role in bipolar spindle assembly, maturation of duplicated
centrosomes by recruiting proteins including D-Tacc24, γ-tubulin25, SPD-2, and centromeric ChToh27.
Recently role of Aurora A in the promotion of nuclear envelop breakdown has been described.15

Aurora A is essential for the formation of mitotic spindle. It is necessary for the recruitment of several
different proteins important to the spindle formation. Among these target proteins are TACC, a
microtubule-associated protein that stabilizes centrosomal microtubules and Kinesin 5, a motor protein
involved in the formation of the bipolar mitotic spindle.14 γ-tubulins, the base structure from which
centrosomal microtubules polymerize, are also recruited by Aurora A.[4] Without Aurora kinase A the
centrosome does not accumulate the quantity of γ-tubulin that normal centrosomes recruit prior to
entering anaphase.Though the cell cycle continues even in the absence of deficient γ-tubulin, the
centrosome never fully matures.Aurora kinase A is necessary for the proper separation of the
centrosomes after the mitotic spindle has been formed. Without Aurora A, the mitotic spindle,
depending on the organism, will either never separate or will begin to separate only to collapse back
onto itself.16 Moreover, Aurora kinase A also implements proper organization and alignment of the
chromosomes during pro-metaphase. It is directly involved in the interaction of the kinetochore,. In the
absence of Aurora A mad2, a protein that normally dissipates once a proper kinetochore-microtubule
connection is made, remains present even into metaphase.13

Lastly, Aurora kinase A assists in an exit from mitosis by contributing to the completion of cytokinesis.
Though the exact mechanism by which Aurora kinase A helps cytokinesis is unknown, it is well
documented that it relocalizes to the mid-body immediately before the completion of mitosis.13

During the meiosis process, Aurora kinase A phosphorylation directs the cytoplasmic polyadenylation
translation of mRNA's, like the MAP kinase protein MOS, which are essential for the completion of
meiosis in Xenopus Oocytes. Before the first meiotic metaphase, Aurora kinase A activates the
production of MOS. The MOS protein accumulates until it exceeds a threshold and then transduces the
phosphorylation cascade in the map kinase pathway.This signal then activates the kinase RSK which in
turn binds to the protein Myt1. Myt1, in complex with RSK, is now unable to inhibit cdc2. As a
consequence, cdc2 permits entry into meiosis.14A similar Aurora A dependent process regulates the
transition from meiosis I-meiosis II.

The functions of Aurora kinase A are therefore summarised into the following points.

● Plays a role in the regulation of cell cycle progression.

● Is associated with the centrosome and the spindle microtubules during the mitosis.
● 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.[7]
● Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5,
HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2.17
● Regulates KIF2A tubulin depolymerase activity
● Necessary for normal axon formation.
● Plays a role in microtubule remodeling during neurite extension.
● Essentail 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/TP53.17
● Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their
activity.17

ROLE OF AURORA KINASE A IN DISEASE

Aurora kinase A is a target of wnt/ B-Catenin involved in multiple myeloma disease progression. A certain
cancer which affects plasma cells known as multiple myeloma (MM) has complex molecular
characteristics that evolve from monoclonal gammopathy of undetermined significance; a very prevalent
premalignant condition. B-Catenin plays a very huge role in MM tumour progression and proliferation

The reduction of B-catenin levels in MM cells is highly associated with significant transcriptional changes
in aurora kinase A, which is a novel wnt target gene. The transcriptional changes are correlated with
tumorgenesis metastasis and survival in a mouse xenograft model of MM

Dysfunction of these kinase is associated with failure to maintain a stable chromosome content, a state
that can contribute to tumourgenesis. Aurora kinase A is frequently found amplified in a variety of tumour
types and it displays oncogenic activity. But therapeutic inhibition of the kinase has shown a great promise
as potential anti-cancer treatment, most likely because of their essential roles during cell division.

Human Aurora-A was isolated as the product of gene BTAK (breast tumour amplified kinase, also named
STK 15). On chromosome 20q13, a region that is commonly amplified in primary breast tumours,
colorectal cancers and other cancer cell lines, including breast, ovarian, colon, prostate, neuroblastoma
and cervical cell lines.

Over expression of Aurora-A transforms NIH 3T3 cells and Raf-1 fibroblast in vitro: when the cells were
rejected into nude mice, they grew into tumours. But a controversy remains because no more cell lines
were found to be transformed by overexpression of Aurora-A, and over expression of Aurora-A in mouse
model did not result in malignant tumour after a long latency

The effect that small molecule inhibitors will have (or do have) in relation to how it will affect the cell
cycle and/or induce cell death

Small-molecule inhibitors of Aurora kinases are expected to prevent the continuous growth of
cancer cells and control abnormal mitosis. Small molecules inhibitors inhibit kinases by binding
to ATP binding pocket of the kinase

A growing number of aurora kinase inhibitors have been developed, name a few include; VX-
680,MLN-8054, MLN- 8237 ,TC28, Hesperin, ZM- 447439, PHA-680632, Tripolin A

. Aurora kinase A inhibitor ZM447439 inhibit proliferation of cell cycle and induce polyploidy
apoptosis.

VX680 an inhibitor induce apoptosis in leukaemic blast, destroy bipolar spindle this lead to G2/M
phase cell cycle arrest hence induce apoptosis. It also reduce P – AKT, activate caspases

MLNA- 8054 exerts its antitumor activity against human tumor xenografts through inhibition of
Aurora A kinase. MLN8054 treatment of tumor cells results in inhibition of the activating pT288,
spindle defects, G2/M accumulation, and cell death through apoptosis.and increase Bax/Bcl2 ratio

Tripolin A inhibits Aurora kinase A, in mammalian cells, while it is used to reveal a new way of
regulating the function of its substrates, i.e. by altering the distribution of HURP on spindle MTs.
It induces mitotic spindle defect and spindle poles abnormalities.

A study was done which showed that Inhibition of Aurora-A kinase induce cell death in EOC stem cells.
The study focused on the possible effect of Aurora-A inhibition in these cells, Since the EOC stem cells
represent the chemo-resistant cell population. A panel of EOC stem cells was treated with a novel Aurora-
A kinase inhibitor, MK-5108, which exhibits potent activity against Aurora-A in an ATP-competitive
manner. Results showed that Inhibition of Aurora-A by MK-5108 had signifcant inhibitory effects on the
growth of EOC stem cells. Cell death induced by MK-5108 was associated with cell cycle arrest, due to the
presence of multi-nucleated cells. This cells were observed after treatment with MK-5108 revealed a
significant decrease in the number of cells at G1 with high percentage of cells that were arrested in G2/M
phase. Aurora-A has been shown to be involved in cell cycle regulation such as, in cytokines, hence
inhibition of Aurora-A induces cell cycle arrest or cell death.

References
 1. Anna S. NikonovaIAIGSRLDJ,aEAG. Aurora-A kinase (AURKA) in normal and pathological
cell growth. HHS Public Access. 2012 August; 70(4).

2.Marumoto T ZDSH. Aurora-A - a guardian of poles. PubMed. 2005 January; 5(1).

3.Asteriti IA. Frontiers in Oncology. [Online].; 2015 [cited 2017 May 2. Available from:
http://journal.frontiersin.org/article/10.3389/fonc.2015.00283/full.

4.Lentini L. atlas genetics oncology. [Online].; 2008 [cited 2017 April 02. Available from:
http://atlasgeneticsoncology.org/Genes/GC_AURKA.html.

5.WIKI. wikipedia. [Online].; 2017 [cited 2017 April 02. Available from:
https://en.wikipedia.org/wiki/Aurora_A_kinase#cite_note-Crane_2004-6.

6.MadhuKollareddy PDDZMH. Aurora kinases:structure, functions and their association with

cancer. Biomed Pap Med FacUnivPalacky Olomouc Czech Repub. 2008 January; 152(1):27-33

7.Selena G BaRB. The structure of C29OA: C393A provides structural insights into kinase
regulation. Structural biology ccommunications. 2015 February

8.Agnese V, et al. The role of Aurora-A inhibitors in cancer therapy. [Annals of Oncology] 2007;18
(Supplement 6): 47–52. doi:10.1093/annonc/mdm224
9.Chefetz I, et al. Inhibition of Aurora-A kinase induces cell cycle arrest in epithelial ovarian cancer
stem cells by afecting NFκB pathway. [Cell Cycle]. 2011 July 1; 10(13):2206-2214. DOI:
10.4161/cc.10.13.16348
10.Fu J, et al. Roles of Aurora Kinases in Mitosis and Tumorigenesis. [Mol Cancer Res].
2007;5(1):1–10
11.Kollareddy M, et al. AURORA KINASES: STRUCTURE, FUNCTIONS AND THEIR
ASSOCIATION WITH CANCER. [Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub]
2008 January 18; 152(1):27–33

12. Dutta-Simmons J, Zhang Y, Gorgun G, Gatt M, Mani M, Hideshima T et al. Aurora kinase A is
a target of Wnt/ -catenin involved in multiple myeloma disease progression. Blood.
2009;114(13):2699-2708.
13. Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E, Saya H (December 2003).
"Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells". J. Biol.
Chem. 278 (51): 51786–95. doi:10.1074/jbc.M306275200. PMID 14523000
14.Crane R, Gadea B, Littlepage L, Wu H, Ruderman JV (2004). "Aurora A, meiosis and
mitosis" (PDF). Biol. Cell. 96 (3): 215–29. doi:10.1016/j.biolcel.2003.09.008. PMID 15182704.

15.AURORA KINASES: STRUCTURE, FUNCTIONS AND THEIR ASSOCIATION WITH

CANCER MadhuKollareddya , Petr Dzubaka , Daniella Zhelevab , Marian Hajducha *Received:
November 30, 2007; Accepted: January 18, 2008

16.Hannak E, Kirkham M, Hyman AA, Oegema K (December 2001). "Aurora-A kinase is

required for centrosome maturation in Caenorhabditiselegans". J. Cell Biol. 155 (7): 1109–16.
doi:10.1083/jcb.200108051. PMC 2199344Freely accessible. PMID 11748251

17. Lliana Kesissova , et al( march 13, 2013) . Tripolin A a novel small molecules inhibitor of
Aurora A kinase,reveal new regulation of HURP’S distribution on microtubules.
https://doi.org/10.1371/journal.pone.0058485