Disease relevance of AURKA

• AURKA is one of the downstream targets of MAPK1/ERK2 in pancreatic cancer [1].
• Preferential amplification of AURKA 91A (Ile31) in familial colorectal cancers [2].
• We have previously shown by microarray analysis of primary lung carcinomas and matched normal tissue that AURKB (22 out of 37) and AURKA (15 out of 37) transcripts are frequently over-represented in these tumours [3].
• The extent of STK15 expression was not significantly correlated with the size, degree of differentiation, and metastasis status of the tumors [4].
• STK15 mRNA was found overexpressed in 10 of the 15 ovarian cancer cell cultures [5].
• AURKA overexpression is seen in the majority of late stage epithelial ovarian cancers, most likely due to increased AURKA DNA copy numbers and/or chromosome 20 aneusomy [6].

High impact information on AURKA

• In a sample of bladder tumors with wild-type p53, elevated expression of aurora kinase A was correlated with low p53 concentration [7].
• Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53 [7].
• Silencing of aurora kinase A results in less phosphorylation of p53 at Ser315, greater stability of p53 and cell-cycle arrest at G2-M [7].
• Ectopic overexpression of aurora kinase A in mammalian cells induces centrosome amplification, chromosome instability and oncogenic transformation, a phenotype characteristic of loss-of-function mutations of p53 [7].
• Cells depleted of aurora kinase A are more sensitive to cisplatin-induced apoptosis, and elevated expression of aurora kinase A abolishes this response [7].

Chemical compound and disease context of AURKA

• Polymorphisms of the AURKA (STK15/Aurora Kinase) Gene and Breast Cancer Risk (United States) [8].
• A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines [9].
• We describe in this paper isolation of a novel gene named BTAK, encoding a putative member of protein serine/threonine kinase family localized on chromosome 20q13 that is amplified and overexpressed in breast tumor cell lines [9].
• We were also interested in knowing whether any association between Aurora-A and breast cancer was modified by reproductive risk factors reflecting susceptibility to estrogen exposure [10].
• Endothelial Nitric Oxide Synthase (Glu298Asp) Polymorphism is an Independent Risk Factor for Migraine with Aura [11].

Biological context of AURKA

• Thus our results support the importance of AURKA 91A as a low penetrance CRC susceptibility factor [2].
• The degree of overexpression of AURKA was shown to be closely associated with the amplification of chromosome 20q in immortalized HOSE cells [12].
• Quantitative expression analysis detected the overexpression of the AURKA gene in all tumors tested, suggesting a role for this mitotic regulator in the aneuploidy and chromosomal instability observed in RMS [13].
• Aurora-A/BTAK/STK15 localizes to the centrosome in the G(2)-M phase, and its kinase activity regulates the G(2) to M transition of the cell cycle [14].
• These results suggest the highly dynamic nature of the temporal and spatial distributions, as well as the biochemical modification, of the NuRD complex in M phase, probably through an interaction with kinases, including Aurora-A [15].

Anatomical context of AURKA

• The AURKA ANSPC was positively associated with the percentage of cells with the centrosome abnormality [16].
• Using fluorescence in situ hybridization (FISH), we observed that 5 of the 12 cell lines had an AURKA amplification index (AI) (percentage of cells with more than three signals) >60% [16].
• Here we have examined how overexpression of Aurora-A kinase causes centrosome amplification in cultured cells [17].
• Here we show that ectopic expression of Aurora-A induces telomerase activity in human ovarian and breast epithelial cell lines HIOSE118 and MCF-10A [18].
• Here we describe the physical interaction of Plk3 with Aurora A and BubR1 kinases, and the significance of this interaction during terminal differentiation and polyploidization of megakaryocytes [19].

Associations of AURKA with chemical compounds

• The recent determination of the three-dimensional structure of Aurora A has shown that Aurora kinases exhibit unique conformations around the activation loop region [20].
• Inhibitors with isoquinoline and quinazoline moieties were recognized by aurora2 in which H-89 and 6,7-dimethoxyquinazoline compounds exhibited high binding energies compared with that of staurosporine [21].
• Molecular dynamics and docking simulations, targeting the ATP binding site of aurora2 with adenylyl imidodiphosphate (AMP-PNP), staurosporine, and six small molecular S/T kinase inhibitors, identified active-site residues that interact with these inhibitors differentially [21].
• Here we show that p53 is phosphorylated by the mitotic kinase Aurora-A at serine 215 [22].
• As a result, Aurora-A overrides the apoptosis and cell cycle arrest induced by cisplatin and gamma-irradiation, respectively [22].

Physical interactions of AURKA

• The centrosomal kinase Aurora-A/STK15 interacts with a putative tumor suppressor NM23-H1 [23].
• Pull-down assays show that Plk3 physically interacts with Aurora A as well as BubR1 [19].
• A two-hybrid screen identified the kinetochore component CENP-A as a protein that interacts with Aurora-A [24].
• The E2 ubiquitin-conjugating enzyme UBE2N was a preferential binding partner of the 'weak' STK15 Phe31 variant form in yeast two-hybrid screens and in human cells [25].
• Here we show that human Aurora-A binds to TPX2, a prominent component of the spindle apparatus [26].

Enzymatic interactions of AURKA

• We have uncovered the molecular mechanism of Aurora-A activation by determining crystal structures of its phosphorylated form both with and without a 43 residue long domain of TPX2 that we identified as fully functional for kinase activation and protection from dephosphorylation [27].
• Our results demonstrate that Aurora-A phosphorylates CDC25B in vivo at the centrosome during mitosis [28].
• Moreover, Aurora-A phosphorylated HURP in vitro and in vivo [29].
• Here, we show that Aurora-A phosphorylates NDEL1 at Ser251 at the beginning of mitotic entry [30].

Regulatory relationships of AURKA

• Ectopic expression of Aurora-A up-regulates c-Myc [18].
• The mRNA and promoter activities of human telomerase reverse transcriptase (hTERT) are stimulated by Aurora-A [18].
• Conversely, depletion of Aurora-A by siRNA had no detectable influence on the localization of TPX2 [26].
• Furthermore, we showed that the inhibition of Aurora-A-induced phosphorylation of S83 on Lats2 partially perturbed its centrosomal localization [31].
• Here we report that Aurora-A protects ovarian cancer cells from apoptosis induced by chemotherapeutic agent and activates Akt pathway in a p53-dependent manner [32].

Other interactions of AURKA

• Knockdown of ETS2 resulted in a reduction of AURKA expression [1].
• STK15 and NM23 were initially found to interact in yeast in a two-hybrid assay [23].
• Overexpression of Aurora-A was associated with high-grade (grade II-IV), and high-stage (stage IIIB-IV) tumors, p53 mutation, infrequent beta-catenin mutation, and poor outcome [33].
• The AURKA AI was also associated with a lower expression of Ki-67, a higher expression of survivin, and the lack of expression of p16 [16].
• Overexpression and amplification of Aurora-A in hepatocellular carcinoma [33].

Analytical, diagnostic and therapeutic context of AURKA

• Fluorescence in situ hybridization (FISH) with labeled P1 artificial clone (PAC) confirmed the amplification of the chromosomal region (20q13.2-13.3) where AURKA resides [12].
• DNA amplification of AURKA was also confirmed using semi-quantitative PCR [12].
• Western Blot analysis of primary tumor tissues revealed 2-10 times overexpression of STK15 protein compared with normal adjacent tissues from pancreatic cancer patients [4].
• STK15 protein expression was also examined in normal pancreatic tissues and tumors by Western blotting and immunohistochemistry [4].
• Amplification of Aurora-A was determined by Southern blot hybridization in 99 cases [33].

References