Abrogation of AuroraA-TPX2 by novel natural inhibitors: molecular dynamics-based mechanistic analysis

Gupta, Ankita; Jain, Ritu; Wahi, Divya; Goyal, Sukriti; Jamal, Salma; Grover, Abhinav

doi:10.3109/10799893.2015.1041645

Cited by 10 publications

(5 citation statements)

References 49 publications

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“…More interestingly, these PTMs can be used to design original inhibitory strategies different from those targeting the kinase active site. The binding of TPX2 to Aurora-A for instance has been targeted to search for Aurora-A inhibitor [107]. This kind of approach targeting PTMs offers broad prospects for specific inhibition of Aurora kinases.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Aurora Kinases and Their Activity

Vaufrey¹,

Damodaran²,

Gavard³

et al. 2017

Protein Phosphorylation

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The three mitotic protein kinases Aurora-A, B and C are complementary enzymes that regulate multiple mitotic events. To do so, the different kinases must be locally activated, and the control of their activity is tightly regulated in time and space during mitosis. For instance, Aurora-A is first active at the centrosomes, then on microtubules at the spindle pole, Aurora-B is active in the nucleus, then at chromosome kinetochores and later one at the midbody. Aurora kinase activity is regulated in space and time by locally binding to regulators. Aurora kinases must bind to protein partners to be activated. Aurora-A for instance binds to targeting protein for Xenopus kinesin-like protein 2 (TPX2) and is activated at the spindle pole, Aurora-B and Aurora-C to INner CENtromer Protein (INCENP) and is activated on the chromosomes. These activations go through an autophosphorylation of a threonine residue in the T-loop of the kinase. Other protein partners are using different mechanisms to activate Auroras. These allow activation of the kinase at different time and location in the cell. This review is an up-to-date list of regulators of Aurora kinases. The subcellular localization of these regulators explains the presence of an active Aurora kinase. It also explains the changes in the localizations of the Aurora kinases activity observed during cell cycle progression in mitosis. Aurora kinases have been recently reported to be involved in nonmitotic events, and the identity of their activators in these events must be searched.

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Section: Resultsmentioning

confidence: 99%

Regulation of Aurora Kinases and Their Activity

Vaufrey¹,

Damodaran²,

Gavard³

et al. 2017

Protein Phosphorylation

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“…Targeting of the mitotic spindle checkpoint, which induces massive aneuploidy and severe chromosome segregation errors, is being considered for developing new therapeutic strategies for selectively eliminating highly proliferative cancer cells [ 41 – 44 ]. Since TPX2 plays an essential role in mitotic spindle apparatus and subsequently cell division and tumor growth via binding to Aurora-A, many researchers focus on identifying antagonists to blockade this interaction [ 45 ]. Our findings of the regulation of TPX2 expression by Hh signaling provide a novel approach to suppress TPX2 via decreasing its expression level rather than its activity.…”

Section: Discussionmentioning

confidence: 99%

The critical role of dysregulated Hh-FOXM1-TPX2 signaling in human hepatocellular carcinoma cell proliferation

Wang

Yan

et al. 2020

Cell Commun Signal

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Background: Aberrant activation of the Hedgehog (Hh) signaling pathway is frequently observed in hepatocellular carcinoma (HCC), nevertheless, the precise molecular mechanism remains unclear. Forkhead box M1 (FOXM1), a target of the Hh pathway, is a key oncofetal transcription factor and a master cell cycle regulator. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is an oncogene critical for mitosis. However, how these molecular events affect HCC progression remains unclear. Methods: Realtime PCR, immunohistochemistry, western blotting, and analyses of datasets TCGA and Gene Expression Omnibus (GEO) were conducted to assess the expression of TPX2 and FOXM1 at the mRNA and protein levels in HCC samples or HCC cells. Expression and knockdown of TPX2 and FOXM1 were performed to assess their role in regulating HCC cell proliferation in vitro and in vivo. Dual luciferase report assay and chromosome immunoprecipitation (ChIP) were investigated to seek the FOXM1 binding sites in the promoter of TPX2. Results: Specific antagonists (cyclopamine and GANT61) of the Hh pathway down-regulated TPX2, whereas activation of Hh signaling stimulated TPX2 expression. Furthermore, TPX2 over-expression accelerated HCC cell proliferation when upstream events of Hh signaling were inhibited, and TPX2 knockdown significantly alleviated Sonic Hh ligand (Shh)-induced HCC cell proliferation. Reporter assays and ChIP showed that FOXM1 bound to the TPX2 promoter, confirming that TPX2 is a direct downstream target of FOXM1. Xenograft model further verified the cell function and expression regulation of TPX2 and FOXM1 in vivo. Furthermore, FOXM1 regulated TPX2 activity to drive HCC proliferation. Immunohistochemical (IHC) analysis indicated that FOXM1 and TPX2 were highly-expressed in HCC samples and cohort study revealed that FOXM1 and TPX2 may act as negative predictors for the prognosis of patients with HCC. Conclusions: TPX2 acts as a novel downstream target and effector of the Hh pathway, and Hh signaling contributes to HCC proliferation via regulating the FOXM1-TPX2 cascade, suggesting that this signaling axis may be a novel therapeutic target for HCC.

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“…In recent years, molecular dynamics (MD) simulations based studies have demonstrated great potential as a substitute for investigations in understanding the dynamical aspects of protein-ligand interaction, protein folding, and also protein-protein interaction [ 22 – 30 ]. In the present study, to gain insights into the effects of mutations (K753E, L768S and V773L) on the binding strength of lapatinib, MD simulations of the kinase domain of HER-2 (wild and mutants) in complex with the lapatinib were performed.…”

Section: Introductionmentioning

confidence: 99%

Structural investigations on mechanism of lapatinib resistance caused by HER-2 mutants

et al. 2018

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HER-2 belongs to the human epidermal growth factor receptor (HER) family. Via different signal transduction pathways, HER-2 regulates normal cell proliferation, survival, and differentiation. Recently, it was reported that MCF10A, BT474, and MDA-MB-231 cells bearing the HER2 K753E mutation were resistant to lapatinib. Present study revealed that HER-2 mutant K753E showed some contrasting behaviour as compared to wild, L768S and V773L HER-2 in complex with lapatinib while similar to previously known lapatinib resistant L755S HER-2 mutant. Lapatinib showed stable but reverse orientation in binding site of K753E and the highest binding energy among studied HER2-lapatinib complexes but slightly lesser than L755S mutant. Results indicate that K753E has similar profile as L755S mutant for lapatinib. The interacting residues were also found different from other three studied forms as revealed by free energy decomposition and ligplot analysis.

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Abrogation of AuroraA-TPX2 by novel natural inhibitors: molecular dynamics-based mechanistic analysis

Cited by 10 publications

References 49 publications

Regulation of Aurora Kinases and Their Activity

Regulation of Aurora Kinases and Their Activity

The critical role of dysregulated Hh-FOXM1-TPX2 signaling in human hepatocellular carcinoma cell proliferation

Structural investigations on mechanism of lapatinib resistance caused by HER-2 mutants

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