LMTK3 inhibition affects microtubule stability

Cilibrasi, Chiara; Ditsiou, Angeliki; Papakyriakou, Athanasios; Mavridis, George; Eravci, Murat; Stebbing, Justin; Gagliano, Teresa; Giamas, Georgios

doi:10.1186/s12943-021-01345-3

Cited by 8 publications

(8 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LMTK overexpression, on the other hand, phosphorylates ERa, protecting it from proteasomal destruction and, therefore, stabilizing the ERa protein. LMTK3 knockdown decreased estrogen receptor 1 (ESR1) mRNA expression ( Cilibrasi et al, 2021 ). We have used in silico drug design strategies to discover new inhibitors against the LMTK3 target to stop the mechanistic behavior in the cancer pathway.…”

Section: Discussionmentioning

confidence: 99%

Chemoinformatics and machine learning techniques to identify novel inhibitors of the lemur tyrosine kinase-3 receptor involved in breast cancer

Alrumaihi

2024

Front. Mol. Biosci.

View full text Add to dashboard Cite

Breast cancer is still the largest cause of cancer death in women, and around 70% of primary breast cancer patients are estrogen receptor (ER)-positive, which is the most frequent kind of breast cancer. The lemur tyrosine kinase-3 (LMTK3) receptor has been linked to estrogen responsiveness in breast cancer. However, the function of LMTK3 in reaction to cytotoxic chemotherapy has yet to be studied. Breast cancer therapy research remains tricky due to a paucity of structural investigations on LMTK3. We performed structural investigations on LMTK3 using molecular docking and molecular dynamics (MD) simulations of the LMTK3 receptor in complex with the top three inhibitor molecules along with a control inhibitor. Analysis revealed the top three compounds show the best binding affinities during docking simulations. Interactive analysis of hydrogen bonds inferred hotspot residues Tyr163, Asn138, Asp133, Tyr56, Glu52, Ser132, Asp313, and Asp151. Some other residues in the 5-Å region determined strong alkyl bonds and conventional hydrogen bond linkages. Furthermore, protein dynamics analysis revealed significant modifications among the top complexes and the control system. There was a transition from a loop to a-helix conformation in the protein–top1 complex, and in contrast, in complexes top2 and top3, the formation of a stabilizing sheet in the C chain was observed, which limited significant mobility and increased complex stability. Significant structural alterations were observed in the protein–top complexes, including a shorter helix region and the creation of some loop regions in comparison to the control system. Interestingly, binding free energies, including MMGB/PBSA WaterSwap analysis estimation, reveals that the top1 complex system was more stable than other systems, especially in comparison to the control inhibitor complex system. These results suggest a the plausible mode of action for the novel inhibitors. Therefore, the current investigation contributes to understanding the mechanism of action, serving as a basis for future experimental studies.

show abstract

Section: Discussionmentioning

confidence: 99%

Chemoinformatics and machine learning techniques to identify novel inhibitors of the lemur tyrosine kinase-3 receptor involved in breast cancer

Alrumaihi

2024

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…Further characterization of C28 revealed an interesting effect on the cell cycle [ 34 ]. In addition to LMTK3 inhibition, C28 was found to induce apoptosis and G2/M arrest in breast cancer cells, indicating that C28 may exert its anti-cancer effects through an additional mechanism.…”

Section: The Translational Potential Of Lmtk3 In Cancermentioning

confidence: 99%

“…Additionally, LMTK3 was found to directly phosphorylate CDC37; therefore, research is needed into the role of LMTK3 on the HSP90-CDC37 chaperone system as a whole [33]. Further characterization of C28 revealed an interesting effect on the cell cycle [34]. In addition to LMTK3 inhibition, C28 was found to induce apoptosis and G2/M arrest in breast cancer cells, indicating that C28 may exert its anti-cancer effects through an additional mechanism.…”

Section: The Translational Potential Of Lmtk3 In Cancermentioning

confidence: 99%

“…Furthermore, the depletion of LMTK3 by C28 results in microtubule instability with subsequent G2/M cell cycle arrest and cell death through downregulating NUSAP1 and the NUSAP1-regulated protein CDK1. This also reduces the phosphorylation of βIII tubulin at Ser 172[33,34]. CDK1, cyclin-dependent kinase 1; LMTK3, lemur tyrosine kinase 3; NUSAP1, nucleolar and spindle associated protein 1.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The multifaceted role of lemur tyrosine kinase 3 in health and disease

et al. 2021

Self Cite

View full text Add to dashboard Cite

In the last decade, LMTK3 (lemur tyrosine kinase 3) has emerged as an important player in breast cancer, contributing to the advancement of disease and the acquisition of resistance to therapy through a strikingly complex set of mechanisms. Although the knowledge of its physiological function is largely limited to receptor trafficking in neurons, there is mounting evidence that LMTK3 promotes oncogenesis in a wide variety of cancers. Recent studies have broadened our understanding of LMTK3 and demonstrated its importance in numerous signalling pathways, culminating in the identification of a potent and selective LMTK3 inhibitor. Here, we review the roles of LMTK3 in health and disease and discuss how this research may be used to develop novel therapeutics to advance cancer treatment.

show abstract

“…Ten years later, LMTK3 is an established cancer driver known to act through diverse mechanisms [5][6][7][8][9][10][11][12][13][14]. Concisely, the crystal structure of the LMTK3 kinase domain has now been solved and its consensus phosphorylation motif has been determined [12].…”

mentioning

confidence: 99%