Protein Kinases: Function, Substrates, and Implication in Diseases

Čipák, Luboš

doi:10.3390/ijms23073560

Cited by 4 publications

(3 citation statements)

References 12 publications

(12 reference statements)

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“…The key enzymes that govern these signaling pathways are protein kinases, which play essential regulatory roles in cells. Inadequate functioning of these enzymes is involved in the development of various diseases, including different cancer types [ 1 ]. However, important as kinases are, they are not sufficient in themselves to maintain an intact signaling cascade.…”

Section: Introductionmentioning

confidence: 99%

Absence of Scaffold Protein Tks4 Disrupts Several Signaling Pathways in Colon Cancer Cells

Jacksi

Schád

Buday

et al. 2023

IJMS

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Tks4 is a large scaffold protein in the EGFR signal transduction pathway that is involved in several cellular processes, such as cellular motility, reactive oxygen species-dependent processes, and embryonic development. It is also implicated in a rare developmental disorder, Frank–ter Haar syndrome. Loss of Tks4 resulted in the induction of an EMT-like process, with increased motility and overexpression of EMT markers in colorectal carcinoma cells. In this work, we explored the broader effects of deletion of Tks4 on the gene expression pattern of HCT116 colorectal carcinoma cells by transcriptome sequencing of wild-type and Tks4 knockout (KO) cells. We identified several protein coding genes with altered mRNA levels in the Tks4 KO cell line, as well as a set of long non-coding RNAs, and confirmed these changes with quantitative PCR on a selected set of genes. Our results show a significant perturbation of gene expression upon the deletion of Tks4, suggesting the involvement of different signal transduction pathways over the well-known EGFR signaling.

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Section: Introductionmentioning

confidence: 99%

Absence of Scaffold Protein Tks4 Disrupts Several Signaling Pathways in Colon Cancer Cells

Jacksi

Schád

Buday

et al. 2023

IJMS

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“…Protein kinases (PKs) are the master regulators of eukaryotic life [1]. Through their phosphotransfer activity, kinases can induce or suppress a wide range of cellular processes, from proliferation to apoptosis [2]. Unsurprisingly, given their central role in organisms, the activity of PKs must be tightly regulated to maintain or achieve homeostasis and their dysregulation often leads to severe disease [2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…Through their phosphotransfer activity, kinases can induce or suppress a wide range of cellular processes, from proliferation to apoptosis [2]. Unsurprisingly, given their central role in organisms, the activity of PKs must be tightly regulated to maintain or achieve homeostasis and their dysregulation often leads to severe disease [2][3][4][5][6]. The role of the Abl1 protein tyrosine kinase in cancers caused by the Philadelphia chromosome phenotype is perhaps the most widely-known example of kinase-mediated oncogenesis [7].…”

Section: Introductionmentioning

confidence: 99%

Compound Mutations in the Abl1 Kinase Cause Inhibitor Resistance by Shifting DFG Flip Mechanisms and Relative State Populations

Monteiro da Silva,

Lam,

Dalgarno

et al. 2024

Preprint

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The intrinsic dynamics of most proteins are central to their function. Protein tyrosine kinases such as Abl1 undergo significant conformational changes that modulate their activity in response to different stimuli. These conformational changes constitute a conserved mechanism for self-regulation that dramatically impacts kinases’ affinities for inhibitors. Few studies have attempted to extensively sample the pathways and elucidate the mechanisms that underlie kinase inactivation. In large part, this is a consequence of the steep energy barriers associated with many kinase conformational changes, which present a significant obstacle for computational studies using traditional simulation methods. Seeking to bridge this knowledge gap, we present a thorough analysis of the “DFG flip” inactivation pathway in Abl1 kinase. By leveraging the power of the Weighted Ensemble methodology, which accelerates sampling without the use of biasing forces, we have comprehensively simulated DFG flip events in Abl1 and its inhibitor-resistant variants, revealing a rugged landscape punctuated by potentially druggable intermediate states. Through our strategy, we successfully simulated dozens of uncorrelated DFG flip events distributed along two principal pathways, identified the molecular mechanisms that govern them, and measured their relative probabilities. Further, we show that the compound Glu255Lys/Val Thr315Ile Abl1 variants owe their inhibitor resistance phenotype to an increase in the free energy barrier associated with completing the DFG flip. This barrier stabilizes Abl1 variants in conformations that can lead to loss of binding for Type-II inhibitors such as Imatinib or Ponatinib. Finally, we contrast our Abl1 observations with the relative state distributions and propensity for undergoing a DFG flip of evolutionarily-related protein tyrosine kinases with diverging Type-II inhibitor binding affinities. Altogether, we expect that our work will be of significant importance for protein tyrosine kinase inhibitor discovery, while also furthering our understanding of how enzymes self-regulate through highly-conserved molecular switches.

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Recent updates on c-Src kinase and Src-Abl nonreceptor tyrosine kinases inhibitors

Navneesh,

Pandey,

Shakya

et al. 2024

Current Molecular Targets of Heterocyclic Compounds for Cancer Therapy

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Protein Kinases: Function, Substrates, and Implication in Diseases

Abstract: Protein kinases are important enzymes, involved in the regulation of various cellular processes [...]

Cited by 4 publications

References 12 publications

Absence of Scaffold Protein Tks4 Disrupts Several Signaling Pathways in Colon Cancer Cells

Absence of Scaffold Protein Tks4 Disrupts Several Signaling Pathways in Colon Cancer Cells

Compound Mutations in the Abl1 Kinase Cause Inhibitor Resistance by Shifting DFG Flip Mechanisms and Relative State Populations

Recent updates on c-Src kinase and Src-Abl nonreceptor tyrosine kinases inhibitors

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