Cited by 30Protein Structure and DynamicsComputational Drug Discovery MethodsProtein Kinase Regulation and GTPase Signaling

Presence and utility of intrinsically disordered regions in kinases

Kathiriya, Jaymin J, Pathak, Ravi Ramesh, Clayman, Eric, Xue, Bin, Uversky, Vladimir N, Davé, Vrushank·2014·Molecular BioSystems

Abstract

Since aberrant cell signaling pathways underlie majority of pathophysiological morbidities, kinase inhibitors are routinely used for pharmacotherapy. However, most kinase inhibitors suffer from adverse off-target effects. Inhibition of one kinase in a pathogenic signaling pathway elicits multiple compensatory feedback signaling loops, reinforcing the pathway rather than inhibiting it, leading to chemoresistance. Thus, development of novel computational strategies providing predictive evidence to inhibit a specific set of kinases to mitigate an aberrant signaling pathway with minimum side-effects is imperative. First, our analyses reveal that many kinases contain intrinsically disordered regions, which may participate in facilitating protein–protein interactions at the kinome level. Second, we employ a kinome-wide approach to identify intrinsic disorder and streamline a methodology that adds to the knowledge of therapeutically targeting kinase cascades to treat diseases. Furthermore, we find that within the kinome network, some kinases with intrinsically disordered regions have a high topological score, likely acting as kinome modulators. Third, using network analysis, we demonstrate that 5 kinases emerge as topologically most significant, forming kinome sub-networks, comprising of other kinases and transcription factors that are known to serve as drivers of disease pathogenesis. To support these findings, we have biologically validated the interplay between kinome modulators SRC and AKT kinases and uncovered their novel function in regulating transcription factors of the SMAD family. Taken together, we identify novel kinome modulators driven by intrinsic disorder, and biologically validate the thesis that therapeutic disruption of the function of kinome modulators engaged in regulatory cross-talk between disparate pathways can lead to reduced oncogenic potential in cancer cells.

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Crossref · 10.1039/c4mb00224e

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  • Many kinases include IDRs, which facilitate the intermolecular interactions critical for the function and specificity of the signaling cascade.

    “Many kinases include IDRs, which facilitate the intermolecular interactions critical for the function and specificity of the signaling cascade [318].”

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Authors
Kathiriya, J. J., Pathak, R. R., Clayman, E., Xue, B., Uversky, V. N., & Davé, V.
Affiliations
  • University of South Florida (US)
  • Russian Academy of Sciences (RU)
Corresponding author
Davé, Vrushank
Venue
Molecular BioSystems
Published
2014-07-30
Volume
10
Issue
11
Pages
2876-2888
ISSN
  • 1742-2051 (ISSN-L)
  • 1742-206X
OpenAlex
W2010144808
Cited by
30
References
119
Citations by year
2026: 3 · 2025: 2 · 2024: 1 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 3
FWCI
1.64
Type
journal article
Language
en
Open access
closed
Locations
  • Molecular BioSystems (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Commons - University of South Florida (University of South Florida) (submittedVersion)
Funders
  • American Heart Association (SDG-155-N)
  • H. Lee Moffitt Cancer Center and Research Institute (Lung SPORE Career Development)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
intrinsically disordered regions, kinases, kinome, kinase inhibitors, off-target effects, chemoresistance, protein-protein interaction, Src kinase, Akt kinase, Smad transcription factors, kinase cascade, cancer therapy, compensatory signaling
MeSH terms
Dasatinib, Cell Line, Gene Expression Regulation, Heterocyclic Compounds, 3-Ring, Humans, Protein Kinases, Pyrimidines, Thiazoles, Signal Transduction, Computational Biology, Protein Kinase Inhibitors, Cell Proliferation, Smad Proteins, Intrinsically Disordered Proteins

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