Document Details Document Type : Article In Journal  Document Title : Presence and utility of intrinsically disordered regions in kinases Presence and utility of intrinsically disordered regions in kinases   Document Language : English  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.  ISSN : 1742-206X  Journal Name : MOLECULAR BIOSYSTEMS  Volume : 10  Issue Number : 11  Publishing Year : 1434 AH 2014 AD  Article Type : Article  Added Date : Tuesday, August 1, 2017  Researchers Researcher Name (Arabic) Researcher Name (English) Researcher Type Dr Grade Email Jaymin Kathiriya Kathiriya, Jaymin Researcher     Ravi Pathak Pathak, Ravi Researcher     Eric Clayman Clayman, Eric Researcher     Bin Xue Xue, Bin Researcher     Vladimir Uversky Uversky, Vladimir Researcher     Vrushank Dave Dave, Vrushank Researcher     Files File Name Type Description  42384.pdf pdf   Back To Researches Page