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  • br Concluding Remarks and Future Perspectives Our understand

    2022-08-12


    Concluding Remarks and Future Perspectives Our understanding of substrate targeting mechanisms utilized by kinases has grown tremendously in the past few years, but challenges still remain in relating these mechanisms to the organization of complex signaling networks. Substrate prediction based on linear kinase recognition motifs remains difficult, especially considering that multiple substrate binding modes are possible, and that indirect kinase–substrate interactions may override direct interactions in some contexts. Predicting ‘low-quality’, yet authentic kinase substrates is a particular challenge, as both the activity of the kinase and the differential effects of levels of phosphorylation have various biological consequences. New approaches, such as NMR spectroscopy [28] and molecular dynamics simulations [10], which can address how kinase dynamics influence substrate recognition, may be useful in providing a deeper understanding of determinants of substrate quality for a given kinase. In this way, basic biochemical principles will facilitate the development of a systems-level view of protein kinases and their associated signaling networks.
    Acknowledgments This work was supported by NIH grants R01 GM104047 and R01 GM102262. We thank Deborah Schechtman and Paulo Oliveira for sharing coordinates of the PKC-tubulin complex model, and Natalie Ahn for sharing coordinates of the ERK2-DEF substrate interaction model.
    Introduction Cyclin-dependent kinases (CDKs) are serine/threonine kinases that are regulated through their interaction with a cyclin subunit. CDKs are categorized based on their action through one of two different biological mechanisms: CDKs that play an important role in glibenclamide regulation by binding to multiple cyclins, and CDKs that control transcriptional regulation by binding to a single cyclin. In mammals, the CDK family is grouped into the cell cycle-related (CDK1, CDK2, CDK4/6, etc.) and transcriptional (CDK7, CDK8, CDK9, CDK12, CDK19, etc.) subfamilies. Although various pan-CDK inhibitors known to function as cell-cycle regulators have demonstrated antitumor efficacy in clinical trials, the antitumor activity of some of these have been reported as also arising from their effects on transcriptional regulation through the inhibition of CDK7 and CDK9, which are members of the transcriptional CDK subfamily. CDK8 has been reported to act as a transcriptional regulator, and has been found to be glibenclamide overexpressed in colorectal cancer (CRC) and adenocarcinoma relative to adjacent normal tissue. Furthermore, CDK8 was identified as a major oncogenic driver for amplification at 13q12.13–12q12.2 in CRC in two RNA interference-based loss-of-function screens. Immunohistochemical analysis of the CDK8 expression correlated with the tumor grade, stage and the local recurrence or metastasis in extrauterine leiomyosarcoma, and is associated with shorter relapse-free survival in breast cancer. CDK8 plays various roles in different signaling pathways to modulate gene expression levels as a part of the Mediator complex (CDK8, MED12, MED13, and cyclin-C), such as in the regulation of RNA polymerase (RNAP) II, activation at the nucleosome level by phosphorylation at Ser10 of histone H3, enhancement of β-catenin dependent gene expression by phosphorylation of E2F1,2(a), 2(c), 2(f), 12 activation of INFγ-dependent gene expression by phosphorylation of STAT1, inhibition of Notch1-dependent gene expression by phosphorylation of ICN1, modulation of TGF-β signaling,2(c), 15 and regulation of p27 protein expression by Skp2-mediated p27 ubiquitination and degradation. These biological effects of CDK8 on context-related gene expression may be beneficial for patients suffering from various types of tumors.4, 17 Current pan-CDK inhibitors in clinical trials have potential risks, such as narrow therapeutic windows due to their indiscriminate toxicity toward normal cells, and complications in attempting to understand their mechanisms of action.1, 2 Therefore, a highly selective inhibitor of CDK8 could be a promising candidate for cancer therapy. Although CDK192(c), 2(b), 18 is closely related to CDK8 in terms of structure and its association with C-type cyclins, its biological role is unclear.