Abstract
DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been associated with all the hallmarks of cancer, from genomic instability to increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant to tumor onset and progression. In accordance with an involvement of DYRK kinases in the regulation of tumorigenic processes, an increasing number of research studies have been published in recent years showing either alterations of DYRK gene expression in tumor samples and/or providing evidence of DYRK-dependent mechanisms that contribute to tumor initiation and/or progression. In the present article, we will review the current understanding of the role of DYRK family members in cancer initiation and progression, providing an overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently available.
Highlights
The first cancer gene identified, the proto-oncogene c-Src, was found to encode a protein kinase [1]
Of all the Dual-specificity tyrosine-regulated kinases (DYRKs), only DYRK1A has been identified in high-throughput cancer studies, initially as a potential tumor suppressor using Tumor Suppressor and Oncogene Explorer (TUSON), a method developed to predict the potential of a given gene to act as a tumor suppressor, or oncogene, by computing somatic mutation profiles and copy number alterations (CNAs) [41]
More experimental evidence indicates that DYRK protein kinases are a novel class of “kinase-of-interest” in cancer
Summary
The first cancer gene identified, the proto-oncogene c-Src, was found to encode a protein kinase [1]. Class II DYRKs present a N-terminal autophosphorylation accessory region (NAPA) domain, essential for catalytic activation [6] (Figure 1A). N-terminal domain of DYRK3 serves to localize it to stress granules [16] Both the histidine run in DYRK1A and the N-terminus of DYRK3 participate in the generation of phase-separated subcellular compartments [17,18]. Accessibility to substrates due to changes in the subcellular localization In this regard, and given the constitutive nature of DYRK kinase activity, the regulation of their intracellular levels becomes crucial to modulate their functions, and altering the DYRK expression acquires additional importance in terms of their impact on normal cell fitness
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