DYRK3

DYRK3 (dual-specificity tyrosine phosphorylation-regulated kinase 3) functions as a serine/threonine and tyrosine kinase involved in cellular stress responses and proteostasis^[1]. Mechanistically, DYRK3 phosphorylates components of stress granules and liquid-liquid phase separation structures, thereby regulating protein solubility and phase transition during nutrient deprivation or hypoxic stress^[1]. In disease models, DYRK3 activity influences tumor cell survival by controlling proteasome function and modulating key transcription factors, including heat-shock factor 1 and c-Myc^[1]. Compared with related isoforms such as DYRK1A and DYRK2, DYRK3 exhibits a distinct cytoplasmic localization and preferential engagement with stress granule substrates rather than nuclear transcriptional regulators^[1][2]. Small-molecule inhibitors of DYRK3, characterized by high selectivity within the CMGC kinase family, have demonstrated the ability to disrupt stress-mediated proteostasis and reduce tumor cell proliferation in preclinical studies^[3][4]. These inhibitors, often based on pyrimidine or imidazopyridazine scaffolds, facilitate mechanistic studies and provide a foundation for experimental applications targeting DYRK3-dependent pathways^[3][4]. Overall, DYRK3 serves as a regulatory kinase coordinating cellular adaptation to environmental stress, distinguishing itself from other DYRK isoforms through substrate specificity and cytoplasmic function, with emerging potential for therapeutic intervention^[2][1].