Insights from the protein interaction Universe of the multifunctional “Goldilocks” kinase DYRK1A

Abstract

Human Dual specificity tyrosine (Y)-Regulated Kinase 1A (DYRK1A) is encoded by a dosage-dependent gene located in the Down syndrome critical region of human chromosome 21. The known substrates of DYRK1A include proteins involved in transcription, cell cycle control, DNA repair and other processes. However, the function and regulation of this kinase is not fully understood, and the current knowledge does not fully explain the dosage-dependent function of this kinase. Several recent proteomic studies identified DYRK1A interacting proteins in several human cell lines. Interestingly, several of known protein substrates of DYRK1A were undetectable in these studies, likely due to a transient nature of the kinase-substrate interaction. It is possible that the stronger-binding DYRK1A interacting proteins, many of which are poorly characterized, are involved in regulatory functions by recruiting DYRK1A to the specific subcellular compartments or distinct signaling pathways. Better understanding of these DYRK1A-interacting proteins could help to decode the cellular processes regulated by this important protein kinase during embryonic development and in the adult organism. Here, we review the current knowledge of the biochemical and functional characterization of the DYRK1A protein-protein interaction network and discuss its involvement in human disease.

Dyrk1a is required for craniofacial development inXenopus laevis

“…DYRK1A could also regulate cell numbers and growth in the face via its roles in the cell cycle. This protein has actually been shown to suppress cell cycle by modulating several cell cycle regulators such as D cyclins, CDK inhibitors, p53, the LIN52 subunit of DREAM complex as well as the spindle microtubules (Fernandez-Martinez et al, 2015; Iness et al, 2019; Litovchick et al, 2011; Liu et al, 2014)(Ananthapadmanabhan et al, 2023). Therefore, Dyrk1a deficiency might then be expected to increase proliferation in the developing embryo.…”

“…DYRK1A ( D ual- s pecificity Tyrosine ( Y ) R egulated K inase) is a multifunctional kinase that phosphorylates protein substrates involved in a wide range of cellular process such as cell cycle, transcription, signaling, and apoptosis (reviewed in (Ananthapadmanabhan et al, 2023; Atas-Ozcan et al, 2021; Fernandez-Martinez et al, 2015)). Therefore, it is not surprising that proper dosage of this protein is critical for a variety of developmental processes.…”