DYRK1-mediated phosphorylation of endocytic components is required for extracellular lumen expansion in ascidian notochord

BACKGROUND: The biological tube is a basal biology structure distributed in all multicellular animals, from worms to humans, and has diverse biological functions. Formation of tubular system is crucial for embryogenesis and adult metabolism. Ascidian Ciona notochord lumen is an excellent in vivo model for tubulogenesis. Exocytosis has been known to be essential for tubular lumen formation and expansion. The roles of endocytosis in tubular lumen expansion remain largely unclear. RESULTS: In this study, we first identified a dual specificity tyrosine-phosphorylation-regulated kinase 1 (DYRK1), the protein kinase, which was upregulated and required for ascidian notochord extracellular lumen expansion. We demonstrated that DYRK1 interacted with and phosphorylated one of the endocytic components endophilin at Ser263 that was essential for notochord lumen expansion. Moreover, through phosphoproteomic sequencing, we revealed that in addition to endophilin, the phosphorylation of other endocytic components was also regulated by DYRK1. The loss of function of DYRK1 disturbed endocytosis. Then, we demonstrated that clathrin-mediated endocytosis existed and was required for notochord lumen expansion. In the meantime, the results showed that the secretion of noto-chord cells is vigorous in the apical membrane. CONCLUSIONS: We found the co-existence of endocytosis and exocytosis activities in apical membrane during lumen formation and expansion in Ciona notochord. A novel signaling pathway is revealed that DYRK1 regulates the endocytosis by phosphorylation that is required for lumen expansion. Our finding thus indicates a dynamic balance between endocytosis and exocytosis is crucial to maintain apical membrane homeostasis that is essential for lumen growth and expansion in tubular organogenesis.

New Perspectives of Dyrk1A Role in Neurogenesis and Neuropathologic Features of Down Syndrome

Down syndrome (DS) is one of the most common genetic disorders accompanying with mental retardation, cognitive impairment, and deficits in learning and memory. The brains with DS also display many neuropathological features including alteration in neurogenesis and synaptogenesis and early onset of Alzheimer's disease (AD)-like symptoms. Triplication of all or a part of human chromosome 21, especially the 21q22.1~21q22.3 region called 'Down syndrome critical region (DSCR)', has been considered as the main cause of DS. One gene product of DSCR, dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A), has been highlighted as a key contributor to the neural consequences of DS. This minireview summarizes accumulating recent reports about Dyrk1A involvement in the neuritogenesis, synaptogenesis, and AD-like neurofibrillary tangle formation, which is mainly focusing on Dyrk1A-mediated regulation of cytoskeletal proteins, such as tubulin, actin, and microtubule-associated protein tau. Understanding the molecular mechanisms of these phenomena may provide us a rational for new preventive and therapeutic treatment of DS.

Dyrk1A Positively Stimulates ASK1-JNK Signaling Pathway during Apoptotic Cell Death

Dual-specificity tyrosine (Y)-phosphorylation-regulated protein kinase 1A (Dyrk1A) is the mammalian homologue of Drosophila melanogaster minibrain and its human gene is mapped to the Down syndrome critical region of chromosome 21. Dyrk1A phosphorylates several transcription factors, including NFAT and CREB and a number of cytosolic proteins such as APP, tau, and alpha-synuclein. Although Dyrk1A is involved in the control of cell growth and postembryonic neurogenesis, its potential role during cell death and signaling pathway is not clearly understood. In the present study, we show that Dyrk1A is activated under the condition of apoptotic cell death. In addition, Dyrk1A is coupled to JNK1 activation, and directly interacts with apoptosis signal-regulating kinase 1 (ASK1). Moreover, Dyrk1A positively regulates ASK1-mediated JNK1-signaling, and appears to directly phosphorylate ASK1. These data indicate that Dyrk1A regulates cell death through facilitating ASK1-mediated signaling events.