Dual-specificity tyrosine-regulated kinases (DYRKs) are a conserved family of protein kinases that 1) self-activated by autophosphorylation on tyrosine residues and 2) phosphorylate exogenous substrates on serine/threonine residues. DYRK family members share a conserved kinase domain and N-terminal DH box (DYRK homology) but differ in their N- and C-terminal extensions. The kinase activity of all DYRKs depends on the YTY motif in the activation loop, which mimics the characteristic TXY motif found in the mitogen-activated protein kinases (MAPKs). This suggests a similar regulatory mechanism shared between DYRKs and MAPKs. However, unlike MAPKs, phosphorylation on tyrosine in DYRK's activation loop is an autophosphorylation event that does not require any upstream kinase.
Phylogenetic analysis suggests that two DYRK subfamilies exist. The DYRK1 family includes mammalian DYRK1A and DYRK1B, minibrain (mnb) in Drosophila melanogaster, and C. elegans MBK1. In Drosophila melanogaster, mutations in minibrain (mnb) affect postembryonic neurogenesis. Human DYRK1A maps to the Down's syndrome critical region on Chromosome 21 and is overexpressed in Down's syndrome brain, suggesting a similar role in mammalian neurogenesis. Furthermore, recent studies have shown that DYRK1 can regulate Shh signaling by enhancing Glil-dependent gene expression.
The DYRK2 subfamily is present in several eukaryotic organisms, including mammalian DYRK2, Drosophila DYRK2, C. elegans MBK-2, and S. pombe Pomlp. Pomlp and MBK-2 both play important roles in cell division and cell polarity. In addition, MBK-2 is required for timely degradation of some maternally inherited proteins, such as MEI-1, OMA-1 and germ plasm components. In C. elegans, MBK-2 phosphorylates MEI-1 and OMA-1 directly; the phosphate-labeled MEI-1 and OMA-1 then become the targets of protein degradation machinery in the early embryos. Interestingly, a recent study has shown that mammalian DYRK2 negatively regulates Shh signaling by directly phosphorylating and inducing proteosome-dependent degradation of the key Hh pathway-regulated transcription factor, GLI2, suggesting a similar cellular function of DYRK2 across species. Moreover, mammalian DYRK2 has also been reported to relocate from cytoplasm to nucleus and phosphorylate p53 directly at Ser46 in response to DNA damage. While different DYRKs have evolved to recognize a variety of substrates in different cell types, a common function linking all DYRKs may be the coordinate regulation of cell cycle, cell growth and cell differentiation. Although DYRK family kinases have been implicated in a wide variety of cellular and developmental processes, the regulatory mechanisms of DYRKs are still poorly understood.
MBK-2 is a DYRK family kinase; it contains a serine-threonine kinase domain, an activation loop with tyrosine kinase phosphorylation sites, and a serine-rich domain (26 serines in total) on the amino terminus. By using in silico search for protein domains or motifs, we found that there were two putative phosphorylation sites (S68 and T470) for proline-directed protein kinases. These made us think that MBK-2 could be regulated by phosphorylation or dephosphorylation. MBK-2 activity could also be regulated by its ability to access its substrates. MBK-2 is present on the cortex of the oocytes and metaphase I embryos. During anaphase of meiosis I, MBK-2 becomes to localize to cortical puncta. These puncta get internalized during meiosis II and MBK-2 is then released into cytoplasm.
Reference:Chih-Chien Cheng. REGULATION OF MBK-2/DYRK DURING THE OOCYTE-TO-EMBRYO TRANSITION
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