The expression of the testis-specific Dyrk4 kinase is highly restricted to step 8 spermatids but is not required for male fertility in mice

Sacher, Frank; Möller, Christina; Bone, Wilhelm; Gottwald, Ulrich; Fritsch, Martin

doi:10.1016/j.mce.2006.12.041

Cited by 42 publications

(37 citation statements)

References 50 publications

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“…Alternative Splicing Alters the Subcellular Localization of DYRK4-Human DYRK4 (the 520-amino acid isoform) is located in the cytosol of COS-7 cells when expressed exogenously (23). We confirmed this distribution in HeLa cells using wild-type human DYRK4 520 and two kinase-deficient mutants (the KR mutant where Lys-133 in the ATP-binding , and the alternatively spliced exon 6/3 is underlined.…”

Section: Human Andsupporting

confidence: 53%

“…Similarly, two different human DYRK4 protein products can be predicted as follows: a 520-amino acid protein described previously (hDYRK4 520 , translated from accession number NM_003845; see Ref. 23) and a 635-amino acid protein (hDYRK4 635 , translated from accession number AK308260; supplemental Fig. S1B).…”

Section: Methodsmentioning

confidence: 99%

“…In contrast to DYRK2 and DYRK3, very little is known about the function of the other mammalian class II DYRK, DYRK4, and no substrate has been identified for this kinase. Rat and murine DYRK4s were reported to be testis-specific kinases expressed only in stage VIII post-meiotic spermatids (4,23). However, Dyrk4-deficient mice are fertile (23), which could possibly reflect some redundancy in function of the class II DYRKs, all of which are strongly expressed in the testis.…”

mentioning

confidence: 99%

“…Rat and murine DYRK4s were reported to be testis-specific kinases expressed only in stage VIII post-meiotic spermatids (4,23). However, Dyrk4-deficient mice are fertile (23), which could possibly reflect some redundancy in function of the class II DYRKs, all of which are strongly expressed in the testis. Conversely, it remains unclear whether DYRK4 can phosphorylate the same substrates as other DYRKs and thus substitute for a loss of DYRK3 or DYRK2.…”

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confidence: 99%

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Splice Variants of the Dual Specificity Tyrosine Phosphorylation-regulated Kinase 4 (DYRK4) Differ in Their Subcellular Localization and Catalytic Activity

Papadopoulos

Arató

Lilienthal³

et al. 2011

Journal of Biological Chemistry

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Dual specificity tyrosine phosphorylation-regulated kinases, DYRKs, are a family of conserved protein kinases that play key roles in the regulation of cell differentiation, proliferation, and survival. Of the five mammalian DYRKs, DYRK4 is the least studied family member. Here, we show that several splice variants of DYRK4 are expressed in tissue-specific patterns and that these variants have distinct functional capacities. One of these variants contains a nuclear localization signal in its extended N terminus that mediates its interaction with importin ␣3 and ␣5 and that is capable of targeting a heterologous protein to the nucleus. Consequently, the nucleocytoplasmic mobility of this variant differs from that of a shorter isoform in live cell imaging experiments. Other splicing events affect the catalytic domain, including a three-amino acid deletion within subdomain XI that markedly reduces the enzymatic activity of DYRK4. We also show that autophosphorylation of a tyrosine residue within the activation loop is necessary for full DYRK4 kinase activity, a defining feature of the DYRK family. Finally, by comparing the phosphorylation of an array of 720 peptides, we show that DYRK1A, DYRK2, and DYRK4 differ in their target recognition sequence and that preference for an arginine residue at position P ؊3 is a feature of DYRK1A but not of DYRK2 and DYRK4. Therefore, we highlight the use of subcellular localization as an important regulatory mechanism for DYRK proteins, and we propose that substrate specificity could be a source of functional diversity among DYRKs.Dual specificity tyrosine phosphorylation-regulated kinases (DYRKs) 3 are members of an evolutionarily conserved family of protein kinases that play key roles in the regulation of cell differentiation, proliferation, and survival (1, 2). DYRKs share a conserved kinase domain and adjacent N-terminal DYRK homology (DH)-box, although they differ in their N-and Cterminal extensions (3). From a phylogenetic point of view, DYRKs are divided into two subclasses that can be identified through the presence of specific protein motifs (2). Class I DYRKs harbor a functional, bipartite nuclear localization signal (NLS) N-terminal to the DH-box, and a C-terminal PEST or GAS region. This class includes the Drosophila minibrain kinase (mnb), Caenorhabditis elegans MBK-1, and mammalian DYRK1A and DYRK1B (4 -6). Class II DYRKs do not present any known protein domain within the N-and C-terminal extensions, except for the NAPA domain N-terminal to the DH-box (7), and they include mammalian DYRK2, DYRK3, and DYRK4, Drosophila dDYRK2 (smi35), C. elegans MBK-2 and Schizosaccharomyces pombe Pom1p (4,5,8,9).DYRKs contain a conserved Tyr-Xaa-Tyr motif in the activation loop, and the phosphorylation of the second tyrosine residue is essential for full catalytic activity of all the DYRKs tested to date (2, 10). Using dDYRK2 as a model, it has been shown that this critical tyrosine residue is autophosphorylated during translation (11), although notably, mature DYRKs only phosphoryl...

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Section: Human Andsupporting

confidence: 53%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Splice Variants of the Dual Specificity Tyrosine Phosphorylation-regulated Kinase 4 (DYRK4) Differ in Their Subcellular Localization and Catalytic Activity

Papadopoulos

Arató

Lilienthal³

et al. 2011

Journal of Biological Chemistry

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“…Among class 2 DYRKs, DYRK4 expression is predominant in testes, yet is apparently nonessential (31). DYRK2 is more broadly expressed and, like at least certain DYRKs of lower species, appears to be stress-activated and to attenuate cell growth (16,17).…”

Section: Erythroblasts Exhibited Enhanced Cd71mentioning

confidence: 99%

DYRK3 Dual-specificity Kinase Attenuates Erythropoiesis during Anemia

Bogacheva

Bogachev

Menon

et al. 2008

Journal of Biological Chemistry

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During anemia erythropoiesis is bolstered by several factors including KIT ligand, oncostatin-M, glucocorticoids, and erythropoietin. Less is understood concerning factors that limit this process. Experiments performed using dual-specificity tyrosine-regulated kinase-3 (DYRK3) knock-out and transgenic mice reveal that erythropoiesis is attenuated selectively during anemia. DYRK3 is restricted to erythroid progenitor cells and testes. DYRK3 ؊/؊ mice exhibited essentially normal hematological profiles at steady state and reproduced normally. In response to hemolytic anemia, however, reticulocyte production increased severalfold due to DYRK3 deficiency. During 5-fluorouracil-induced anemia, both reticulocyte and red cell formation in DYRK3 ؊/؊ mice were elevated. In short term transplant experiments, DYRK3 ؊/؊ progenitors also supported enhanced erythroblast formation, and erythropoietic advantages due to DYRK3-deficiency also were observed in 5-fluorouracil-treated mice expressing a compromised erythropoietin receptor EPOR-HM allele. As analyzed ex vivo, DYRK3 ؊/؊ erythroblasts exhibited enhanced CD71 pos Ter119 pos cell formation and 3 HdT incorporation. Transgenic pA2gata1-DYRK3 mice, in contrast, produced fewer reticulocytes during hemolytic anemia, and pA2gata1-DYRK3 progenitors were compromised in late pro-erythroblast formation ex vivo. Finally, as studied in erythroid K562 cells, DYRK3 proved to effectively inhibit NFAT (nuclear factor of activated T cells) transcriptional response pathways and to co-immunoprecipitate with NFATc3. Findings indicate that DYRK3 attenuates (and possibly apportions) red cell production selectively during anemia.

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Multiple functions of DYRK2 in cancer and tissue development

Yoshida

2019

FEBS Letters

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Dual‐specificity tyrosine‐regulated kinases (DYRKs) are evolutionarily conserved from yeast to mammals. Accumulating studies have revealed that DYRKs have important roles in regulation of the cell cycle and survival. DYRK2, a member of the class II DYRK family protein, is a key regulator of p53, and phosphorylates it at Ser46 to induce apoptosis in response to DNA damage. Moreover, recent studies have uncovered that DYRK2 regulates G1/S transition, epithelial‐mesenchymal‐transition, and stemness in human cancer cells. DYRK2 also appears to have roles in tissue development in lower eukaryotes. Thus, the elucidation of mechanisms for DYRK2 during mammalian tissue development will promote the understanding of cell differentiation, tissue homeostasis, and congenital diseases as well as cancer. In this review, we discuss the roles of DYRK2 in tumor cells. Moreover, we focus on DYRK2‐dependent developmental mechanisms in several species including fly (Drosophila), worm (Caenorhabditis elegans), zebrafish (Danio rerio), and mammals.

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The expression of the testis-specific Dyrk4 kinase is highly restricted to step 8 spermatids but is not required for male fertility in mice

Cited by 42 publications

References 50 publications

Splice Variants of the Dual Specificity Tyrosine Phosphorylation-regulated Kinase 4 (DYRK4) Differ in Their Subcellular Localization and Catalytic Activity

Splice Variants of the Dual Specificity Tyrosine Phosphorylation-regulated Kinase 4 (DYRK4) Differ in Their Subcellular Localization and Catalytic Activity

DYRK3 Dual-specificity Kinase Attenuates Erythropoiesis during Anemia

Multiple functions of DYRK2 in cancer and tissue development

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