Multiple functions of DYRK2 in cancer and tissue development

Yoshida, Saishu; Yoshida, Kiyotsugu

doi:10.1002/1873-3468.13601

Cited by 34 publications

(30 citation statements)

References 104 publications

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“…In this work, the authors observed that DYRK2 inversely correlates with CD44 + /CD24 − subpopulation and KLF4 expression. Consequently, DYRK2 downregulation leads to a sphere-forming ability, thus indicating self-renewal capacity [78,79]. In the same sense and as we have previously mentioned, several studies have described DYRK2 ability to regulate c-Myc and SNAIL levels, both considered key stemness proteins [44].…”

Section: Dyrk2 and Diseasesupporting

confidence: 64%

Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

Correa-Sáez

Jiménez‐Izquierdo

Garrido‐Rodríguez

et al. 2020

Cell. Mol. Life Sci.

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Members of the dual-specificity tyrosine-regulated kinase (DYRKs) subfamily possess a distinctive capacity to phosphorylate tyrosine, serine, and threonine residues. Among the DYRK class II members, DYRK2 is considered a unique protein due to its role in disease. According to the post-transcriptional and post-translational modifications, DYRK2 expression greatly differs among human tissues. Regarding its mechanism of action, this kinase performs direct phosphorylation on its substrates or acts as a priming kinase, enabling subsequent substrate phosphorylation by GSK3β. Moreover, DYRK2 acts as a scaffold for the EDVP E3 ligase complex during the G2/M phase of cell cycle. DYRK2 functions such as cell survival, cell development, cell differentiation, proteasome regulation, and microtubules were studied in complete detail in this review. We have also gathered available information from different bioinformatic resources to show DYRK2 interactome, normal and tumoral tissue expression, and recurrent cancer mutations. Then, here we present an innovative approach to clarify DYRK2 functionality and importance. DYRK2 roles in diseases have been studied in detail, highlighting this kinase as a key protein in cancer development. First, DYRK2 regulation of c-Jun, c-Myc, Rpt3, TERT, and katanin p60 reveals the implication of this kinase in cell-cycle-mediated cancer development. Additionally, depletion of this kinase correlated with reduced apoptosis, with consequences on cancer patient response to chemotherapy. Other functions like cancer stem cell formation and epithelial-mesenchymal transition regulation are also controlled by DYRK2. Furthermore, the pharmacological modulation of this protein by different inhibitors (harmine, curcumine, LDN192960, and ID-8) has enabled to clarify DYRK2 functionality.

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Section: Dyrk2 and Diseasesupporting

confidence: 64%

Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

Correa-Sáez

Jiménez‐Izquierdo

Garrido‐Rodríguez

et al. 2020

Cell. Mol. Life Sci.

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“…DYRK2 is a class II DYRK that has been more intensely studied in terms of its involvement in the events associated with tumor progression. The biochemistry and biology of DYRK2 was covered in recent reviews [ 126 , 127 ], and thus, here, we will center on the activity of this kinase in the context of tumor biology.…”

Section: Dyrk2mentioning

confidence: 99%

The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities

Boni

Rubio-Pérez

López‐Bigas

et al. 2020

Cancers

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DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been associated with all the hallmarks of cancer, from genomic instability to increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant to tumor onset and progression. In accordance with an involvement of DYRK kinases in the regulation of tumorigenic processes, an increasing number of research studies have been published in recent years showing either alterations of DYRK gene expression in tumor samples and/or providing evidence of DYRK-dependent mechanisms that contribute to tumor initiation and/or progression. In the present article, we will review the current understanding of the role of DYRK family members in cancer initiation and progression, providing an overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently available.

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“…In human cancer cells, we have functionally identified DYRK2 as a regulator of p53-induced apoptosis in response to DNA damage ( Taira et al, 2007 ) and of G1/S transition ( Taira et al, 2012 ). During development in lower eukaryotes, MBK2, which is an ortholog of DYRK2 in Caenorhabditis elegans , regulates maternal-protein degradation during the oocyte-to-embryo transition via a ubiquitin-dependent mechanism ( Pellettieri et al, 2003 ; Pang et al, 2004 ; Lu and Mains, 2007 ; Yoshida and Yoshida, 2019 ). While these reports lead us to speculate that DYRK2 must also play important roles in mammalian development, no reports are available regarding the mechanistic role of DYRK2 in vivo.…”

Section: Introductionmentioning

confidence: 99%

The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis

Yoshida

Aoki

Fujiwara

et al. 2020

eLife

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Mammalian Hedgehog (Hh) signaling plays key roles in embryogenesis and uniquely requires primary cilia. Functional analyses of several ciliogenesis-related genes led to the discovery of the developmental diseases known as ciliopathies. Hence, identification of mammalian factors that regulate ciliogenesis can provide insight into the molecular mechanisms of embryogenesis and ciliopathy. Here, we demonstrate that DYRK2 acts as a novel mammalian ciliogenesis-related protein kinase. Loss of Dyrk2 in mice causes suppression of Hh signaling and results in skeletal abnormalities during in vivo embryogenesis. Deletion of Dyrk2 induces abnormal ciliary morphology and trafficking of Hh pathway components. Mechanistically, transcriptome analyses demonstrate down-regulation of Aurka and other disassembly genes following Dyrk2 deletion. Taken together, the present study demonstrates for the first time that DYRK2 controls ciliogenesis and is necessary for Hh signaling during mammalian development.

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Multiple functions of DYRK2 in cancer and tissue development

Cited by 34 publications

References 104 publications

Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities

The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis

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