DYRK1A: a down syndrome-related dual protein kinase with a versatile role in tumorigenesis

Laham, Amina Jamal; Saber-Ayad, Maha; El‐Awady, Raafat

doi:10.1007/s00018-020-03626-4

Cited by 53 publications

(57 citation statements)

References 148 publications

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“…Thus, unbiased identification of DYRK2 as a protein/kinase involved in potential protumorigenic role along with its substrates such as p53, c-Myc, and c-Jun further fuels the need to stratify cancers into subtypes before embarking on DYRK2 molecular studies. This duality of protumorigenic and antitumorigenic roles has been reported for the paralogue DYRK1A as well ( 111 , 112 ) ( Fig. 3 and Table 1 ), and hence, there is a clear precedence for such controversial roles in the DYRK family.…”

Section: Dyrk2 In Lung Cancer: Unresolved Issuessupporting

confidence: 70%

“…Furthermore, ectopic overexpression of DYRK2 often results in false-positive substrate phosphorylation/binding and such experiments should always be accompanied with controls to ascertain the physiological/bona fide roles of the kinase. Like its paralogue DYRK1A ( 111 , 112 ) and many other kinases, DYRK2 may indeed play both protumorigenic and antitumorigenic roles in different cancer types and subtypes, which is often determined by spatiotemporal interactions between kinases and specific substrates. Novel cancer therapeutic targets are a need of the hour, and hence, controversies delaying the establishment of a potential target or a tumor suppressor need to be objectively and quickly addressed.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Emerging roles of DYRK2 in cancer

Tandon

Vega

Banerjee

2021

Journal of Biological Chemistry

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Over the last decade, the CMGC kinase DYRK2 has been reported as a tumor suppressor across various cancers triggering major antitumor and proapoptotic signals in breast, colon, liver, ovary, brain, and lung cancers, with lower DYRK2 expression correlated with poorer prognosis in patients. Contrary to this, various medicinal chemistry studies reported robust antiproliferative properties of DYRK2 inhibitors, whereas unbiased ‘omics’ and genome-wide association study-based studies identified DYRK2 as a highly overexpressed kinase in various patient tumor samples. A major paradigm shift occurred in the last 4 years when DYRK2 was found to regulate proteostasis in cancer via a two-pronged mechanism. DYRK2 phosphorylated and activated the 26S proteasome to enhance degradation of misfolded/tumor-suppressor proteins while also promoting the nuclear stability and transcriptional activity of its substrate, heat-shock factor 1 triggering protein folding. Together, DYRK2 regulates proteostasis and promotes protumorigenic survival for specific cancers. Indeed, potent and selective small-molecule inhibitors of DYRK2 exhibit in vitro and in vivo anti-tumor activity in triple-negative breast cancer and myeloma models. However, with conflicting and contradictory reports across different cancers, the overarching role of DYRK2 remains enigmatic. Specific cancer (sub)types coupled to spatiotemporal interactions with substrates could decide the procancer or anticancer role of DYRK2. The current review aims to provide a balanced and critical appreciation of the literature to date, highlighting top substrates such as p53, c-Myc, c-Jun, heat-shock factor 1, proteasome, or NOTCH1, to discuss DYRK2 inhibitors available to the scientific community and to shed light on this duality of protumorigenic and antitumorigenic roles of DYRK2.

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Section: Dyrk2 In Lung Cancer: Unresolved Issuessupporting

confidence: 70%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Emerging roles of DYRK2 in cancer

Tandon

Vega

Banerjee

2021

Journal of Biological Chemistry

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“…And DYRK1A has the characteristic of duality in tumorigenesis. Some studies indicate its possible role as a tumor suppressor gene; however, others prove its pro-oncogenic activity (32). S100A2, which involves a number of cellular processes such as cell cycle progression and differentiation, was dysregulated in lung, gastric, esophageal, ovarian, bladder, breast, thyroid, melanoma and pancreatic cancer (33).…”

Section: Resultsmentioning

confidence: 99%

Network-based protein-protein interaction prediction method maps perturbations of cancer interactome

Qiu

Chen

Zhong

et al. 2020

Preprint

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AbstractThe landscape of the gene relationship/network (such as activation, expression, phosphorylation, and binding) in cancer is found different from the general (non-disease) situation, and gene network perturbations are supposed to be the main cause of cancer. Thus, it makes no sense to use a regular gene relationship prediction method to map the cancer gene network. Here, we established a novel prediction method that we dubbed network-based cancer gene relationship (NECARE), which achieved a high performance with a Matthews correlation coefficient (MCC) = 0.71±0.01 and an F1 = 89±0.7%. Then, we investigated the cancer interactome atlas and revealed a large-scale perturbation in the gene network in cancer using NECARE. We found 2287 genes, which were named cancer hub genes, that were enriched with gene interaction perturbations, and over 56% of cancer treatment-related genes were hub genes. We further assessed the association of hub genes with the prognosis of 32 types of cancers and found that hub genes were significantly related to the cancer outcomes. Furthermore, the mutations occurring on residues that bind to macromolecules were overrepresented at cancer hub genes. By coimmunoprecipitation (co-IP), we confirmed that the NECARE prediction method was highly reliable and was 90% accurate. NECARE is available at: https://github.com/JiajunQiu/NECARE.

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“…Because of their multiple activities, aberrant expression and/or activity of all these kinases have been frequently associated to cancer development. For studies regarding the role of these kinases in cancer, we refer the interested readers to dedicated reviews and references therein (Czubaty and Piekielko-Witkowska, 2017;Nikas et al, 2019;Laham et al, 2020).…”

Section: Cellular Functions and Regulatory Mechanisms Of Cmgc Kinasesmentioning

confidence: 99%

“…In contrast to the other two main families of SR protein kinases, SRPKs and CLKs, DYRKs enzymes are mostly known for their activities in a wide variety of processes such as cell growth, differentiation and transcription but only a few studies have indicated that some of these enzymes, in particular DYRK1A, can regulate the activity of SR proteins (Aranda et al, 2011;Laham et al, 2020). DYRK1A and DYRK1B belong to the class I group of DYRKs kinases that are functionally different from those of class II group, which includes DYRK2, 3 and 4.…”

Section: Dyrk1a/bmentioning

confidence: 99%

Interplay Between CMGC Kinases Targeting SR Proteins and Viral Replication: Splicing and Beyond

Pastor

Shkreta²,

Chabot³

et al. 2021

Front. Microbiol.

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Protein phosphorylation constitutes a major post-translational modification that critically regulates the half-life, intra-cellular distribution, and activity of proteins. Among the large number of kinases that compose the human kinome tree, those targeting RNA-binding proteins, in particular serine/arginine-rich (SR) proteins, play a major role in the regulation of gene expression by controlling constitutive and alternative splicing. In humans, these kinases belong to the CMGC [Cyclin-dependent kinases (CDKs), Mitogen-activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and Cdc2-like kinases (CLKs)] group and several studies indicate that they also control viral replication via direct or indirect mechanisms. The aim of this review is to describe known and emerging activities of CMGC kinases that share the common property to phosphorylate SR proteins, as well as their interplay with different families of viruses, in order to advance toward a comprehensive knowledge of their pro- or anti-viral phenotype and better assess possible translational opportunities.

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DYRK1A: a down syndrome-related dual protein kinase with a versatile role in tumorigenesis

Cited by 53 publications

References 148 publications

Emerging roles of DYRK2 in cancer

Emerging roles of DYRK2 in cancer

Network-based protein-protein interaction prediction method maps perturbations of cancer interactome

Interplay Between CMGC Kinases Targeting SR Proteins and Viral Replication: Splicing and Beyond

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