Functions and regulation of the serine/threonine protein kinase CK1 family: moving beyond promiscuity

Fulcher, Luke J.; Sapkota, Gopal P.

doi:10.1042/bcj20200506

Cited by 42 publications

(46 citation statements)

References 149 publications

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“…CK1α is one of the seven isoforms (α, β, γ1, γ2, γ3, δ, and ε) of the CK1 serine/threonine kinases family, whose members share homology in the N-terminal kinase domain and similar substrate preferences [ 18 ].…”

Section: General Features Of Ck1α and Ck2: Structure Regulation mentioning

confidence: 99%

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Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2

Spinello

Fregnani

Tubi

et al. 2021

IJMS

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Disturbance of protein kinase activity may result in dramatic consequences that often lead to cancer development and progression. In tumors of blood origin, both tyrosine kinases and serine/threonine kinases are altered by different types of mutations, critically regulating cancer hallmarks. CK1α and CK2 are highly conserved, ubiquitously expressed and constitutively active pleiotropic kinases, which participate in multiple biological processes. The involvement of these kinases in solid and blood cancers is well documented. CK1α and CK2 are overactive in multiple myeloma, leukemias and lymphomas. Intriguingly, they are not required to the same degree for the viability of normal cells, corroborating the idea of “druggable” kinases. Different to other kinases, mutations on the gene encoding CK1α and CK2 are rare or not reported. Actually, these two kinases are outside the paradigm of oncogene addiction, since cancer cells’ dependency on these proteins resembles the phenomenon of “non-oncogene” addiction. In this review, we will summarize the general features of CK1α and CK2 and the most relevant oncogenic and stress-related signaling nodes, regulated by kinase phosphorylation, that may lead to tumor progression. Finally, we will report the current data, which support the positioning of these two kinases in the therapeutic scene of hematological cancers.

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Section: General Features Of Ck1α and Ck2: Structure Regulation mentioning

confidence: 99%

“…Regarding CK1α, the development of selective inhibitors of CK1α is challenging, due to the high degree of homology among CK1 family isoforms [ 18 ]. So far, the pharmacological inactivation with the dual CK1α/CK1δ inhibitor D4476, exerted in cells from MM and other malignancies, produces a cytotoxic effect.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2

Spinello

Fregnani

Tubi

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…It is known that the Hippo and Wnt pathways equally regulate the nuclear transcriptional activity and are closely connected to each other on multiple levels [ 74 , 75 , 76 ]. It has been reported that CK1ɛ isoform phosphorylates YAP/TAZ after priming phosphorylation from LATS1/2 and following CK1ɛ binding to MST1/2.…”

Section: Discussionmentioning

confidence: 99%

“…Under these conditions phosphorylation of DVL is reduced, leading to inhibition of Wnt Signaling. Also, YAP/TAZ complex bind to the cytoplasmic DVL1, preventing phosphorylation and abrogating the complex translocation to the nucleus [ 74 , 75 ]. The A178V DVL1 substitution here described may promote Wnt activation and the expression of target genes by interfering with YAP/TAZ binding sites or preventing the CK1-dependend phosphorylation of DVL1.…”

Section: Discussionmentioning

confidence: 99%

Evidence of Cooperation between Hippo Pathway and RAS Mutation in Thyroid Carcinomas

Carneiro

Bim

Buzatto

et al. 2021

Cancers

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Thyroid cancer incidences have been steadily increasing worldwide and are projected to become the fourth leading cancer diagnosis by 2030. Improved diagnosis and prognosis predictions for this type of cancer depend on understanding its genetic bases and disease biology. RAS mutations have been found in a wide range of thyroid tumors, from benign to aggressive thyroid carcinomas. Based on that and in vivo studies, it has been suggested that RAS cooperates with other driver mutations to induce tumorigenesis. This study aims to identify genetic alterations or pathways that cooperate with the RAS mutation in the pathogenesis of thyroid cancer. From a cohort of 120 thyroid carcinomas, 11 RAS-mutated samples were identified. The samples were subjected to RNA-Sequencing analyses. The mutation analysis in our eleven RAS-positive cases uncovered that four genes that belong to the Hippo pathway were mutated. The gene expression analysis revealed that this pathway was dysregulated in the RAS-positive samples. We additionally explored the mutational status and expression profiling of 60 RAS-positive papillary thyroid carcinomas (PTC) from The Cancer Genome Atlas (TCGA) cohort. Altogether, the mutational landscape and pathway enrichment analysis (gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genome (KEGG)) detected the Hippo pathway as dysregulated in RAS-positive thyroid carcinomas. Finally, we suggest a crosstalk between the Hippo and other signaling pathways, such as Wnt and BMP.

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“…However, the participation of RNA helicases in almost all aspects of RNA metabolism increases the safety risks of inhibitors and requires thorough evaluation as multiple vital processes can be interfered with [30]. For example, DDX3 can act as an allosteric activator of casein kinase 1 (CK1) in the Wnt/β-catenin pathway [31], TBK1/IKKε and IFN induction [32], NF-κB signal pathway [33], DNA-damage induced apoptosis [34], etc.…”

Section: Introductionmentioning

confidence: 99%

Level of Murine DDX3 RNA Helicase Determines Phenotype Changes of Hepatocytes In Vitro and In Vivo

Sergeeva

Abakumova

Kurochkin

et al. 2021

IJMS

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DDX3 RNA helicase is intensively studied as a therapeutic target due to participation in the replication of some viruses and involvement in cancer progression. Here we used transcriptome analysis to estimate the primary response of hepatocytes to different levels of RNAi-mediated knockdown of DDX3 RNA helicase both in vitro and in vivo. We found that a strong reduction of DDX3 protein (>85%) led to similar changes in vitro and in vivo—deregulation of the cell cycle and Wnt and cadherin pathways. Also, we observed the appearance of dead hepatocytes in the healthy liver and a decrease of cell viability in vitro after prolonged treatment. However, more modest downregulation of the DDX3 protein (60–65%) showed discordant results in vitro and in vivo—similar changes in vitro as in the case of strong knockdown and a different phenotype in vivo. These results demonstrate that the level of DDX3 protein can dramatically influence the cell phenotype in vivo and the decrease of DDX3, for more than 85% leads to cell death in normal tissues, which should be taken into account during the drug development of DDX3 inhibitors.

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Functions and regulation of the serine/threonine protein kinase CK1 family: moving beyond promiscuity

Cited by 42 publications

References 149 publications

Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2

Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2

Evidence of Cooperation between Hippo Pathway and RAS Mutation in Thyroid Carcinomas

Level of Murine DDX3 RNA Helicase Determines Phenotype Changes of Hepatocytes In Vitro and In Vivo

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