Casein kinase 1α: biological mechanisms and theranostic potential

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Abstract

Casein kinase 1α (CK1α) is a multifunctional protein belonging to the CK1 protein family that is conserved in eukaryotes from yeast to humans. It regulates signaling pathways related to membrane trafficking, cell cycle progression, chromosome segregation, apoptosis, autophagy, cell metabolism, and differentiation in development, circadian rhythm, and the immune response as well as neurodegeneration and cancer. Given its involvement in diverse cellular, physiological, and pathological processes, CK1α is a promising therapeutic target. In this review, we summarize what is known of the biological functions of CK1α, and provide an overview of existing challenges and potential opportunities for advancing theranostics.

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Cell cycle proteins as promising targets in cancer therapy

Tobias Otto, Piotr Sicinski (2017)

Cancer is characterized by uncontrolled tumour cell proliferation resulting from aberrant activity of various cell cycle proteins. Therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrate that some of these proteins are not essential for proliferation of non-transformed cells

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DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival.

Timothy Peterson, Mathieu Laplante, Carson C. Thoreen … (2009)

The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of multiple myelomas harboring cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel mTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for activating PI3K/Akt signaling and promoting cell survival.

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Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex.

Yun Zhong, Qing Wang, Xianting Li … (2009)

Beclin 1, a mammalian autophagy protein that has been implicated in development, tumour suppression, neurodegeneration and cell death, exists in a complex with Vps34, the class III phosphatidylinositol-3-kinase (PI(3)K) that mediates multiple vesicle-trafficking processes including endocytosis and autophagy. However, the precise role of the Beclin 1-Vps34 complex in autophagy regulation remains to be elucidated. Combining mouse genetics and biochemistry, we have identified a large in vivo Beclin 1 complex containing the known proteins Vps34, p150/Vps15 and UVRAG, as well as two newly identified proteins, Atg14L (yeast Atg14-like) and Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein). Characterization of the new proteins revealed that Atg14L enhances Vps34 lipid kinase activity and upregulates autophagy, whereas Rubicon reduces Vps34 activity and downregulates autophagy. We show that Beclin 1 and Atg14L synergistically promote the formation of double-membraned organelles that are associated with Atg5 and Atg12, whereas forced expression of Rubicon results in aberrant late endosomal/lysosomal structures and impaired autophagosome maturation. We hypothesize that by forming distinct protein complexes, Beclin 1 and its binding proteins orchestrate the precise function of the class III PI(3)K in regulating autophagy at multiple steps.

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Author and article information

Contributors

Xiaoming Yang:

ORCID: http://orcid.org/0000-0003-2482-8673

206-685-6967 , xmyang@zju.edu.cn , xmyang@uw.edu

Journal

Journal ID (nlm-ta): Cell Commun Signal

Journal ID (iso-abbrev): Cell Commun. Signal

Title: Cell Communication and Signaling : CCS

Publisher: BioMed Central (London )

ISSN (Electronic): 1478-811X

Publication date (Electronic): 24 May 2018

Publication date PMC-release: 24 May 2018

Publication date Collection: 2018

Volume: 16

Electronic Location Identifier: 23

Affiliations

[1 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Radiology, Sir Run Run Shaw Hospital, School of Medicine, , Zhejiang University, ; Zhejiang, 310016 Hangzhou China

[2 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Orthopaedics, Second Affiliated Hospital, School of Medicine, , Zhejiang University, ; Zhejiang, 310009 Hangzhou China

[3 ]ISNI 0000000122986657, GRID grid.34477.33, Image-Guided Bio-Molecular Intervention Research, Department of Radiology, , University of Washington School of Medicine, ; Seattle, WA 98109 USA

Author information

Xiaoming Yang http://orcid.org/0000-0003-2482-8673

Article

Publisher ID: 236

DOI: 10.1186/s12964-018-0236-z

PMC ID: 5968562

PubMed ID: 29793495

SO-VID: 146bd670-9eb5-494a-b337-90fd555e79b3

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 18 April 2018

Date accepted : 16 May 2018

Funding

Funded by: National Key Basic Research Program (973 Program)

Award ID: 2014CB744505

Award Recipient : Xiaoming Yang

Funded by: Key Program of National Natural Science Foundation of China

Award ID: 81430040

Award Recipient : Xiaoming Yang

Funded by: General Program of National Natural Science Foundation of China

Award ID: 81571738

Award Recipient : Jihong Sun

Funded by: National Key Research and Development Program of China

Award ID: 2016YFA0100900

Award Recipient : Jihong Sun

Funded by: Medical and Health Program of Zhejiang Province

Award ID: 2016146039

Award ID: 2017209189

Award Recipient : Miaofeng Zhang

Custom metadata

ScienceOpen disciplines: Cell biology

Keywords: casein kinase 1α,wnt/β-catenin signaling,nf-κb signaling,hedgehog signaling,autophagy,neurodegenerative disease,cell cycle,host defense response

Data availability:

ScienceOpen disciplines: Cell biology

Keywords: casein kinase 1α, wnt/β-catenin signaling, nf-κb signaling, hedgehog signaling, autophagy, neurodegenerative disease, cell cycle, host defense response

Casein kinase 1α: biological mechanisms and theranostic potential

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Most cited references 202

Cell cycle proteins as promising targets in cancer therapy

DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival.

Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex.

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