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Updates of Calcineurin/NFAT Signaling in Human Health and Diseases
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Updates of Calcineurin/NFAT Signaling in Human Health and Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (26 May 2022) | Viewed by 12853

Special Issue Editor

Dr. Osamu Kaminuma

E-Mail Website
Guest Editor
Hiroshima University, Hiroshima, Japan
Interests: allery; developmental biology; genome editing; immune regulation; intracellular signaling; kinase and phosphatase; transcription factor; T cell

Special Issue Information

Dear Colleagues,

The intracelluar signaling cascade regulated by a phosphatase, calcineurin, and its substrate transcription factor, nuclear factor of activated T cells (NFAT), has been demonstrated to play a crucial role not only in the development, differentiation, and function of immune, cardiovascular, nervous, bone, urinary, and genital organs but also in inducing various diseases, including cancer, in those organs. The versatile function of this cascade is achieved by forming a molecular family consisting of multipe genes and splicing variants with extensive diversity in expressing organs, target genes and proteins, and effects. Since the discovery of calcineurin inhibitors, cyclosporin and tacrolimus, as immunosuppressants for preventing graft-versus-host disease and graft rejection in the 1980s, their application has been expanded for treating various immune-related diseases. Their usages are frequently accompanied by broad and/or serious side effects, though new medicines superior to cyclosporin or tacrolimus have not been generated for almost 40 years. To break through this situation, this Special Issue will focus on, but not be limited to, recent advances across physiological and pathophysiological functions, underlying molecular mechanisms, and attempts to generate new regulators of calcineurin/NFAT signaling. Based on the prospective contribution of authors at the forefront of calcineurin/NFAT study, I would be happy if this issue could help to create new means of overcoming veteran immunosuppressants.

Dr. Osamu Kaminuma
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • allergy
  • bone metabolism
  • calcineurin
  • cancer
  • cell cycle
  • immunosuppressant
  • osmolarity
  • reproduction
  • NFAT

Published Papers (3 papers)

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Review

17 pages, 763 KiB  
Review
Decoding the Phosphatase Code: Regulation of Cell Proliferation by Calcineurin
by Takahiro Masaki and Midori Shimada
Int. J. Mol. Sci. 2022, 23(3), 1122; https://doi.org/10.3390/ijms23031122 - 20 Jan 2022
Cited by 15 | Viewed by 3764
Abstract
Calcineurin, a calcium-dependent serine/threonine phosphatase, integrates the alterations in intracellular calcium levels into downstream signaling pathways by regulating the phosphorylation states of several targets. Intracellular Ca2+ is essential for normal cellular physiology and cell cycle progression at certain critical stages of the [...] Read more.
Calcineurin, a calcium-dependent serine/threonine phosphatase, integrates the alterations in intracellular calcium levels into downstream signaling pathways by regulating the phosphorylation states of several targets. Intracellular Ca2+ is essential for normal cellular physiology and cell cycle progression at certain critical stages of the cell cycle. Recently, it was reported that calcineurin is activated in a variety of cancers. Given that abnormalities in calcineurin signaling can lead to malignant growth and cancer, the calcineurin signaling pathway could be a potential target for cancer treatment. For example, NFAT, a typical substrate of calcineurin, activates the genes that promote cell proliferation. Furthermore, cyclin D1 and estrogen receptors are dephosphorylated and stabilized by calcineurin, leading to cell proliferation. In this review, we focus on the cell proliferative functions and regulatory mechanisms of calcineurin and summarize the various substrates of calcineurin. We also describe recent advances regarding dysregulation of the calcineurin activity in cancer cells. We hope that this review will provide new insights into the potential role of calcineurin in cancer development. Full article
(This article belongs to the Special Issue Updates of Calcineurin/NFAT Signaling in Human Health and Diseases)
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14 pages, 1419 KiB  
Review
Isoform-Selective NFAT Inhibitor: Potential Usefulness and Development
by Noriko Kitamura and Osamu Kaminuma
Int. J. Mol. Sci. 2021, 22(5), 2725; https://doi.org/10.3390/ijms22052725 - 8 Mar 2021
Cited by 16 | Viewed by 3562
Abstract
Nuclear factor of activated T cells (NFAT), which is the pharmacological target of immunosuppressants cyclosporine and tacrolimus, has been shown to play an important role not only in T cells (immune system), from which their name is derived, but also in many biological [...] Read more.
Nuclear factor of activated T cells (NFAT), which is the pharmacological target of immunosuppressants cyclosporine and tacrolimus, has been shown to play an important role not only in T cells (immune system), from which their name is derived, but also in many biological events. Therefore, functional and/or structural abnormalities of NFAT are linked to the pathogenesis of diseases in various organs. The NFAT protein family consists of five isoforms, and each isoform performs diverse functions and has unique expression patterns in the target tissues. This diversity has made it difficult to obtain ideal pharmacological output for immunosuppressants that inhibit the activity of almost all NFAT family members, causing serious and wide-ranging side effects. Moreover, it remains unclear whether isoform-selective NFAT regulation can be achieved by targeting the structural differences among NFAT isoforms and whether this strategy can lead to the development of better drugs than the existing ones. This review summarizes the role of the NFAT family members in biological events, including the development of various diseases, as well as the usefulness of and problems associated with NFAT-targeting therapies, including those dependent on current immunosuppressants. Finally, we propose a novel therapeutic strategy based on the molecular mechanisms that enable selective regulation of specific NFAT isoforms. Full article
(This article belongs to the Special Issue Updates of Calcineurin/NFAT Signaling in Human Health and Diseases)
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19 pages, 471 KiB  
Review
Finely-Tuned Calcium Oscillations in Osteoclast Differentiation and Bone Resorption
by Hiroyuki Okada, Koji Okabe and Sakae Tanaka
Int. J. Mol. Sci. 2021, 22(1), 180; https://doi.org/10.3390/ijms22010180 - 26 Dec 2020
Cited by 24 | Viewed by 4903
Abstract
Calcium (Ca2+) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption via calcineurin. Many modifiers are involved [...] Read more.
Calcium (Ca2+) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption via calcineurin. Many modifiers are involved in the fine-tuning of Ca oscillations in osteoclasts. In addition to macrophage colony-stimulating factors (M-CSF; CSF-1) and RANKL, costimulatory signaling by immunoreceptor tyrosine-based activation motif-harboring adaptors is important for Ca oscillation generation and osteoclast differentiation. DNAX-activating protein of 12 kD is always necessary for osteoclastogenesis. In contrast, Fc receptor gamma (FcRγ) works as a key controller of osteoclastogenesis especially in inflammatory situation. FcRγ has a cofactor in fine-tuning of Ca oscillations. Some calcium channels and transporters are also necessary for Ca oscillations. Transient receptor potential (TRP) channels are well-known environmental sensors, and TRP vanilloid channels play an important role in osteoclastogenesis. Lysosomes, mitochondria, and endoplasmic reticulum (ER) are typical organelles for intracellular Ca2+ storage. Ryanodine receptor, inositol trisphosphate receptor, and sarco/endoplasmic reticulum Ca2+ ATPase on the ER modulate Ca oscillations. Research on Ca oscillations in osteoclasts has still many problems. Surprisingly, there is no objective definition of Ca oscillations. Causality between Ca oscillations and osteoclast differentiation and/or function remains to be examined. Full article
(This article belongs to the Special Issue Updates of Calcineurin/NFAT Signaling in Human Health and Diseases)
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