Cnnm4 deficiency suppresses Ca2+ signaling and promotes cell proliferation in the colon epithelia

Hasegawa, Ayaka; Funato, Yosuke; Tran, Ha Nam; Mori, Masayuki; Mori, Yasuo; Sato, Toshiro; Miki, Hiroaki

doi:10.1038/s41388-019-0682-0

Cited by 16 publications

(18 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, it has been shown that Cnnm4 deficiency suppresses Ca 2+ signaling and promotes cell proliferation in the colon epithelia. These results establish the functional interplay between Mg 2+ and Ca 2+ in the colon epithelia, which is crucial for maintaining the dynamic homeostasis of the epithelial tissue [98].…”

Section: Mg 2+ -Regulated Signaling Pathways In Digestive Cancer Cellsmentioning

confidence: 57%

“…TRPM7 possess a functional kinase domain able to phosphorylate serine or threonine residues, while MAGT1 is implicated in protein glycosylation. Additionally, it has been suggested that CNNM4 expression could regulate TRP channel expression such as TRPV1 [98]. Therefore, it is possible that transcriptomic regulations and/or posttranslational modifications can occur between TRPM7, MAGT1 and CNNM4 in digestive cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, TRPM7 is involved in processes occurring at late stages of colon carcinogenesis like EMT, cell migration, invasion and chemoresistance. Recently, Yamazaki et al have demonstrated that CNNM4 deficiency accelerates epithelial colon cell proliferation in mice [98]. Moreover, primary organoids growth is also enhanced in CNNM4-deficient mice.…”

Section: Regulation Of Digestive Cancer Cell Fates By Magnesium Transportersmentioning

confidence: 99%

See 2 more Smart Citations

Mg2+ Transporters in Digestive Cancers

et al. 2021

View full text Add to dashboard Cite

Despite magnesium (Mg2+) representing the second most abundant cation in the cell, its role in cellular physiology and pathology is far from being elucidated. Mg2+ homeostasis is regulated by Mg2+ transporters including Mitochondrial RNA Splicing Protein 2 (MRS2), Transient Receptor Potential Cation Channel Subfamily M, Member 6/7 (TRPM6/7), Magnesium Transporter 1 (MAGT1), Solute Carrier Family 41 Member 1 (SCL41A1), and Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM) proteins. Recent data show that Mg2+ transporters may regulate several cancer cell hallmarks. In this review, we describe the expression of Mg2+ transporters in digestive cancers, the most common and deadliest malignancies worldwide. Moreover, Mg2+ transporters’ expression, correlation and impact on patient overall and disease-free survival is analyzed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Finally, we discuss the role of these Mg2+ transporters in the regulation of cancer cell fates and oncogenic signaling pathways.

show abstract

Section: Mg 2+ -Regulated Signaling Pathways In Digestive Cancer Cellsmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Regulation Of Digestive Cancer Cell Fates By Magnesium Transportersmentioning

confidence: 99%

See 1 more Smart Citation

Mg2+ Transporters in Digestive Cancers

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Studies of the mammalian CNNMs have demonstrated an essential role in Mg 2+ homeostasis. CNNM2 is essential in mice while loss of CNNM4 leads to male infertility and susceptibility to cancer (Funato et al, 2014; Yamazaki et al, 2019; Yamazaki et al, 2016). CNNM proteins act as tumor suppressors by depressing Mg 2+ -dependent energy metabolism and AMPK/mTOR signaling (Funato et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…PRL binding to CNNMs is regulated by PRL phosphorylation in response to Mg 2+ levels (Gulerez et al, 2016; Kozlov et al, 2020). PRLs are highly oncogenic and promote cancer metastasis through their suppression of CNNM proteins (Funato et al, 2014; Yamazaki et al, 2019). The structures of a CNNM protein in both an active and inactive conformation provides a framework for understanding human CNNMs and the development of therapeutic approaches for regulating their activity.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of a bacterial CNNM magnesium transporter

Chen

Kozlov

Armitano

et al. 2021

Preprint

View full text Add to dashboard Cite

CBS-pair domain divalent metal cation transport mediators (CNNMs) are a broadly conserved family of integral membrane proteins with close to 90,000 protein sequences known. CNNM proteins are associated with Mg2+ transport but it is not known if they mediate transport themselves or regulate other transporters. Here, we determined the crystal structure of an archaeal CNNM protein with Mg2+-ATP bound. The structure reveals a novel transmembrane fold for the DUF21 domain, the largest family of domains of unknown function. The protein has a negatively charged cavity that penetrates halfway through the membrane suggesting it functions as a cation transporter. The cytosolic portion of the protein is comprised of highly charged four-helix bundle and a CBS-pair domain. HDX-MS experiments, molecular dynamics, and additional crystal structures show that the cytosolic domains undergo large conformational changes upon nucleotide binding suggesting a mechanism of regulation shared between human and bacterial orthologs. The molecular characterization of CNNM proteins has profound implications for understanding their biological functions in human diseases, including cancer, and in animals, bacteria and plants.

show abstract

Stem/Proliferative and Differentiated Cells within Primary Murine Colonic Epithelium Display Distinct Intracellular Free Ca²⁺ Signal Codes

Mestril

Kim

Hinman

et al. 2021

Adv Healthcare Materials

View full text Add to dashboard Cite

The second messenger, intracellular free calcium (Ca 2+ ), acts to transduce mitogenic and differentiation signals incoming to the colonic epithelium. A self-renewing monolayer of primary murine colonic epithelial cells is formed over a soft, transparent hydrogel matrix for the scalable analysis of intracellular Ca 2+ transients. Cultures that are enriched for stem/proliferative cells exhibit repetitive, high frequency (≈25 peaks h −1 ), and short pulse width (≈25 s) Ca 2+ transients. Upon cell differentiation the transient frequency declines by 50% and pulse width widens by 200%. Metabolites and growth factors that are known to modulate stem cell proliferation and differentiation through Wnt and Notch signaling pathways, including CHIR-99021, N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenylglycine-1,1-dimethylethyl ester (DAPT), bone morphogenetic proteins (BMPs), and butyrate, also modulate Ca 2+ oscillation patterns in a consistent manner. Increasing the stiffness of the supportive matrix from 200 Pa to 3 GPa shifts Ca 2+ transient patterns toward those resembling differentiated cells. The ability to monitor Ca 2+ oscillations with the spatial and temporal resolution offered by this platform, combined with its amenability to high-content screens, provides a powerful tool for investigating real-time communication within a wide range of primary tissues in addition to the colonic epithelium.

show abstract

Cnnm4 deficiency suppresses Ca2+ signaling and promotes cell proliferation in the colon epithelia

Cited by 16 publications

References 30 publications

Mg2+ Transporters in Digestive Cancers

Mg2+ Transporters in Digestive Cancers

Crystal structure of a bacterial CNNM magnesium transporter

Stem/Proliferative and Differentiated Cells within Primary Murine Colonic Epithelium Display Distinct Intracellular Free Ca²⁺ Signal Codes

Contact Info

Product

Resources

About

Cnnm4 deficiency suppresses Ca2+ signaling and promotes cell proliferation in the colon epithelia

Cited by 16 publications

References 30 publications

Mg2+ Transporters in Digestive Cancers

Mg2+ Transporters in Digestive Cancers

Crystal structure of a bacterial CNNM magnesium transporter

Stem/Proliferative and Differentiated Cells within Primary Murine Colonic Epithelium Display Distinct Intracellular Free Ca2+ Signal Codes

Contact Info

Product

Resources

About

Stem/Proliferative and Differentiated Cells within Primary Murine Colonic Epithelium Display Distinct Intracellular Free Ca²⁺ Signal Codes