Essential Role of the Zinc Transporter ZIP9/SLC39A9 in Regulating the Activations of Akt and Erk in B-Cell Receptor Signaling Pathway in DT40 Cells

Taniguchi, Masanari; Fukunaka, Ayako; Hagihara, Mitsue; Watanabe, Keiko; Kamino, Shinichiro; Kambe, Taiho; Enomoto, Shuichi; Hiromura, Makoto

doi:10.1371/journal.pone.0058022

Cited by 95 publications

(63 citation statements)

References 51 publications

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“…A family of zinc transporters (ZIPs), classified as fourteen isoforms, was identified (Grotz et al, 1998). ZIP9 and ZIP13 are expressed in the Golgi apparatus (Taniguchi et al, 2013), ZIP7 is expressed in the endoplasmic reticulum (Taylor et al, 2004), and the others are expressed in the cellular membrane (Fukada and Kambe, 2011). Since they are responsible for upregulating the concentration of zinc ions in the cytoplasm, ZIPs may be involved in the induction of MT expression via MTF-1 activation.…”

Section: Discussionmentioning

confidence: 99%

Induction of metallothionein isoforms by copper diethyldithiocarbamate in cultured vascular endothelial cells

et al. 2016

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-Metallothionein (MT) plays a central role in cellular defense against heavy metals and oxidative stress. Since the induction of MT requires the activation of metal response element (MRE)-binding transcription factor-1 (MTF-1) by binding of zinc ions, inorganic zinc is regarded as a typical MT inducer. However, in a previous report, we showed that inorganic zinc could not induce MT in vascular endothelial cells. While it is suggested that endothelial MT presents mechanisms different from those of other cell types, these remain unclear. In this study, we investigated whether the induction of endothelial MT expression involves the Nrf2-ARE pathway using copper(II) bis(diethyldithiocarbamate), termed Cu10, using a culture system of bovine aortic endothelial cells. Cu10 induced MT-1/2 protein expression and increased the expression of mRNAs for MT-1A, MT-1E, and MT-2, MT isoforms expressed in the cells. Cu10 activated not only the MTF-1-MRE, but also the Nrf2-ARE pathway. MTF-1 knockdown resulted in the repression of Cu10-induced MT-1 and -2 expression. Cu10-induced MT-1 expression was down-regulated by Nrf2 knockdown. However, MT-2 expression was not affected by Nrf2 knockdown. These results suggest that the expression of endothelial MT is up-regulated by the Nrf2-ARE pathway as well as by the MTF-1-MRE pathway. Moreover, MT-1 regulation mechanisms differ from that of MT-2. Specifically, the present data support the hypothesis that MT-1 participates in the biological defense system, while MT-2 mainly regulates intracellular zinc metabolism.

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Section: Discussionmentioning

confidence: 99%

Induction of metallothionein isoforms by copper diethyldithiocarbamate in cultured vascular endothelial cells

et al. 2016

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“…ZIP9 is localized to the Golgi apparatus and the cell surface (274,409). The Golgilocated ZIP9 plays a crucial role in B-cell receptor (BCR) signaling through regulation of Akt and ERK activity by translocating zinc from the Golgi lumen (397). The cell surface ZIP9 can function as a membrane androgen receptor and contributes to testosterone-induced prostate and breast cancer apoptosis through both zinc transporter functions and androgen signaling (25, 409).…”

Section: Zip9 (Zipi Subfamily)mentioning

confidence: 99%

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Kambe

Tsuji

Hashimoto

et al. 2015

Physiological Reviews

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848

797

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Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/ sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.

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“…Consistent with this, we found that in the absence of ZnT4, Akt expression was much lower in the lactating mammary gland. Accumulation of intracellular Zn decreases Akt expression (53), and the inability to mobilize Zn pools from the Golgi apparatus may also reduce Akt signaling (47). Whether reduced Akt expression in C57BL/6J lm/lm mice was a direct effect of dysregulated Zn homeostasis in the Golgi apparatus, global defects in Golgi organization and signaling scaffolds (35), ZnT2-mediated Zn accumulation into vesicles withholding Zn from activating Akt phosphorylation, or further alterations in cellular Zn homeostasis, is not currently understood.…”

Section: Ck8mentioning

confidence: 99%

ZnT4 (SLC30A4)-null (“lethal milk”) mice have defects in mammary gland secretion and hallmarks of precocious involution during lactation

McCormick

Lee

Hennigar

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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McCormick NH, Lee S, Hennigar SR, Kelleher SL. ZnT4 (SLC30A4)-null ("lethal milk") mice have defects in mammary gland secretion and hallmarks of precocious involution during lactation. Am J Physiol Regul Integr Comp Physiol 310: R33-R40, 2016. First published November 4, 2015 doi:10.1152/ajpregu.00315.2014.-During lactation, highly specialized secretory mammary epithelial cells (MECs) produce and secrete huge quantities of nutrients and nonnutritive factors into breast milk. The zinc (Zn) transporter ZnT4 (SLC30A4) transports Zn into the trans-Golgi apparatus for lactose synthesis, and across the apical cell membrane for efflux from MECs into milk. This is consistent with observations in "lethal milk" (lm/lm) mice, which have a truncation mutation in SLC30A4, and present with not only low milk Zn concentration, but also smaller mammary glands, decreased milk volume, and lactation failure by lactation day 2. However, the molecular underpinnings of these defects are not understood. Here, we used lactating C57BL/6J lm/lm (ZnT4-null) mice to explore the consequences of a ZnT4-null phenotype on mammary gland function during early lactation. Lactating C57BL/6J lm/lm mice had significantly fewer, smaller, and collapsed alveoli comprising swollen, lipid-filled MECs during early lactation. These defects were associated with decreased Akt expression and STAT5 activation, indicative of defects in MEC secretion. In addition, increased expression of ZnT2, TNF-␣, and cleaved e-cadherin concomitant with increased activation of STAT3 implicated the loss of ZnT4 in precocious activation of involution. Collectively, our study indicates that the loss of ZnT4 has profound consequences on MEC secretion and may promote tissue remodeling in the mammary gland during early lactation.zinc; lactation; mammary gland; SLC30A4; ZnT4 ZNT4 (SLC30A4) IS A ZINC (Zn) transporter that is expressed in numerous tissues, including the liver (13), lung (13), small intestine (28), and mammary gland (13). ZnT4 is particularly important for mammary gland function, as ZnT4 expression increases dramatically during lactation (23). Previous studies in vitro established that ZnT4 transports Zn into the transGolgi apparatus of the mammary epithelial cell (MEC) and delivers Zn to critical Zn-dependent proteins, including galactosyltransferase (a resident Golgi protein that is vital for lactose production) and carbonic anhydrase VI (a secreted milk enzyme that is vital for infant alimentary tract pH balance) (15). The "lethal milk" mouse (C57BL/6J lm/lm ) carries a spontaneous truncation mutation in SLC30A4, resulting in non-sense-mediated decay of ZnT4 mRNA (29). During lactation, ZnT4-null mice have ϳ35% lower milk Zn concentration than their wild-type littermates (37). Although this implicates ZnT4 in Zn secretion into milk, studies in breastfeeding women have yet to identify defects in ZnT4 in women with low milk Zn levels or find an association with transient neonatal Zn deficiency in exclusively breastfed infants (4,14,20). Moreover, ZnT4-null mice have s...

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Essential Role of the Zinc Transporter ZIP9/SLC39A9 in Regulating the Activations of Akt and Erk in B-Cell Receptor Signaling Pathway in DT40 Cells

Cited by 95 publications

References 51 publications

Induction of metallothionein isoforms by copper diethyldithiocarbamate in cultured vascular endothelial cells

Induction of metallothionein isoforms by copper diethyldithiocarbamate in cultured vascular endothelial cells

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

ZnT4 (SLC30A4)-null (“lethal milk”) mice have defects in mammary gland secretion and hallmarks of precocious involution during lactation

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