Ctr1 Is an Apical Copper Transporter in Mammalian Intestinal Epithelial Cells in Vivo That Is Controlled at the Level of Protein Stability

Nose, Yohei; Wood, L. Kent; Kim, Byung-Eun; Prohaska, Joseph R.; Fry, R. S.; Spears, J. W.; Thiele, Dennis J.

doi:10.1074/jbc.m110.143826

Cited by 135 publications

(113 citation statements)

References 38 publications

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“…5A,B), suggesting that these Cu þ transporters undergo post-translational modification. In mammals, the Ctr1 Cu þ transporter is glycosylated at two positions within the N terminus [20][21][22][23] . We used a protein deglycosylation enzyme mix that removes both N-and O-glycosylation to determine whether C. neoformans Cu transporters are glycosylated.…”

Section: Resultsmentioning

confidence: 99%

Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

et al. 2014

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Section: Resultsmentioning

confidence: 99%

Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

et al. 2014

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“…Copper transport by DMT1 therefore could be further tested in additional mammalian expression systems or in rodent models in which DMT1 is lacking or overexpressed. Meanwhile, there is strong evidence that absorption and cellular uptake of copper is served by alternative transport systems, among which are the copper transporter 1 (70,71) and an anion transporter that appears capable of transporting copper-chloride complexes (72).…”

Section: Discussionmentioning

confidence: 99%

Substrate Profile and Metal-ion Selectivity of Human Divalent Metal-ion Transporter-1

Illing

Shawki

Cunningham

et al. 2012

Journal of Biological Chemistry

227

195

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Background: DMT1 plays essential roles in iron homeostasis, but questions remain about which other metals this transporter serves. Results: DMT1 exhibits substrate selectivity Cd 2ϩ Ͼ Fe 2ϩ Ͼ Co 2ϩ , Mn 2ϩ Ͼ Ͼ Ni 2ϩ , VO 2ϩ , Zn 2ϩ . Conclusion: DMT1 is an iron-preferring transporter that does not transport copper. Significance: These findings will help in predicting the contribution of DMT1 to absorption and cellular uptake of metal ions.

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“…The absorption of 64 Cu from an intragastric dose did not differ between DMT1 int/int and DMT1 ϩ/ϩ mice, confirming that copper does not rely on DMT1 for its absorption. We previously found that Ctr1, a high-affinity copper transporter (32), is localized to both the apical membrane and endosomal compartments of mammalian enterocytes (44). Intestinal ablation of Ctr1 in the mouse produced a severe copper deficiency and early lethality (43), establishing Ctr1 as the primary mechanism serving copper uptake at the intestinal brush border, and these studies together indicate no role for DMT1 in this process.…”

Section: G644 Role Of Intestinal Dmt1 In Metal Homeostasismentioning

confidence: 99%

Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

Shawki

Anthony

Nose

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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120

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Divalent metal-ion transporter-1 (DMT1) is a widely expressed iron-preferring membrane-transport protein that serves a critical role in erythroid iron utilization. We have investigated its role in intestinal metal absorption by studying a mouse model lacking intestinal DMT1 (i.e., DMT1 int/int ). DMT1 int/int mice exhibited a profound hypochromicmicrocytic anemia, splenomegaly, and cardiomegaly. That the anemia was due to iron deficiency was demonstrated by the following observations in DMT1 int/int mice: 1) blood iron and tissue nonheme-iron stores were depleted; 2) mRNA expression of liver hepcidin (Hamp1) was depressed; and 3) intraperitoneal iron injection corrected the anemia, and reversed the changes in blood iron, nonheme-iron stores, and hepcidin expression levels. We observed decreased total iron content in multiple tissues from DMT1 int/int mice compared with DMT1 ϩ/ϩ mice but no meaningful change in copper, manganese, or zinc. DMT1 int/int mice absorbed 64 Cu and 54 Mn from an intragastric dose to the same extent as did DMT1 ϩ/ϩ mice but the absorption of 59 Fe was virtually abolished in DMT1 int/int mice. This study reveals a critical function for DMT1 in intestinal nonheme-iron absorption for normal growth and development. Further, this work demonstrates that intestinal DMT1 is not required for the intestinal transport of copper, manganese, or zinc. copper absorption; iron deficiency; iron-deficiency anemia; iron-refractive iron-deficiency anemia; manganese absorption; SLC11A2; zinc metabolism IRON DEFICIENCY is the most prevalent micronutrient deficiency worldwide (4, 50). Its deficiency leads to irondeficiency anemia, and to neurological and developmental disorders in children (3, 4). Since there exists no regulated mechanism for the excretion of iron, regulation of the whole body iron economy is achieved by tightly controlling absorption of the metal (21). Failure to regulate iron absorption in a manner appropriate to iron status is characteristic of several hereditary iron-overload disorders and iron-refractive iron-deficiency anemia (12,19,21).Divalent metal-ion transporter-1 (DMT1; reviewed in Ref. 52) is a widely expressed mammalian proton-coupled iron transporter (23,38). Mice in which the SLC11A2 gene coding for DMT1 was globally inactivated (i.e., SLC11A2 Ϫ/Ϫ ) exhibited a severe hypochromic-microcytic anemia and did not survive more than 7 days (22). A critical role for DMT1 in erythroid iron acquisition was confirmed by the following observations: 1) transfusion of red blood cells, but not parenteral iron injections, improved survival of SLC11A2 Ϫ/Ϫ mice; and 2) lethal dose-irradiated wild-type mice into which the investigators transplanted hematopoietic stem cells from SLC11A2 Ϫ/Ϫ mice exhibited defective erythropoiesis (22). The microcytic (mk) mouse and Belgrade (b) rat models, inbred strains that harbor a Gly185¡Arg mutation in DMT1 (17, 18), also exhibited an anemia phenotype. Parenteral iron injections partially improved the condition, and tissue or vesicle preparations from the m...

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Ctr1 Is an Apical Copper Transporter in Mammalian Intestinal Epithelial Cells in Vivo That Is Controlled at the Level of Protein Stability

Cited by 135 publications

References 38 publications

Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

Substrate Profile and Metal-ion Selectivity of Human Divalent Metal-ion Transporter-1

Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

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