QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Monty, J.-F. Articles by Kramer, D. R. Search for Related Content PubMed PubMed Citation Articles by Monty, J.-F. Articles by Kramer, D. R.

---

Biochemical and Molecular Actions of Nutrients

Copper Exposure Induces Trafficking of the Menkes Protein in Intestinal Epithelium of ATP7A Transgenic Mice¹

Center for Cellular and Molecular Biology, School of Biological and Chemical Sciences, Deakin University, Burwood, Victoria, Australia

²To whom correspondence should be addressed. E-mail: dkramer{at}deakin.edu.au.

ABSTRACT

The final steps in the absorption and excretion of copper at the molecular level are accomplished by 2 closely related proteins that catalyze the ATP-dependent transport of copper across the plasma membrane. These proteins, ATP7A and ATP7B, are encoded by the genes affected in human genetic copper-transport disorders, namely, Menkes and Wilson diseases. We studied the effect of copper perfusion of an isolated segment of the jejunum of ATP7A transgenic mice on the intracellular distribution of ATP7A by immunofluorescence of frozen sections. Our results indicate that ATP7A is retained in the trans-Golgi network under copper-limiting conditions, but relocalized to a vesicular compartment adjacent to the basolateral membrane in intestines perfused with copper. The findings support the hypothesis that the basolateral transport of copper from the enterocyte into the portal blood may involve ATP7A pumping copper into a vesicular compartment followed by exocytosis to release the copper, rather than direct pumping of copper across the basolateral membrane.

KEY WORDS: • dietary copper • copper absorption • transgenic mice • ATP7A • intestine

Copper ions are essential for maintaining cellular and physiological functions, but excess levels are potentially toxic. This utility and toxicity arise from copper’s ability to shuttle between 2 ionic states, allowing the metal to be employed as a cofactor in oxidation-reduction reactions and the unbound ion to catalyze free radical formation (1). Studies in mammalian and yeast cells revealed a conserved network of proteins involved in cellular copper homeostasis (2–4). These include the SLC31 (Ctr) family of copper importers (5), a trio of cytoplasmic protein chaperones (6), and the copper-transporting ATPases (3,7). Humans express 2 related copper-transporting ATPases, ATP7A and ATP7B, which are differentially expressed during development and in adult tissues (8).

The ATP7A and ATP7B copper transporters have 2 roles in cells, a biosynthetic role and protective role. The biosynthetic role requires the protein to be located at the trans-Golgi network (TGN)³ (3) where it pumps copper from the cytosol into the TGN lumen for incorporation into nascent proteins (3,9). ATP7A and ATP7B are regulated by copper within cultured cells. In response to raised copper levels, the locations of both ATP7A and ATP7B are shifted toward the cell periphery to facilitate the removal of copper from the cell (3,10). This redistribution of ATP7A is dependent on the ability of the protein to bind copper within conserved cytoplasmic metal binding sites (11) and is regulated by the phosphorylation state of the protein (12).

Physiologic copper levels are regulated by balancing the rates of biliary copper excretion and dietary copper absorption. Dietary copper absorption requires active transport across the basolateral membrane (1). In contrast, the biliary secretion of copper requires an active transport step across the apical membrane of hepatocytes (13). One hypothesis for the differential expression of ATP7A and ATP7B in intestinal epithelial cells and hepatocytes, respectively, is to permit the trafficking of the copper pump to the correct membrane. This relation is further supported by the expression of ATP7A and ATP7B in the kidney and mammary gland, respectively. Copper absorption across the epithelium of kidney tubules involves an apical-to-basolateral mechanism, whereas the mammary gland secretes copper via a basolateral-to-apical membrane mechanism (8).

Menkes syndrome is an X-linked disease that is generally fatal in early childhood due to the markedly reduced activity of copper-dependent enzymes and systemic copper deficiency (14–16). The absorption of dietary copper is incomplete in Menkes disease, i.e., the intestinal epithelial cells accumulate copper due to an inability to transport absorbed copper to the blood (17). Studies in human volunteers found that prolonged exposures to elevated dietary copper reduced the efficiency of uptake, suggesting that copper uptake is a regulated by copper exposure (18). Given the central role of ATP7A in copper uptake, it is considered to be a potential target for regulation of copper uptake in the intestine.

We employed a perfusion technique to study the effect of transient copper exposure on the cellular distribution of ATP7A in intestinal epithelial cells of ATP7A transgenic mice. We propose that the basolateral transport of copper involves a vesicular compartment that is analogous to the apical recycling endosomes described for the apical biliary secretion of copper by the action of ATP7B in hepatocytes (19).

MATERIALS AND METHODS

    Animals. ATP7A transgenic mice were generated by microinjection of C57BL/6 fertilized eggs (Mouseworks, Monash University, Melbourne, Australia) with a linearized plasmid pCMB346 carrying the ATP7A cDNA containing a myc antibody epitope (20) under the transcription control of a CAG promoter [cytomegalovirus enhancer, chicken ß-actin promoter, rabbit ß-globin poly(A)]. The presence of the transgene in pups was identified by PCR amplification of genomic DNA isolated from tails: sense oligonucleotide Y2H7 (5'-TCTCTCTTCCTTAAACTTTAC) corresponding to the 3' end sequence of ATP7A and the antisense oligonucleotide SP6 (ATTTAGGTGACACTATAG). The transgenic mice were maintained as heterozygotes under standard conditions at an ambient temperature of 21–23°C, with a 12-h light:dark cycle, and free access to a laboratory mouse food (Barastoc, Ridley AgriProducts) and water. These studies were approved by Deakin University Animal Welfare Committee (projects A1/1999 and A20/A2001).

    Intestinal perfusion. Mice were food deprived for 12 h and then anesthetized with an i.p. injection of ketamine (50 mg/kg) and xylazine (10 mg/kg) diluted in normal saline. A 5-cm segment of the proximal jejunum was tied off using cotton suture thread and a transverse cut was made at the distal end. The segment containing a patent blood supply was placed on sterile gauze and moistened with warm saline; the rest of the intestine was gently reinserted into the abdominal cavity. A 23-gauge butterfly cannula (Vacutainer) was inserted into the proximal end of the segment and tied in place. The cannula was connected to a perfusion pump (Minipuls 200, Gilson) set to a 0.1 mL/min flow rate. Each segment was perfused with 0.5 mL of warmed (to 37°C) HBSS (Sigma) to flush the contents of the segment. The HBSS solution was then replaced by warmed HBSS containing either, 5, 50, 100, or 200 µmol/L of CuCl_2, bathocuproine disulfonic acid (BCS), MnCl₂, or CoCl₂. For experiments using AgCl, the intestines were flushed with normal saline and then perfused with aqueous solutions of AgCl. Segments were then challenged for an additional 60 min with the above solutions. The functional integrity of the perfused jejunum segment was assessed by visual inspection of the mesenteric blood vessels, by the lack of blood in the perfusate, and by measuring the volume of the collected effluent.

    Isolation of epithelial cells. After perfusion, the segment was opened lengthwise and washed in 3 changes of warmed PBS. The segments were then placed into a warmed solution of 3 mmol/L EDTA and 0.3mmol/L dithiothreitol in PBS and shaken vigorously for 15–30 s. The supernatant was transferred to a sterile tube, and the intestine washed 3 times in PBS with shaking. The supernatants containing the released epithelial cells were pooled and centrifuged at 1000 x g for 5 min and the intestinal epithelial cell pellet resuspended in PBS.

    Immunofluorescence microscopy. Immunofluorescence was conducted on a fixed and permeabilized 5-µm frozen section following a 2-step staining protocol (21) using affinity purified sheep antisera raised to the N-terminus of ATP7A (anti-Menkes antibody) (3) diluted (1/1000) in 0.1% bovine serum albumin (BSA) in PBS (PBS-BSA) followed by donkey anti-sheep IgG Alexa 488 diluted (1/2000) in PBS-BSA (Chemicon).

    Western blot analyses. Intestinal epithelial cell pellets were homogenized in 0.1% Triton X-100 in 0.1 mol/L Tris-HCL, pH 7.2, by being passed 3 times through a 25-gauge needle and then further disrupted by sonication on ice (Fisher Scientific Model 550 Sonic Dismembartor). The homogenate was then centrifuged at 1500 x g for 15 min to pellet debris followed by ultracentrifugation of the supernatant at 100,000 x g for 1 h (Optima TLX ULTRA Centrifuge, Beckman TLA 100.4). A 50-µg sample of the membrane protein pellet was then separated by electrophoresis to prepare membranes for Western Blot analysis as described (21). ATP7A was detected using anti-Menkes antibody (diluted 1:1000) followed by horseradish peroxidase-conjugated donkey anti-sheep IgG (Chemicon) (1:4000). Bands were revealed using the Lumi-Light Chemiluminescence blotting kit (Roche). In some experiments, the transgenic ATP7A protein was detected using rabbit anti-c-myc antisera (1:1000) (Sigma) as the primary antibody followed by horseradish peroxidase-conjugated donkey anti-rabbit IgG (1:2000) (Chemicon).

RESULTS

    Expression of ATP7A-myc transgene. We characterized the expression levels and cellular location of ATP7A in membrane fractions of isolated intestinal epithelial cells or frozen sections, respectively, from heterozygous ATP7A transgenic mice and nontransgenic littermates. Western blot analyses revealed an 8-fold increase in a 178-kDa band in intestinal cell extracts in the transgenic mice, which corresponded to the predicted molecular weights of the endogenous mouse Atp7a protein and the ATP7A-myc transgene product (Fig. 1A). The membranes were then reprobed with rabbit polyclonal antisera to an engineered c-myc epitope within the transgene to confirm the specificity of the anti-Menkes antibody (Fig. 1B).

View larger version (41K): [in this window] [in a new window]   FIGURE 1 ATP7A expression levels in intestinal epithelial cells in transgenic and nontransgenic mice. Western blot analyses were conducted using (A) affinity purified antibodies directed against the ATP7A N-terminus (diluted 1:1000), followed by horseradish peroxidase-conjugated donkey anti-sheep IgG (diluted 1:2000) and/or (B) anti-c-myc polyclonal rabbit antibodies followed by horseradish peroxidase-conjugated donkey anti-rabbit IgG. Bands in both blots were revealed by chemiluminescence. The positions of the molecular weight are marked on the right in kDa (Bio-Rad). The expression of ATP7A in frozen sections of intestine of (C) untreated, heterozygous ATP7A transgenic mice or (D) nontransgenic littermates was revealed by immunofluorescence using the anti- ATP7A N-terminus antibody (1:2000) followed by affinity-purified 488-conjugated donkey anti-sheep IgG antibodies (1:4000).

    Response of ATP7A to intestinal copper challenge. Next, we employed a perfusion technique to study the response of ATP7A to copper challenge in the intestine. Briefly, this technique involved the perfusion of solutions of copper chloride via a cannula inserted into an isolated segment of the proximal small intestine in an anesthetized mouse. In these studies, we compared the effects of the duration and dose of copper exposure on the location of ATP7A in the villous epithelium. ATP7A was localized to the apical perinuclear region (presumably at the TGN) when copper was chelated with 100 µmol/L BCS (Fig. 2A) or when the intestines were challenged with saline or a low level of copper (10 µmol/L CuCl₂) (Fig. 2B and C). In contrast, ATP7A was shifted to sub-basolateral vesicles in response to copper challenges of the intestine lumen 50 µmol/L CuCl₂ (Fig. 2D–F). Relocalization of the ATP7A protein was observable as early as 30 min after challenge with high copper exposures and showed a uniform distribution in all cells along the villi after 1 h (not shown). The redistribution of ATP7A in response to 100 µmol/L CuCl₂, was reversible by perfusing the intestine for another 30 min with 100 µmol/L BCS (data not shown). Western blot analysis of epithelial cells isolated from the intestinal segments perfused with 100 µmol/L CuCl₂ or 100 µmol/L BCS revealed no difference in the level of ATP7A protein (Fig. 2G).

View larger version (72K): [in this window] [in a new window]   FIGURE 2 Copper-induced trafficking of ATP7A in copper-perfused mouse intestine. Intestinal segments were perfused for 1 h with (A) 100 µmol/L of BCS, (B) HBSS or (C–F) CuCl2 solutions in HBSS at the following concentrations: (C) 10 µmol/L (D) 50 µmol/L (E) 100 µmol/L, and (F) 200 µmol/L. ATP7A was detected using anti-ATP7A antibodies (1:2000) followed by affinity-purified 488-conjugated donkey anti-sheep IgG (1:4000). (A–F) a.m. = apical membrane; b.m. = basolateral membrane. (G) Western blot analysis of ATP7A levels in membrane fractions of isolated intestinal epithelial cells from intestinal segments perfused with HBSS (lane 1), 100 µmol/L BCS (lane 2), or 100 µmol/L CuCl2 in HBSS (lane 3) using anti-ATP7A antibodies (diluted 1:1000), followed by horseradish peroxidase-conjugated donkey anti-sheep IgG (diluted 1:2000), and chemiluminescence.

View larger version (133K): [in this window] [in a new window]   FIGURE 3 ATP7A is induced to traffic to the basolateral region by silver but not by manganese or cobalt. Intestinal segments of ATP7A transgenic mice were perfused for 1 h with (A) 100 µmol/L MnCl2 in HBSS, (B) 100 µmol/L CoCl2 in HBSS, (C) 100 µmol/L NiCl2, or (D) 100 µmol/L AgCl in water. ATP7A was detected using anti-ATP7A antibodies (1:2000) followed by affinity-purified 488-conjugated donkey anti-sheep IgG (1:4000). a.m. = apical membrane; b.m. = basolateral membrane.

DISCUSSION

The results of this study provide new information about the regulation of copper uptake from the diet. Using a transgenic mouse expressing the Menkes gene, ATP7A, we demonstrated for the first time that the ATP7A protein in intestinal enterocytes undergoes copper-induced trafficking. The ATP7A protein in the intestine of these transgenic animals was located at the apical perinuclear region of the enterocytes in nonchallenged mice and after exposure to low copper solutions. Importantly, ATP7A trafficked rapidly to basolateral vesicles in response to copper perfusion of the intestine. This supports a mechanism of regulated transmucosal copper absorption in which brief exposures to increased copper result in a shift in the localization of ATP7A to the basolateral region. We suggest that this response of ATP7A facilitates copper delivery into the circulation.

ATP7A was shown previously to traffic to the plasma membrane when copper levels are elevated in cultured cells, facilitating the efflux of excess copper from the cells (3). An unexpected result of this study was the localization of ATP7A to sub-basolateral membrane vesicles after copper exposure rather than to the basolateral membrane as found in polarized MDCK cells exposed to copper (22). There was no evidence of basolateral location of ATP7A in the copper-perfused small intestine. The difference between our results and those of Greenough et al. (22) may be due to differences in cell type or alterations in localization in a cultured cell model compared with an in vivo situation. Nevertheless, both sets of data support the contention that ATP7A is involved in the transport of copper across the basolateral membrane of the enterocyte.

A similar copper-induced trafficking of ATP7B in hepatocytes appears to underlie regulation of biliary excretion of copper. Movement of ATP7B from the TGN to subapical vesicles was described in cultured polarized hepatocytes and in the liver of copper-loaded rats (10,19). Roelofsen et al. (23) provided data that, in polarized HepG2 cells, ATP7B traffics first to vesicles and then is located on the apical membrane. These conclusions are supported in part by the distribution of ATP7B in rat liver. Schaefer et al. (19) found that in copper-deficient rats, ATP7B was localized in the TGN of hepatocytes, but when the rats were copper loaded, the protein was distributed in multiple vesicular structures; however, these authors did not find any ATP7B on the canalicular (apical) membrane.

Subapical vesicles are thought to be a subpopulation of endosomes known as recycling endosomes (24); unlike early endosomes, they are not thought to fuse with lysosomes (25). Given the similarities in the structure and function of ATP7A and ATP7B, it is notable that in vivo, ATP7A appears to traffic using subplasma membrane vesicular intermediates as well. This raises the possibility that the mechanism of copper uptake may involve a basolateral pool of recycling endosomes.

We envision the following scenario by which ATP7A may function to deliver copper ions to the circulation. After the initial rise of intracellular copper levels, ATP7A is released from the TGN and traffics toward the basolateral membrane in vesicles, possibly involving the Rab5 and Rab7 proteins (26). During transport, ATP7A receives copper from the ATOX chaperone and pumps the ions into vesicular lumens. These vesicles eventually fuse with the membrane and exocytose the transported copper. If this fusion step is slow, as was shown in cultured hepatocytes with ATP7B, this may account for why basolateral membrane labeling of ATP7A was not revealed during the 30- to 60-min challenge undertaken in these experiments.

We cannot rule out the possibility that some ATP7A traffics directly to the basolateral membrane during the initial exposure and is subsequently incorporated into (recycling) endosomal vesicles, which then become the predominant location of ATP7A after 30–60 min of copper exposure. We speculate that the subplasma membrane vesicular localization of ATP7A and ATP7B during copper exposures may facilitate the transfer of copper from ATOX-1 to the transporters’ metal binding sites by increasing the membrane surface area of potential sites of interaction among the molecules.

We also evaluated the effect on localization of ATP7A using various transition metals. ATP7A was responsive to silver ions, as was demonstrated previously (3), and was localized to the basolateral vesicles within the epithelium in sections from AgCl-perfused intestine. However, ATP7A was unresponsive to perfusions with multivalent metals, cadmium, nickel, and manganese. The ability of AgCl to induce trafficking of ATP7A suggests that both Ag(I) and Cu(I) ions are able to interact with the metal binding sites within the N terminus of ATP7A as a component of the copper-induced trafficking signal.

Decreased efficiency of uptake of copper was shown to occur at high dietary intakes (1,18). Our data appear to rule out the possibility that high exposures to copper may result in the targeting of ATP7A to the apical membrane of the intestinal cells to pump the excess copper back into the intestinal lumen. We have never observed apical membrane staining using the anti-Menkes antibody under any copper exposure conditions. Alternatively, it is possible that the copper-induced redistribution of ATP7A to basolateral vesicles may represent a form of regulation of copper uptake by copper sequestration in the vesicles. We are presently investigating the kinetics of copper uptake in perfused transgenic intestines to formally rule out this possibility.

ACKNOWLEDGMENTS

We wish to acknowledge Maree McGlynn for help and advice with animal husbandry.

FOOTNOTES

¹ Supported by the International Copper Association, and the National Health and Medical Research Council of Australia.

³ Abbreviations used: BCS, bathocuproine disulfonic acid; BSA, bovine serum albumin; TGN, trans-Golgi network.

Manuscript received 3 June 2005. Initial review completed 5 August 2005. Revision accepted 15 September 2005.

LITERATURE CITED

1. Linder MC, Hazegh-Azam M. Copper biochemistry and molecular biology. Am J Clin Nutr. 1996;63(5):797S-7810.[Abstract/Free Full Text]

2. Kuo Y-M, Zhou B, Cosco D, Gitschier J. The copper transporter CTR1 provides as essential function in mammalian embryonic development. Proc Natl Acad Sci U S A. 2001;98:6836-6841.[Abstract/Free Full Text]

3. Petris MJ, Mercer JFB, Culvenor JG, Lockhart P, Gleeson PA, Camakaris J. Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking. EMBO J. 1996;15(22):6084-6095.[Medline]

4. Petrukhin K, Lutsenko S, Chernov I, Ross BM, Kaplan JH, Gilliam TC. Characterization of the Wilson disease gene encoding a copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions. Hum Mol Genet. 1994;3:1647-1656.[Abstract/Free Full Text]

5. Petris MJ. The SLC31 (Ctr) copper transporter family. Pflugers Arch. 2003;447:752-755.[Medline]

6. Harrison M, Jones CE, Dameron CT. Copper chaperones: function, structure and copper-binding properties. J Biol Inorg Chem. 1999;4:145-153.[Medline]

7. Yamaguchi Y, Heiny ME, Suzuki M, Gitlin JD. Biochemical characterization and intracellular localization of the Menkes disease protein. Proc Natl Acad Sci U S A. 1996;93:14030-14035.[Abstract/Free Full Text]

8. Kramer DR, Llanos RM, Mercer JFB. Molecular basis of copper transport: cellular and physiological functions of menkes and Wilson disease proteins (ATP7A and ATP7B). Zatta P eds. Molecular basis of copper transport: cellular and physiological functions of menkes and Wilson disease proteins (ATP7A and ATP7B). Metal ions and neurodegenerative diseases. :1-31 World Scientific Singapore.

9. Petris MJ, Strausak D, Mercer JFB. The Menkes copper transporter is required for the activation of tyrosinase. Hum Mol Genet. 2000;9:2845-2851.[Abstract/Free Full Text]

10. Schaefer M, Roelofsen H, Wolters H, Hofmann WJ, Muller M, Kuipers F, Stremmel W, Vonk RJ. Localization of the Wilson’s disease protein in human liver. Gastroenterology. 1999;117:1380-1385.[Medline]

11. Lutsenko S, Petrukhin K, Cooper MJ, Gilliam CT, Kaplan JH. N-terminal domains of human copper-transporting adenosine triphosphatases (the Wilson’s and Menkes disease proteins) bind copper selectively in vivo and in vitro with stoichiometry of one copper per metal-binding repeat. J Biol Chem. 1997;272:18939-18944.[Abstract/Free Full Text]

12. Voskoboinik I, Camakaris J, Mercer JFB. Understanding the mechanism and function of copper P-type ATP-ases. Adv Prot Chem. 2002;60:123-150.[Medline]

13. Gitlin JD. Wilson disease. Gastroenterology. 2003;125:1868-1877.[Medline]

14. Chelly J, Turmer Z, Tonnerson T, Petterson A, Ishikawa-Brush Y, Tommerup N, Horn N, Monaco AP. Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nat Genet. 1993;3:14-19.[Medline]

15. Mercer JFB, Livingston J, Hall BK, Paynter JA, Begy C, Chandrasekharappa S, Lockhart P, Grimes A, Bhave M, et al. Isolation of a partial candidate gene for Menkes disease by positional cloning. Nat Genet. 1993;3:20-25.[Medline]

16. Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nat Genet. 1993;3:7-13.[Medline]

17. Mercer JFB. Menkes syndrome and animal models. Am J Clin Nutr. 1998;5:1027S-1028S.

18. Turnlund JR, Keyes WR, Peiffer GL, Scott KS. Copper absorption, excretion and retention by young men consuming low dietary copper determined by using the stable isotope ⁶⁵Cu. Am J Clin Nutr. 1998;67:1219-1225.[Abstract]

19. Schaefer M, Hopkins RG, Failla ML, Gitlin JD. Hepatocyte-specific localization and copper-dependent trafficking of the Wilson’s disease protein in the liver. Am J Physiol. 1999;276:G639-G646.[Medline]

20. Petris MJ, Mercer JFB. The Menkes protein (ATP7A; MNK) cycles via the plasma membrane both in basal and elevated extracellular copper using a C-terminal di-leucine endocytic signal. Hum Mol Genet. 1999;8:2107-2115.[Abstract/Free Full Text]

21. Cater MA, Forbes JR, La Fontaine S, Cox D, Mercer JFB. Intracellular trafficking of the human Wilson protein: the role of the six N-terminal metal-binding sites. Biochem J. 2004;380:805-813.[Medline]

22. Greenough M, Pase L, Voskoboinik I, Petris MJ, Wilson O’Brien A, Camakaris J. Signals regulating trafficking of Menkes (MNK; ATP7A) copper-translocating P-type ATPase in polarized MDCK cells. Am J Physiol Cell Physiol. 2004;287:1463-1471.

23. Roelofsen H, Wolters H, Van Luyn MJA, Miura N, Kuipers F, Vonk RJ. Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion. Gastroenterology. 2000;119:782-793.[Medline]

24. Hoekstra D, Tyteca D, van IJzendoorn SCD. The subapical compartment: a traffic center in membrane polarity development. J Cell Sci. 2004;117:2183-2192.[Abstract/Free Full Text]

25. Fölsch H. The building blocks for basolateral vesicles in polarized epithelial cells. Trends Cell Biol. 2005;15:222-228.[Medline]

26. Pascale MC, Franceschelli S, Moltedo O, Belleudi F, Torrisi MR, Bucci C, La Fontaine S, Mercer JFB, Leone A. Endosomal trafficking of the Menkes copper ATPase ATP7A is mediated by vesicles containing the Rab7 and Rab5 GTPase. Exp Cell Res. 2003;291:377-385.[Medline]

This article has been cited by other articles:

				B.-X. Ke, R. M. Llanos, and J. F. B. Mercer ATP7A Transgenic and Nontransgenic Mice Are Resistant to High Copper Exposure J. Nutr., April 1, 2008; 138(4): 693 - 697. [Abstract] [Full Text] [PDF]

				R. Linz, N. L. Barnes, A. M. Zimnicka, J. H. Kaplan, B. Eipper, and S. Lutsenko Intracellular targeting of copper-transporting ATPase ATP7A in a normal and Atp7b / kidney Am J Physiol Renal Physiol, January 1, 2008; 294(1): F53 - F61. [Abstract] [Full Text] [PDF]

				Z. G. Holloway, R. Grabski, T. Szul, M. L. Styers, J. A. Coventry, A. P. Monaco, and E. Sztul Activation of ADP-ribosylation factor regulates biogenesis of the ATP7A-containing trans-Golgi network compartment and its Cu-induced trafficking Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1753 - C1767. [Abstract] [Full Text] [PDF]

				P de Bie, P Muller, C Wijmenga, and L W J Klomp Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes J. Med. Genet., November 1, 2007; 44(11): 673 - 688. [Abstract] [Full Text] [PDF]

				B.-E. Kim and M. J Petris Phenotypic diversity of Menkes disease in mottled mice is associated with defects in localisation and trafficking of the ATP7A protein J. Med. Genet., October 1, 2007; 44(10): 641 - 646. [Abstract] [Full Text] [PDF]

				S. Lutsenko, N. L. Barnes, M. Y. Bartee, and O. Y. Dmitriev Function and Regulation of Human Copper-Transporting ATPases Physiol Rev, July 1, 2007; 87(3): 1011 - 1046. [Abstract] [Full Text] [PDF]

				L. Nyasae, R. Bustos, L. Braiterman, B. Eipper, and A. Hubbard Dynamics of endogenous ATP7A (Menkes protein) in intestinal epithelial cells: copper-dependent redistribution between two intracellular sites Am J Physiol Gastrointest Liver Physiol, April 1, 2007; 292(4): G1181 - G1194. [Abstract] [Full Text] [PDF]

				B.-X. Ke, R. M. Llanos, M. Wright, Y. Deal, and J. F. B. Mercer Alteration of copper physiology in mice overexpressing the human Menkes protein ATP7A Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2006; 290(5): R1460 - R1467. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Monty, J.-F. Articles by Kramer, D. R. Search for Related Content PubMed PubMed Citation Articles by Monty, J.-F. Articles by Kramer, D. R.