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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4268-4275. Prepublished online as a Blood First Edition Paper on September 5, 2008; DOI 10.1182/blood-2008-04-150953. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2008-04-150953v1 112/10/4268    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Foot, N. J Articles by Kumar, S. Search for Related Content PubMed PubMed Citation Articles by Foot, N. J Articles by Kumar, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 14, 2008 Accepted August 7, 2008 Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2 Natalie J Foot, Hazel E Dalton, Linda M Shearwin-Whyatt, Loretta Dorstyn, Seong-Seng Tan, Baoli Yang, and Sharad Kumar* Department of Haematology, Hanson Institute, IMVS, Adelaide, SA, Australia Brain Development Group, Howard Florey Institute, Melbourne, Victoria, Australia Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States * Corresponding author; email: sharad.kumar{at}imvs.sa.gov.au. Many ion channels and transporters are regulated by ubiquitination mediated by the Nedd4 family of HECT-type ubiquitin ligases (E3s). These E3s commonly interact with substrates via their WW domains that bind to specific motifs in target proteins. However, not all potential targets of these E3s contain WW-binding motifs. Therefore, accessory proteins may mediate the interaction between Nedd4 family members and their targets. Here we report that the divalent metal ion transporter DMT1, the primary non-heme iron transporter in mammals, is regulated by ubiquitination mediated by the Nedd4 family member WWP2. DMT1 interacts with two WW domain interacting proteins, Ndfip1 and Ndfip2, previously proposed to have roles in protein trafficking. This promotes DMT1 ubiquitination and degradation by WWP2. Consistent with these observations, Ndfip1-/- mice show increased DMT1 activity and a concomitant increase in hepatic iron deposition, indicating an essential function of Ndfip1 in iron homeostasis. This novel mechanism of regulating iron homeostasis suggests that Ndfips and WWP2 may contribute to diseases involving aberrant iron transport. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Howitt, U. Putz, J. Lackovic, A. Doan, L. Dorstyn, H. Cheng, B. Yang, T. Chan-Ling, J. Silke, S. Kumar, et al. Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons PNAS, September 8, 2009; 106(36): 15489 - 15494. [Abstract] [Full Text] [PDF]

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