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Blood, 15 September 2008, Vol. 112, No. 6, pp. 2539-2545. Prepublished online as a Blood First Edition Paper on June 3, 2008; DOI 10.1182/blood-2008-04-149773. This Article Full Text (PDF) Supplemental Table All Versions of this Article: blood-2008-04-149773v1 112/6/2539    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 Folgueras, A. R Articles by Velasco, G. Search for Related Content PubMed PubMed Citation Articles by Folgueras, A. R Articles by Velasco, G. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 4, 2008 Accepted May 6, 2008 The membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis Alicia R Folgueras, Fernando Martin de Lara, Alberto M Pendas, Cecilia Garabaya, Francisco Rodriguez, Aurora Astudillo, Teresa Bernal, Ruben Cabanillas, Carlos Lopez-Otin*, and Gloria Velasco Departamento de Bioquimica y Biologia Molecular, Universidad de Oviedo-IUOPA, Oviedo, Spain Servicio de Anatomia Patologica, Hospital Universitario Central de Asturias, Oviedo, Spain Servicio de Hematologia, Hospital Universitario Central de Asturias, Oviedo, Spain Servicio de Otorrinolaringologia, Hospital Universitario Central de Asturias, Oviedo, Spain * Corresponding author; email: clo{at}uniovi.es. Proteolytic events at the cell surface are essential in the regulation of signal transduction pathways. Over the last years, the family of type II transmembrane serine proteases (TTSPs) has acquired an increasing relevance due to their privileged localization at the cell surface, although our current understanding of the biological function of most TTSPs is very limited. Here we demonstrate that matriptase-2 (Tmprss6), a recently described member of the TTSP family, is an essential regulator of iron homeostasis. Thus, Tmprss6-/- mice display an overt phenotype of alopecia and a severe iron deficiency anemia. These hematological alterations found in Tmprss6-/- mice are accompanied by a marked up-regulation of hepcidin, a negative regulator of iron export into plasma. Likewise, Tmprss6-/- mice have reduced ferroportin expression in the basolateral membrane of enterocytes and accumulate iron in these cells. Iron-dextran therapy rescues both alopecia and hematological alterations of Tmprss6-/- mice, providing causal evidence that the anemic phenotype of these mutant mice results from the blockade of intestinal iron export into plasma after dietary absorption. Based on these findings, we conclude that matriptase-2 activity represents a novel and relevant step in hepcidin regulation and iron homeostasis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Iron homeostasis: casting new roles Karin E. Finberg Blood 2008 112: 2181. [Full Text] [PDF] This article has been cited by other articles: A. J. Ramsay, V. Quesada, M. Sanchez, C. Garabaya, M. P. Sarda, M. Baiget, A. Remacha, G. Velasco, and C. Lopez-Otin Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms Hum. Mol. Genet., October 1, 2009; 18(19): 3673 - 3683. [Abstract] [Full Text] [PDF] T. H. Bugge, T. M. Antalis, and Q. Wu Type II Transmembrane Serine Proteases J. Biol. Chem., August 28, 2009; 284(35): 23177 - 23181. [Abstract] [Full Text] [PDF] B. Chung, T. Chaston, J. Marks, S. K. Srai, and P. A. Sharp Hepcidin Decreases Iron Transporter Expression in Vivo in Mouse Duodenum and Spleen and in Vitro in THP-1 Macrophages and Intestinal Caco-2 Cells J. Nutr., August 1, 2009; 139(8): 1457 - 1462. [Abstract] [Full Text] [PDF] A. J. Ramsay, J. D. Hooper, A. R. Folgueras, G. Velasco, and C. Lopez-Otin Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis Haematologica, June 1, 2009; 94(6): 840 - 849. [Abstract] [Full Text] [PDF] L. Silvestri, F. Guillem, A. Pagani, A. Nai, C. Oudin, M. Silva, F. Toutain, C. Kannengiesser, C. Beaumont, C. Camaschella, et al. Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia Blood, May 28, 2009; 113(22): 5605 - 5608. [Abstract] [Full Text] [PDF] C. Camaschella and L. Silvestri New and old players in the hepcidin pathway Haematologica, October 1, 2008; 93(10): 1441 - 1444. [Full Text] [PDF] F. Guillem, S. Lawson, C. Kannengiesser, M. Westerman, C. Beaumont, and B. Grandchamp Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency Blood, September 1, 2008; 112(5): 2089 - 2091. [Abstract] [Full Text] [PDF]

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