Published online 18 April 2009
Haematologica, Vol 94, Issue 6, 840-849 doi:10.3324/haematol.2008.001867
Copyright © 2009 by Ferrata Storti Foundation
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Review Article

Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis

Andrew J. Ramsay1, John D. Hooper2, Alicia R. Folgueras1, Gloria Velasco1, Carlos López-Otín1

1 Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Spain
2 Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia

Correspondence: Carlos Lopez-Otin, Departamento de Bioquímica y Biología Molecular Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain. E-mail:clo{at}uniovi.es

Maintaining the body’s levels of iron within precise boundaries is essential for normal physiological function. Alterations of these levels below or above the healthy limit lead to a systemic deficiency or overload in iron. The type-two transmembrane serine protease (TTSP), matriptase-2 (also known as TMPRSS6), is attracting significant amounts of interest due to its recently described role in iron homeostasis. The finding of this regulatory role for matriptase-2 was originally derived from the observation that mice deficient in this protease present with anemia due to elevated levels of hepcidin and impaired intestinal iron absorption. Further in vitro analysis has demonstrated that matriptase-2 functions to suppress bone morphogenetic protein stimulation of hepcidin transcription through cell surface proteolytic processing of the bone morphogenetic protein co-receptor hemojuvelin. Consistently, the anemic phenotype of matriptase-2 knockout mice is mirrored in humans with matripase-2 mutations. Currently, 14 patients with iron-refractory iron deficiency anemia (IRIDA) have been reported to harbor various genetic mutations that abrogate matriptase-2 proteolytic activity. In this review, after overviewing the membrane anchored serine proteases, in particular the TTSP family, we summarize the identification and characterization of matriptase-2 and describe its functional relevance in iron metabolism.

Key words: Matriptase-2, proteolytic regulator, iron homeostasis.




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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.
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