The role of TMPRSS6/matriptase-2 in iron regulation and anemia

Frontiers in Pharmacology

Volumn 5 MAY, Issue , 2014, Pages

  Wang, Chia Yu ^a   Meynard, Delphine ^b   Lin, Herbert Y ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b France   (France)

Author keywords

IRIDA; Iron; Iron overload; Matriptase 2; TMPRSS6

Indexed keywords

HEPCIDIN; IRON; MATRIPTASE 2; SERINE PROTEINASE; UNCLASSIFIED DRUG;

ANEMIA; BREAST CANCER; CANCER GROWTH; CANCER PROGNOSIS; CARCINOGENESIS; DRUG TARGETING; ENZYME ACTIVITY; ENZYME ANALYSIS; ENZYME REGULATION; GENE EXPRESSION; GENE MUTATION; GENETIC ASSOCIATION; HAPLOINSUFFICIENCY; HORMONAL REGULATION; HUMAN; IRON BALANCE; IRON DEFICIENCY ANEMIA; IRON METABOLISM; IRON OVERLOAD; NONHUMAN; PATHOPHYSIOLOGY; PHENOTYPE; REVIEW; TMPRSS6 GENE;

EID: 84904626934     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2014.00114     Document Type: Review

References (74)

1. Ahmad, K. A., Ahmann, J. R., Migas, M. C., Waheed, A., Britton, R. S., Bacon, B. R., et al. (2002). Decreased liver hepcidin expression in the Hfe knockout mouse. Blood Cells Mol. Dis. 29, 361-366. doi: 10.1006/bcmd.2002.0575
2. Altamura, S., D'Alessio, F., Selle, B., and Muckenthaler, M. U. (2010). A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA. Biochem. J. 431, 363-371. doi: 10.1042/BJ20100668
3. An, P., Wu, Q., Wang, H., Guan, Y., Mu, M., Liao, Y., et al. (2012). TMPRSS6, but not TF, TFR2 or BMP2 variants are associated with increased risk of iron-deficiency anemia. Hum. Mol. Genet. 21, 2124-2131. doi: 10.1093/hmg/dds028
4. Andriopoulos, B. Jr., Corradini, E., Xia, Y., Faasse, S. A., Chen, S., Grgurevic, L., et al. (2009). BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat. Genet. 41, 482-487. doi: 10.1038/ng.335
5. Babitt, J. L., Huang, F. W., Wrighting, D. M., Xia, Y., Sidis, Y., Samad, T. A., et al. (2006). Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38, 531-539. doi: 10.1038/ng1777
6. Babitt, J. L., Huang, F. W., Xia, Y., Sidis, Y., Andrews, N. C., and Lin, H. Y. (2007). Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J. Clin. Invest. 117, 1933-1939. doi: 10.1172/JCI31342
7. Benyamin, B., Ferreira, M. A., Willemsen, G., Gordon, S., Middelberg, R. P., Mcevoy, B. P., et al. (2009). Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat. Genet. 41, 1173-1175. doi: 10.1038/ng.456
8. Camaschella, C. (2013). Treating iron overload. N. Engl. J. Med. 368, 2325-2327. doi: 10.1056/NEJMcibr1304338
9. Chambers, J. C., Zhang, W., Li, Y., Sehmi, J., Wass, M. N., Zabaneh, D., et al. (2009). Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat. Genet. 41, 1170-1172. doi: 10.1038/ng.462
10. Chen, W., Sun, C. C., Chen, S., Meynard, D., Babitt, J. L., and Lin, H. Y. (2013). A novel validated enzyme-linked immunosorbent assay to quantify soluble hemojuvelin in mouse serum. Haematologica 98, 296-304. doi: 10.3324/haematol.2012.070136
11. Corradini, E., Garuti, C., Montosi, G., Ventura, P., Andriopoulos, B. Jr., Lin, H. Y., et al. (2009). Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis. Gastroenterology 137, 1489-1497. doi: 10.1053/j.gastro.2009.06.057
12. De Falco, L., Sanchez, M., Silvestri, L., Kannengiesser, C., Muckenthaler, M. U., Iolascon, A., et al. (2013). Iron refractory iron deficiency anemia. Haematologica 98, 845-853. doi: 10.3324/haematol.2012.075515
13. Du, X., She, E., Gelbart, T., Truksa, J., Lee, P., Xia, Y., et al. (2008). The serine protease TMPRSS6 is required to sense iron deficiency. Science 320, 1088-1092. doi: 10.1126/science.1157121
14. Finberg, K. E. (2013). Striking the target in iron overload disorders. J. Clin. Invest. 123, 1424-1427. doi: 10.1172/JCI68889
15. Finberg, K. E., Heeney, M. M., Campagna, D. R., Aydinok, Y., Pearson, H. A., Hartman, K. R., et al. (2008). Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat. Genet. 40, 569-571. doi: 10.1038/ng.130
16. Finberg, K. E., Whittlesey, R. L., and Andrews, N. C. (2011). Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice. Blood 117, 4590-4599. doi: 10.1182/blood-2010-10.315507
17. Finberg, K. E., Whittlesey, R. L., Fleming, M. D., and Andrews, N. C. (2010). Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood 115, 3817-3826. doi: 10.1182/blood-2009-05-224808
18. Folgueras, A. R., De Lara, F. M., Pendas, A. M., Garabaya, C., Rodriguez, F., Astudillo, A., et al. (2008). Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood 112, 2539-2545. doi: 10.1182/blood-2008-04-149773
19. Frydlova, J., Fujikura, Y., Vokurka, M., Necas, E., and Krijt, J. (2013). Decreased hemojuvelin protein levels in mask mice lacking matriptase-2-dependent proteolytic activity. Physiol. Res. 62, 405-411.
20. Gan, W., Guan, Y., Wu, Q., An, P., Zhu, J., Lu, L., et al. (2012). Association of TMPRSS6 polymorphisms with ferritin, hemoglobin, and type 2 diabetes risk in a Chinese Han population. Am. J. Clin. Nutr. 95, 626-632. doi: 10.3945/ajcn.111.025684
21. Gardenghi, S., Ramos, P., Marongiu, M. F., Melchiori, L., Breda, L., Guy, E., et al. (2010). Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemic mice. J. Clin. Invest. 120, 4466-4477. doi: 10.1172/JCI41717
22. Giannetti, A. M., and Bjorkman, P. J. (2004). HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface. J. Biol. Chem. 279, 25866-25875. doi: 10.1074/jbc.M401467200
23. Guillem, F., Lawson, S., Kannengiesser, C., Westerman, M., Beaumont, C., and Grandchamp, B. (2008). Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency. Blood 112, 2089-2091. doi: 10.1182/blood-2008-05-154740
24. Guo, S., Casu, C., Gardenghi, S., Booten, S., Aghajan, M., Peralta, R., et al. (2013). Reducing TMPRSS6 ameliorates hemochromatosis and beta-thalassemia in mice. J. Clin. Invest. 123, 1531-1541. doi: 10.1172/JCI66969
25. Hartikainen, J. M., Tuhkanen, H., Kataja, V., Eskelinen, M., Uusitupa, M., Kosma, V. M., et al. (2006). Refinement of the 22q12-q13 breast cancer-associated region: evidence of TMPRSS6 as a candidate gene in an eastern Finnish population. Clin. Cancer Res. 12, 1454-1462. doi: 10.1158/1078-0432.CCR-05-1417
26. Inouye, K., Tsuzuki, S., Yasumoto, M., Kojima, K., Mochida, S., and Fushiki, T. (2010). Identification of the matriptase second CUB domain as the secondary site for interaction with hepatocyte growth factor activator inhibitor type-1. J. Biol. Chem. 285, 33394-33403. doi: 10.1074/jbc.M110.115816
27. Jaspers, A., Caers, J., Le Gac, G., Ferec, C., Beguin, Y., and Fillet, G. (2013). A novel mutation in the CUB sequence of matriptase-2 (TMPRSS6) is implicated in iron-resistant iron deficiency anaemia (IRIDA). Br. J. Haematol. 160, 564-565. doi: 10.1111/bjh.12147
28. Kang, J. Y., Dolled-Filhart, M., Ocal, I. T., Singh, B., Lin, C. Y., Dickson, R. B., et al. (2003). Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer. Cancer Res. 63, 1101-1105.
29. Kautz, L., Meynard, D., Besson-Fournier, C., Darnaud, V., Al Saati, T., Coppin, H., et al. (2009). BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. Blood 114, 2515-2520. doi: 10.1182/blood-2009-02-206771
30. Kautz, L., Meynard, D., Monnier, A., Darnaud, V., Bouvet, R., Wang, R. H., et al. (2008). Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 112, 1503-1509. doi: 10.1182/blood-2008-03-143354
31. Krijt, J., Fujikura, Y., Ramsay, A. J., Velasco, G., and Necas, E. (2011). Liver hemojuvelin protein levels in mice deficient in matriptase-2 (Tmprss6). Blood Cells Mol. Dis. 47, 133-137. doi: 10.1016/j.bcmd.2011.04.009
32. Lakhal, S., Schodel, J., Townsend, A. R., Pugh, C. W., Ratcliffe, P. J., and Mole, D. R. (2011). Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: new link between hypoxia signaling and iron homeostasis. J. Biol. Chem. 286, 4090-4097. doi: 10.1074/jbc.M110.173096
33. Lee, P., Hsu, M. H., Welser-Alves, J., and Peng, H. (2012). Severe microcytic anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 and Tmprss6. Blood Cells Mol. Dis. 48, 173-178. doi: 10.1016/j.bcmd.2011.12.005
34. Lenoir, A., Deschemin, J. C., Kautz, L., Ramsay, A. J., Roth, M. P., Lopez-Otin, C., et al. (2011). Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6. Blood 117, 647-650. doi: 10.1182/blood-2010-07-295147
35. Li, H., Rybicki, A. C., Suzuka, S. M., Von Bonsdorff, L., Breuer, W., Hall, C. B., et al. (2010). Transferrin therapy ameliorates disease in beta-thalassemic mice. Nat. Med. 16, 177-182. doi: 10.1038/nm.2073
36. Maurer, E., Gutschow, M., and Stirnberg, M. (2012). Matriptase-2 (TMPRSS6) is directly up-regulated by hypoxia inducible factor-1: identification of a hypoxia-responsive element in the TMPRSS6 promoter region. Biol. Chem. 393, 535-540. doi: 10.1515/hsz-2011-0221
37. Maurer, E., Gutschow, M., and Stirnberg, M. (2013). Hepatocyte growth factor activator inhibitor type 2 (HAI-2) modulates hepcidin expression by inhibiting the cell surface protease matriptase-2. Biochem. J. 450, 583-593. doi: 10.1042/BJ20121518
38. Melis, M. A., Cau, M., Congiu, R., Sole, G., Barella, S., Cao, A., et al. (2008). A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematologica 93, 1473-1479. doi: 10.3324/haematol.13342
39. Meynard, D., Kautz, L., Darnaud, V., Canonne-Hergaux, F., Coppin, H., and Roth, M. P. (2009). Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat. Genet. 41, 478-481. doi: 10.1038/ng.320
40. Meynard, D., Sun, C. C., Wu, Q., Chen, W., Chen, S., Nelson, C. N., et al. (2013). Inflammation Regulates TMPRSS6 Expression via STAT5. PLoS ONE 8:e82127. doi: 10.1371/journal.pone.0082127
41. Meynard, D., Vaja, V., Sun, C. C., Corradini, E., Chen, S., Lopez-Otin, C., et al. (2011). Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood 118, 747-756. doi: 10.1182/blood-2011-04-348698
42. Nai, A., Pagani, A., Mandelli, G., Lidonnici, M. R., Silvestri, L., Ferrari, G., et al. (2012). Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia. Blood 119, 5021-5029. doi: 10.1182/blood-2012-01-401885
43. Nai, A., Pagani, A., Silvestri, L., and Camaschella, C. (2010). Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice. Blood 116, 851-852. doi: 10.1182/blood-2010-04-278655
44. Nai, A., Pagani, A., Silvestri, L., Campostrini, N., Corbella, M., Girelli, D., et al. (2011). TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals. Blood 118, 4459-4462. doi: 10.1182/blood-2011-06-364034
45. Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., et al. (2004). Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090-2093. doi: 10.1126/science.1104742
46. Nicolas, G., Bennoun, M., Devaux, I., Beaumont, C., Grandchamp, B., Kahn, A., et al. (2001). Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc. Natl. Acad. Sci. U.S.A. 98, 8780-8785. doi: 10.1073/pnas.151179498151179498
47. Niederkofler, V., Salie, R., and Arber, S. (2005). Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J. Clin. Invest. 115, 2180-2186. doi: 10.1172/JCI25683
48. Oberst, M., Anders, J., Xie, B., Singh, B., Ossandon, M., Johnson, M., et al. (2001). Matriptase and HAI-1 are expressed by normal and malignant epithelial cells in vitro and in vivo. Am. J. Pathol. 158, 1301-1311. doi: 10.1016/S0002-9440(10)64081-3
49. Parr, C., Sanders, A. J., Davies, G., Martin, T., Lane, J., Mason, M. D., et al. (2007). Matriptase-2 inhibits breast tumor growth and invasion and correlates with favorable prognosis for breast cancer patients. Clin. Cancer Res. 13, 3568-3576. doi: 10.1158/1078-0432.CCR-06-2357
50. Pellegrino, R. M., Coutinho, M., D'Ascola, D., Lopes, A. M., Palmieri, A., Carnuccio, F., et al. (2012). Two novel mutations in the tmprss6 gene associated with iron-refractory iron-deficiency anaemia (irida) and partial expression in the heterozygous form. Br. J. Haematol. 158, 668-672. doi: 10.1111/j.1365-2141.2012.09198.x
51. Peng, H., Truksa, J., and Lee, P. (2010). EPO-mediated reduction in Hamp expression in vivo corrects iron deficiency anaemia in TMPRSS6 deficiency. Br. J. Haematol. 151, 106-109. doi: 10.1111/j.1365-2141.2010.08306.x
52. Pinnix, Z. K., Miller, L. D., Wang, W., D'Agostino, R. Jr., Kute, T., Willingham, M. C., et al. (2010). Ferroportin and iron regulation in breast cancer progression and prognosis. Sci. Transl. Med. 2:43ra56. doi: 10.1126/scisignal.3001127
53. Ramsay, A. J., Hooper, J. D., Folgueras, A. R., Velasco, G., and Lopez-Otin, C. (2009a). Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis. Haematologica 94, 840-849. doi: 10.3324/haematol.2008.001867
54. Ramsay, A. J., Quesada, V., Sanchez, M., Garabaya, C., Sarda, M. P., Baiget, M., et al. (2009b). Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms. Hum. Mol. Genet. 18, 3673-3683. doi: 10.1093/hmg/ddp315
55. Ramsay, A. J., Reid, J. C., Velasco, G., Quigley, J. P., and Hooper, J. D. (2008). The type II transmembrane serine protease matriptase-2-identification, structural features, enzymology, expression pattern and potential roles. Front. Biosci. 13:569-579. doi: 10.2741/2702
56. Riddick, A. C., Shukla, C. J., Pennington, C. J., Bass, R., Nuttall, R. K., Hogan, A., et al. (2005). Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues. Br. J. Cancer 92, 2171-2180. doi: 10.1038/sj.bjc.6602630
57. Sanders, A. J., Parr, C., Martin, T. A., Lane, J., Mason, M. D., and Jiang, W. G. (2008). Genetic upregulation of matriptase-2 reduces the aggressiveness of prostate cancer cells in vitro and in vivo and affects FAK and paxillin localisation. J. Cell. Physiol. 216, 780-789. doi: 10.1002/jcp.21460
58. Sanders, A. J., Webb, S. L., Parr, C., Mason, M. D., and Jiang, W. G. (2010). The type II transmembrane serine protease, matriptase-2: possible links to cancer? Anticancer Agents Med. Chem. 10, 64-69. doi: 10.2174/1871520611009010064
59. Sasaki, Y., Noguchi-Sasaki, M., Yasuno, H., Yorozu, K., and Shimonaka, Y. (2012). Erythropoietin stimulation decreases hepcidin expression through hematopoietic activity on bone marrow cells in mice. Int. J. Hematol. 96, 692-700. doi: 10.1007/s12185-012-1217-4
60. Schmidt, P. J., Toran, P. T., Giannetti, A. M., Bjorkman, P. J., and Andrews, N. C. (2008). The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 7, 205-214. doi: 10.1016/j.cmet.2007.11.016
61. Schmidt, P. J., Toudjarska, I., Sendamarai, A. K., Racie, T., Milstein, S., Bettencourt, B. R., et al. (2013). An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine beta-thalassemia intermedia. Blood 121, 1200-1208. doi: 10.1182/blood-2012-09-453977
62. Silvestri, L., Pagani, A., Nai, A., De Domenico, I., Kaplan, J., and Camaschella, C. (2008). The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 8, 502-511. doi: 10.1016/j.cmet.2008.09.012
63. Szabo, R., Hobson, J. P., List, K., Molinolo, A., Lin, C. Y., and Bugge, T. H. (2008). Potent inhibition and global co-localization implicate the transmembrane Kunitz-type serine protease inhibitor hepatocyte growth factor activator inhibitor-2 in the regulation of epithelial matriptase activity. J. Biol. Chem. 283, 29495-29504. doi: 10.1074/jbc.M801970200
64. Tanaka, T., Roy, C. N., Yao, W., Matteini, A., Semba, R. D., Arking, D., et al. (2010). A genome-wide association analysis of serum iron concentrations. Blood 115, 94-96. doi: 10.1182/blood-2009-07-232496
65. Truksa, J., Gelbart, T., Peng, H., Beutler, E., Beutler, B., and Lee, P. (2009). Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6. Br. J. Haematol. 147, 571-581. doi: 10.1111/j.1365-2141.2009.07873.x
66. Tuhkanen, H., Hartikainen, J. M., Soini, Y., Velasco, G., Sironen, R., Nykopp, T. K., et al. (2013). Matriptase-2 gene (TMPRSS6) variants associate with breast cancer survival, and reduced expression is related to triple-negative breast cancer. Int. J. Cancer 133, 2334-2340. doi: 10.1002/ijc.28254
67. Valenti, L., Fracanzani, A. L., Rametta, R., Fraquelli, M., Soverini, G., Pelusi, S., et al. (2012). Effect of the A736V TMPRSS6 polymorphism on the penetrance and clinical expression of hereditary hemochromatosis. J. Hepatol. 57, 1319-1325. doi: 10.1016/j.jhep.2012.07.041
68. Velasco, G., Cal, S., Quesada, V., Sanchez, L. M., and Lopez-Otin, C. (2002). Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins. J. Biol. Chem. 277, 37637-37646. doi: 10.1074/jbc.M203007200
69. Verga Falzacappa, M. V., Vujic Spasic, M., Kessler, R., Stolte, J., Hentze, M. W., and Muckenthaler, M. U. (2007). STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 109, 353-358. doi: 10.1182/blood-2006-07-033969
70. Wallace, D. F., Summerville, L., Lusby, P. E., and Subramaniam, V. N. (2005). First phenotypic description of transferrin receptor 2 knockout mouse, and the role of hepcidin. Gut 54, 980-986. doi: 10.1136/gut.2004.062018
71. Wang, R. H., Li, C., Xu, X., Zheng, Y., Xiao, C., Zerfas, P., et al. (2005). A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2, 399-409. doi: 10.1016/j.cmet.2005.10.010
72. Webb, S. L., Sanders, A. J., Mason, M. D., and Jiang, W. G. (2011). Type II transmembrane serine protease (TTSP) deregulation in cancer. Front. Biosci. (Landmark Ed.) 16:539-552.
73. Webb, S. L., Sanders, A. J., Mason, M. D., and Jiang, W. G. (2012). The influence of matriptase-2 on prostate cancer in vitro: a possible role for beta-catenin. Oncol. Rep. 28, 1491-1497. doi: 10.3892/or.2012.1945
74. Zhang, A. S., Anderson, S. A., Wang, J., Yang, F., Demaster, K., Ahmed, R., et al. (2011). Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein. Blood 117, 1687-1699. doi: 10.1182/blood-2010-06-287292