TMPRSS6-mediated regulation of iron via cleavage of components of the bone morphogenetic protein signaling pathway in liver and bone

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The regulation of iron is crucial for liver and bone homeostasis. The transmembrane serine protease 6 (TMPRSS6) interacts with multiple components of the bone morphogenetic protein (BMP) signaling pathway including the BMP type I receptors ALK2 and ALK3, and thereby reduces the expression of the iron regulatory hormone hepcidin. Physiologically, hepcidin binds to and inactivates the iron exporter ferroportin if serum iron levels have reached sufficient levels. The loss of function mutation in TMPRSS6 causes iron-resistant-iron deficient anemia due to inappropriately high hepcidin levels. Even though aspects of TMPRSS6 binding and function in systemic iron homeostasis and liver regulation have been investigated, a detailed understanding of this regulatory system is elusive. The overall aim of this project is to investigate in depth signaling mechanisms and binding of TMPRSS6. Therefore, we will focus on the three main goals: 1) in silico-modeling of TMPRSS6 interactions with BMP receptors and the iron regulatory proteins Hfe, Hjv, Tfr1 and Tfr2, 2) investigation of TMPRSS6 interactions with components of the BMP signaling pathway and other iron regulatory proteins in vivo in mouse models, and 3) assessing the importance of TMPRSS6 in bone cells. In addition, we will investigate whether changes of systemic iron homeostasis impair the signaling mechanisms, which contributing factors occur, and how activation or blockage affects binding and receptor formation. This proposal will unravel mechanisms of TMPRSS6 actions in liver, iron sensing, and bone.