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The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes

Visual Abstract <img class="highwire-fragment fragment-image" alt="Figure1" src="http://www.bloodjournal.org/content/bloodjournal/130/19/2111/F1.medium.gif" width="440" height="357"/>Download figureOpen in new tabDownload powerpoint The express...

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Bibliographic Details
Main Author: Colucci, Silvia (Author)
Format: Article (Journal)
Language:English
Published: September 1, 2017
In: Blood
Year: 2017, Volume: 130, Issue: 19, Pages: 2111-2120
ISSN:1528-0020
DOI:10.1182/blood-2017-04-780692
Online Access:Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1182/blood-2017-04-780692
Verlag, kostenfrei, Volltext: http://www.bloodjournal.org/content/130/19/2111
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Author Notes:Silvia Colucci, Alessia Pagani, Mariateresa Pettinato, Irene Artuso, Antonella Nai, Clara Camaschella and Laura Silvestri
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Summary:Visual Abstract <img class="highwire-fragment fragment-image" alt="Figure1" src="http://www.bloodjournal.org/content/bloodjournal/130/19/2111/F1.medium.gif" width="440" height="357"/>Download figureOpen in new tabDownload powerpoint The expression of the key regulator of iron homeostasis hepcidin is activated by the BMP-SMAD pathway in response to iron and inflammation and among drugs, by rapamycin, which inhibits mTOR in complex with the immunophilin FKBP12. FKBP12 interacts with BMP type I receptors to avoid uncontrolled signaling. By pharmacologic and genetic studies, we identify FKBP12 as a novel hepcidin regulator. Sequestration of FKBP12 by rapamycin or tacrolimus activates hepcidin both in vitro and in murine hepatocytes. Acute tacrolimus treatment transiently increases hepcidin in wild-type mice. FKBP12 preferentially targets the BMP receptor ALK2. ALK2 mutants defective in binding FKBP12 increase hepcidin expression in a ligand-independent manner, through BMP-SMAD signaling. ALK2 free of FKBP12 becomes responsive to the noncanonical inflammatory ligand Activin A. Our results identify a novel hepcidin regulator and a potential therapeutic target to increase defective BMP signaling in disorders of low hepcidin.
Item Description:Gesehen am 17.08.2018
Physical Description:Online Resource
ISSN:1528-0020
DOI:10.1182/blood-2017-04-780692

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