IMR Press / FBL / Volume 9 / Issue 1 / DOI: 10.2741/1095

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on as a courtesy and upon agreement with Frontiers in Bioscience.


The immunophilin FKBP12: a molecular guardian of the TGF-β family type I receptors

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1 The Benaroya Research Institute at Virginia Mason, 1201 9th Avenue, Seattle, WA 98101, Department of Immunology, University of Washington, Seattle, WA
2 The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
Academic Editor:Di Chen
Front. Biosci. (Landmark Ed) 2004, 9(1), 619–631;
Published: 1 January 2004
(This article belongs to the Special Issue TGFbeta,BMP receptor signaling)

FKBP12 as an immunophilin that binds to two well-known immunosuppressive macrolides, FK506 and rapamycin, has attracted immense attention and its role in mediating the immunosuppressive functions of these macrolides has been extensively studied. Since FKBP12 is a well-conserved protein among many species and is also highly expressed in almost all cells, it must play important roles in cellular function in the absence of macrolides. In one such a role, FKBP12 interacts with and regulates the functional state of the ryanodine Ca2+ channel receptor by altering protein conformation and coordinating multi-protein complex formation. This review summarizes another physiological role of FKBP12 as an interactor and a regulator of the type I serine/threonine kinase receptors of TGF-β superfamily. Current data, derived from detailed biochemical studies as well as from functional studies in various systems, suggest that FKBP12 functions as a "guardian" for the type I receptors to prevent them from leaky signaling under sub-optimal ligand concentrations, thereby providing a molecular "gradient reader" for TGF-β family morphogens. This aspect of FKBP12 function may be critical for cellular responsiveness to morphogenetic gradients of the TGF-β family members during early development, serving to assure the translation of different ligand concentrations into different signaling readouts.

Type I receptor
Type II receptor
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