The immunophilin FKBP12: a molecular guardian of the TGF-beta family type I receptors.
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-beta 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-beta family morphogens. This aspect of FKBP12 function may be critical for cellular responsiveness to morphogenetic gradients of the TGF-beta family members during early development, serving to assure the translation of different ligand concentrations into different signaling readouts.
Wang
Tongwen
T
The Benaroya Research Institute at Virginia Mason, 1201 9th Avenue, Seattle, WA 98101, USA. wangt@vmresearch.org
Donahoe
Patricia K
PK
D000818:Animals; D015220:Calcium Channels / Q000737:chemistry; D005544:Forecasting; D006801:Humans; D020104:Immunophilins / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D022061:Tacrolimus Binding Protein 1A / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015220:Calcium Channels; D018942:Macrolides; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D022061:Tacrolimus Binding Protein 1A; D020104:Immunophilins