Abstract
FKBP12, a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin, is ubiquitously expressed and interacts with proteins in several intracellular signal transduction systems. Although FKBP12 interacts with the cytoplasmic domains of type I receptors of the transforming growth factor-beta (TGF-beta) superfamily in vitro, the function of FKBP12 in TGF-beta superfamily signalling is controversial. FKBP12 also physically interacts stoichiometrically with multiple intracellular calcium release channels including the tetrameric skeletal muscle ryanodine receptor (RyR1). In contrast, the cardiac ryanodine receptor, RyR2, appears to bind selectively the FKBP12 homologue, FKBP12.6. To define the functions of FKBP12 in vivo, we generated mutant mice deficient in FKBP12 using embryonic stem (ES) cell technology. FKBP12-deficient mice have normal skeletal muscle but have severe dilated cardiomyopathy and ventricular septal defects that mimic a human congenital heart disorder, noncompaction of left ventricular myocardium. About 9% of the mutants exhibit exencephaly secondary to a defect in neural tube closure. Physiological studies demonstrate that FKBP12 is dispensable for TGF-beta-mediated signalling, but modulates the calcium release activity of both skeletal and cardiac ryanodine receptors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abnormalities, Multiple / embryology
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Abnormalities, Multiple / etiology
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Abnormalities, Multiple / genetics
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Activins
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Amino Acid Isomerases / deficiency
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Amino Acid Isomerases / genetics
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Amino Acid Isomerases / physiology*
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Animals
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Brain / abnormalities
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Brain / embryology
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Cardiomyopathy, Dilated / embryology
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Cardiomyopathy, Dilated / etiology
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Cardiomyopathy, Dilated / genetics
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Female
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Fetal Death
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Gene Deletion
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Heart Defects, Congenital / embryology
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Heart Defects, Congenital / etiology*
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Heart Defects, Congenital / genetics
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Heart Septal Defects / embryology
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Heart Septal Defects / etiology
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Heart Septal Defects / genetics
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / physiology*
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Inhibins / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Muscle, Skeletal / metabolism
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Ryanodine Receptor Calcium Release Channel / metabolism*
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Signal Transduction
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Tacrolimus Binding Proteins
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Transforming Growth Factor beta / metabolism
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Heat-Shock Proteins
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Ryanodine Receptor Calcium Release Channel
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Transforming Growth Factor beta
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Activins
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Inhibins
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Amino Acid Isomerases
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Tacrolimus Binding Proteins