Regulation of ALK-1 signaling by the nuclear receptor LXRbeta.
The transforming growth factor beta (TGF-beta) receptor, ALK-1, is expressed specifically on endothelial cells and is essential for angiogenesis, as demonstrated by its targeted deletion in mice and its mutation in the human disease hereditary hemorrhagic telangiectasia. Although ALK-1 and another endothelial-specific TGF-beta receptor, endoglin, both bind TGF-beta with identical ... isoform specificity and form a complex together, neither has been shown to signal in response to TGF-beta, and the mechanism by which these receptors signal in endothelial cells remains unknown. Here we report the identification of the nuclear receptor liver X receptor beta (LXRbeta) as a modulator/mediator of ALK-1 signaling. The cytoplasmic domain of ALK-1 specifically binds to LXRbeta in vitro and in vivo. Expression of activated ALK-1 results in translocation of LXRbeta from the nuclear compartment to the cytoplasmic compartment. The interaction of activated ALK-1 with LXRbeta in the cytoplasmic compartment results in the specific phosphorylation of LXRbeta by ALK-1, primarily on serine residues. LXRbeta subsequently modulates signaling by ALK-1 and the closely related TGF-beta receptor, ALK-2, as demonstrated by specific and potent inhibition of ALK-1- and ALK-2-mediated transcriptional responses, establishing LXRbeta as a potential modulator/mediator of ALK-1/ALK-2 signaling.
Mesh Terms:
Activin Receptors, Type I, Activin Receptors, Type II, Amino Acid Sequence, Amino Acids, Animals, Binding Sites, COS Cells, Cell Line, Cercopithecus aethiops, DNA-Binding Proteins, Female, Gene Library, Humans, Lung, Male, Molecular Sequence Data, Organ Specificity, Orphan Nuclear Receptors, Phosphorylation, Protein Transport, Receptors, Cytoplasmic and Nuclear, Recombinant Proteins, Saccharomyces cerevisiae, Signal Transduction, Transfection
Activin Receptors, Type I, Activin Receptors, Type II, Amino Acid Sequence, Amino Acids, Animals, Binding Sites, COS Cells, Cell Line, Cercopithecus aethiops, DNA-Binding Proteins, Female, Gene Library, Humans, Lung, Male, Molecular Sequence Data, Organ Specificity, Orphan Nuclear Receptors, Phosphorylation, Protein Transport, Receptors, Cytoplasmic and Nuclear, Recombinant Proteins, Saccharomyces cerevisiae, Signal Transduction, Transfection
J. Biol. Chem.
Date: Dec. 27, 2002
PubMed ID: 12393874
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