Abstract
Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine signaling to the nucleus through cell surface transmembrane receptor serine/threonine kinases and cytoplasmic effectors, including Smad proteins. We describe a novel modulator of this pathway, TLP (TRAP-1-like protein), which is 25% identical to the previously described Smad4 chaperone, TRAP-1, and shows identical expression patterns in human tissues. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling. Overexpression of TLP represses the ability of TGF-beta to induce transcription from SBE-Luc, a Smad3/4-specific reporter, while it potentiates transcription from ARE-Luc, a Smad2/4-specific reporter. Consistent with this, TLP inhibits the formation of Smad3/4 complexes in the absence of effects on phosphorylation of Smad3, while it affects neither Smad2 phosphorylation nor hetero-oligomerization. We propose that TLP might regulate the balance of Smad2 and Smad3 signaling by localizing Smad4 intracellularly, thus contributing to cellular specificity of TGF-beta transcriptional responses in both normal and pathophysiology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activins / metabolism
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Amino Acid Sequence
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Animals
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Autophagy-Related Proteins
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COS Cells
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Cloning, Molecular
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DNA, Complementary / genetics
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DNA-Binding Proteins / metabolism*
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Endocytosis
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Humans
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Intracellular Signaling Peptides and Proteins*
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Kinetics
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Membrane Proteins*
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Models, Biological
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Molecular Sequence Data
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Phosphorylation
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Protein Structure, Tertiary
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sequence Homology, Amino Acid
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Signal Transduction
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Smad2 Protein
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Smad3 Protein
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Smad4 Protein
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Trans-Activators / metabolism*
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transfection
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Transforming Growth Factor beta / metabolism*
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Vesicular Transport Proteins
Substances
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Autophagy-Related Proteins
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Carrier Proteins
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DNA, Complementary
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Recombinant Proteins
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SMAD2 protein, human
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SMAD3 protein, human
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SMAD4 protein, human
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Smad2 Protein
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Smad3 Protein
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Smad4 Protein
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TGFBRAP1 protein, human
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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VPS39 protein, human
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Vesicular Transport Proteins
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Activins