Abstract
Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that signals to the nucleus through cell surface transmembrane receptors with serine/threonine kinase activity and cytoplasmic effectors, including Smad proteins. Here we describe two novel modulators of this pathway, lipoprotein-receptor related protein (LRP-1) and decorin. Decorin null (Dcn null) myoblasts showed a diminished TGF-beta response that is restored by decorin re-expression. Importantly, this reactivation occurs without changes in the binding to TGF-beta receptors, Smad protein phosphorylation, or Smad-4 nuclear translocation. In wild type myoblasts, inhibition of decorin binding to LRP-1 and depletion of LRP-1 inhibited TGF-beta response to levels similar to those observed in Dcn null myoblasts. Re-expression of decorin in Dcn null myoblasts cannot restore TGF-beta response if the Smad pathway or phosphatidylinositol 3-kinase activity is inhibited, suggesting that this LRP-1-decorin modulatory pathway requires activation of the Smad pathway by TGF-beta and involves phosphatidylinositol 3-kinase activity. This work unveils a new regulatory mechanism for TGF-beta signaling by decorin and LRP-1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Chromones / pharmacology
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Decorin
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Enzyme Inhibitors / pharmacology
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / metabolism*
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Low Density Lipoprotein Receptor-Related Protein-1
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Mice
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Morpholines / pharmacology
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Muscle, Skeletal / cytology
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Muscle, Skeletal / metabolism*
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Myoblasts / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Proteoglycans / genetics
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Proteoglycans / metabolism*
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RNA, Small Interfering
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Receptors, LDL / genetics
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Receptors, LDL / metabolism*
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Signal Transduction / physiology*
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Smad4 Protein / metabolism
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Transfection
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Chromones
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Dcn protein, mouse
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Decorin
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Enzyme Inhibitors
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Extracellular Matrix Proteins
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Low Density Lipoprotein Receptor-Related Protein-1
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Lrp1 protein, mouse
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Proteoglycans
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RNA, Small Interfering
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Receptors, LDL
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Smad4 Protein
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Smad4 protein, mouse
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Transforming Growth Factor beta
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Tumor Suppressor Proteins
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one