A novel modulatory mechanism of transforming growth factor-beta signaling through decorin and LRP-1.
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.
Cabello-Verrugio
Claudio
C
Centro de Regulación Celular y Patología, Departamento de Biología Celular y Molecular, Facultad Millennium Institute for Fundamental and Applied Biology (MIFAB), Pontificia Universidad Católica de Chile, Casilla 114-D Santiago, Chile.
Brandan
Enrique
E
D000818:Animals; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D058575:Decorin; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051901:Smad4 Protein / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D002867:Chromones; D058575:Decorin; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011509:Proteoglycans; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C546879:Dcn protein, mouse; C486645:Lrp1 protein, mouse; C490810:Smad4 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one