A Novel Modulatory Mechanism of Transforming Growth Factor-β 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.