Retinoids regulate TGFβ signaling at the level of Smad2 phosphorylation and nuclear accumulation

Indirect regulation of transforming growth factor (TGF)-beta signaling by retinoids Occurs on a long-term timescale, secondary to transcriptional events. Studies by our group show loss of retinoid X receptor (RXR) alpha results in increased TGF beta in the midgestational heart, which may play a role in the cardiac defects seen in this model [S.W. Kubalak, D.R. Hutson, K.K. Scott and R.A. Shannon, Elevated transforming growth factor beta2 enhances apoptosis and contributes to abnormal outflow tract and aortic sac development in retinoic X receptor alpha knockout embryos, Development 129 (2002) 733-746.]. Acute and direct interactions between retinoid and TGF beta signaling, however, are not clearly understood. Treatment of dispersed hearts and NIH3T3 cells for 1 h with TGF beta and retinoids (dual treatment) resulted in increased phosphorylated Smad2 and Smad3 when compared to treatment with TGF beta alone. Of all dual treatments, those with the RXR agonist Bexarotene, resulted in the highest level of phosphorylated Smad2, a 7-fold increase over TGF beta alone. Additionally, during dual treatment phosphorylation of Smad2 occurs via the TGF beta type 1 receptor but not by increased activation of the receptor. As loss of RXR alpha results in increased levels of Smad2 phosphorylation in response to TGF beta treatment and since nuclear accumulation of phosphorylated Smad2 is decreased during dual treatment, we Propose that RXR alpha directly regulates the activities of Smad2. These data show retinoid signaling influences the TGF beta pathway in all acute and direct manner that has been unappreciated until now. (C) 2008 Elsevier B.V. All rights reserved.