Akt kinase targets association of CBP with SMAD 3 to regulate TGFβ-induced expression of plasminogen activator inhibitor-1

✍ Scribed by Falguni Das; Nandini Ghosh-Choudhury; Balachandar Venkatesan; Xiaonan Li; Lenin Mahimainathan; Goutam Ghosh Choudhury

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 766 KB
• Volume: 214
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21236

✦ Synopsis

Abstract

Transforming growth factor‐β (TGFβ) controls expression of plasminogen activator inhibitor type 1 (PAI‐1), which regulates degradation of extracellular matrix proteins in fibrotic diseases. The TGFβ receptor‐specific Smad 3 has been implicated in the PAI‐1 expression. The mechanism by which non‐Smad signaling contributes to this process is not known. We studied the cross‐talk between Smad 3 and PI 3 kinase/Akt signaling in TGFβ‐induced PAI‐1 expression in renal mesangial cells. Inhibition of PI 3 kinase and Akt kinase blocked TGFβ‐ and Smad 3‐mediated expression of PAI‐1. In contrast, constitutively active PI 3 kinase and Akt kinase increased PAI‐1 expression, similar to TGFβ. Inhibition of PI 3 kinase and Akt kinase had no effect on TGFβ‐induced Smad 3 phosphorylation and its translocation to the nucleus. Notably, inhibition of PI 3 kinase‐dependent Akt kinase abrogated TGFβ‐induced PAI‐1 transcription, without affecting binding of Smad 3 to the PAI‐1 Smad binding DNA element. However, PI 3 kinase inhibition and dominant negative Akt kinase antagonized the association of the transcriptional coactivator CBP with Smad 3 in response to TGFβ, resulting in inhibition of Smad 3 acetylation. Together our findings identify TGFβ‐induced PI 3 kinase/Akt signaling as a critical regulator of Smad 3‐CBP interaction and Smad 3 acetylation, which cause increased PAI‐1 expression. J. Cell. Physiol. 214: 513–527, 2008. © 2007 Wiley‐Liss, Inc.