Akt kinase targets association of CBP with SMAD 3 to regulate TGFbeta-induced expression of plasminogen activator inhibitor-1.
Transforming growth factor-beta (TGFbeta) controls expression of plasminogen activator inhibitor type 1 (PAI-1), which regulates degradation of extracellular matrix proteins in fibrotic diseases. The TGFbeta 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 TGFbeta-induced PAI-1 expression in renal mesangial cells. Inhibition of PI 3 kinase and Akt kinase blocked TGFbeta- and Smad 3-mediated expression of PAI-1. In contrast, constitutively active PI 3 kinase and Akt kinase increased PAI-1 expression, similar to TGFbeta. Inhibition of PI 3 kinase and Akt kinase had no effect on TGFbeta-induced Smad 3 phosphorylation and its translocation to the nucleus. Notably, inhibition of PI 3 kinase-dependent Akt kinase abrogated TGFbeta-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 TGFbeta, resulting in inhibition of Smad 3 acetylation. Together our findings identify TGFbeta-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.
Department of Medicine, University of Texas Health Science Center at San Antonio, Texas, USA.
Falguni
F
Das
Nandini
N
Ghosh-Choudhury
Balachandar
B
Venkatesan
Xiaonan
X
Li
Lenin
L
Mahimainathan
Goutam Ghosh
GG
Choudhury
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D002232:Carbocyanines; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D005786:Gene Expression Regulation / Q000235:genetics; D007678:Kidney Glomerulus / Q000166:cytology; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011233:Precipitin Tests; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000378:metabolism*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D050882:CREB-Binding Protein; D002232:Carbocyanines; D002867:Chromones; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D051057:Proto-Oncogene Proteins c-akt; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C089187:cyanine dye 3; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494920:Akt1 protein, rat