p21-Activated kinase 2 (PAK2) inhibits TGF-β signaling in Madin-Darby canine kidney (MDCK) epithelial cells by interfering with the receptor-Smad interaction

J Biol Chem. 2012 Apr 20;287(17):13705-12. doi: 10.1074/jbc.M112.346221. Epub 2012 Mar 5.


TGF-β (transforming growth factor β) plays a variety of cellular functions mainly through the Smad pathway. Phosphorylation of the carboxyl SXS motif in R-Smads (Smad2 and Smad3) by the type I receptor TβRI is a key step for their activation. It has been reported that the serine/threonine kinase PAK2 (p21-activated kinase 2) can mediate TGF-β signaling in mesenchymal cells. Here, we report that PAK2 restricts TGF-β-induced Smad2/3 activation and transcriptional responsiveness in MDCK epithelial cells. Mechanistically, PAK2 associates with Smad2 and Smad3 in a kinase activity-dependent manner and blocks their activation. PAK2 phosphorylates Smad2 at Ser-417, which is adjacent to the L3 loop that contributes to the TβRI-R-Smad association. Consistently, substitution of Ser-417 with glutamic acid attenuates the interaction of Smad2 with TβRI. Together, our results indicate that PAK2 negatively modulate TGF-β signaling by attenuating the receptor-Smad interaction and thus Smad activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dogs
  • Epithelial Cells / cytology*
  • HEK293 Cells
  • Humans
  • Mice
  • Models, Biological
  • NIH 3T3 Cells
  • Phosphorylation
  • Serine / chemistry
  • Signal Transduction
  • Smad Proteins / metabolism*
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / metabolism*
  • p21-Activated Kinases / metabolism*


  • Smad Proteins
  • Transcription Factors
  • Transforming Growth Factor beta
  • Serine
  • p21-Activated Kinases