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

ABSTRACT

TGF-ß (transforming growth factor ß) 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 TßRI is a key step for their activation. It has been reported that the serine/threonine kinase PAK2 (p21-activated kinase 2) can mediate TGF-ß signaling in mesenchymal cells. Here, we report that PAK2 restricts TGF-ß-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 TßRI-R-Smad association. Consistently, substitution of Ser-417 with glutamic acid attenuates the interaction of Smad2 with TßRI. Together, our results indicate that PAK2 negatively modulate TGF-ß signaling by attenuating the receptor-Smad interaction and thus Smad activation.