title: p21-Activated kinase 2 (PAK2) inhibits TGF-β signaling in Madin-Darby canine kidney (MDCK) epithelial cells by interfering with the receptor-Smad interaction.
abstract: 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.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. yanxiaohua@tsinghua.org.cn
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Yan
authors.forename: Junyu
authors.initials: J
authors.lastname: Zhang
authors.forename: Qinyu
authors.initials: Q
authors.lastname: Sun
authors.forename: Polygena T
authors.initials: PT
authors.lastname: Tuazon
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wu
authors.forename: Jolinda A
authors.initials: JA
authors.lastname: Traugh
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
mesh_terms: D000818:Animals; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D051785:Smad Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D012694:Serine; D054462:p21-Activated Kinases