Itch E3 ligase-mediated regulation of TGF-beta signaling by modulating smad2 phosphorylation.
Protein ubiquitination has been implicated in the intracellular biochemical events transduced by TGF-beta receptor via different mechanisms including the degradation of Smads or their binding proteins. Here we show that loss of Itch E3 ligase in mouse embryonic fibroblasts (MEFs) results in reduced susceptibility of TGF-beta-induced cell growth arrest and decreased phosphorylation of Smad2, without apparent alteration in protein levels for Smad2, Smad4, and Smad7 in Itch-/- MEFs. Itch promotes ubiquitination of Smad2 and augments Smad2 phosphorylation that requires an intact ligase activity of Itch. Moreover, Itch facilitates complex formation between TGF-beta receptor and Smad2 and enhances TGF-beta-induced transcription. This study reveals a previously unrecognized positive TGF-beta signaling pathway via proteolysis-independent ubiquitination.
Bai
Yongli
Y
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Yang
Chun
C
Hu
Kathrin
K
Elly
Chris
C
Liu
Yun-Cai
YC
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005333:Fetus; D005347:Fibroblasts / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases