Inhibition of type III TGF-β receptor aggravates lung fibrotic process.
Transforming growth factor-beta (TGF-β) is a multifunctional cytokine that regulates cell proliferation, death, development or differentiation. In addition, TGF-β is considered a key mediator in fibrogenic processes, and signals either directly or indirectly through types I, II and III (TβRI, II, and III) receptor complexes. The type III TGF-β (TβRIII or betaglycan) is a transmembrane proteoglycan without a functional kinase domain, and is considered as a coreceptor to increase the affinity of ligand binding to TβRII. Little is studied on TGF-β and TβRIII (or betaglycan) signaling, while it is well known about TGF-β ligand and TβRII signaling. In this study, we investigated the effects of TβRIII expression on TGF-β induced differentiation, in view of the finding that TβRIII is significantly downregulated during TGF-β-induced differentiation in fibroblasts. TGF-beta induced alpha-SMA and Procollagen Type I expression were markedly inhibited in fibroblasts stably expressing TβRIII. Endogenous TβRIII expression did not alter the TβRI or TβRII levels, but inhibited Smad 2/3, Akt and ERK phosphorylation. The molecular mechanism of TβRIII action in TGF-β-induced differentiation is associated with both Smad-dependent and Smad-independent pathways. Our results suggest that TβRIII is a novel molecular target for regulation of TGF-β signaling in myofibroblast differentiation.
Ahn
Ji-Yeon
JY
Laboratory of Radiation Sensitization & Protection, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
Park
Sarah
S
Yun
Yeon-Sook
YS
Song
Jie-Young
JY
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D008168:Lung; D051379:Mice; D058628:Myofibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D041681:NIH 3T3 Cells; D011509:Proteoglycans / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
D024042:Collagen Type I; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C071736:betaglycan