title: TbetaRI/Alk5-independent TbetaRII signaling to ERK1/2 in human skin cells according to distinct levels of TbetaRII expression.
abstract: TGFβ binding to the TGFβ receptor (TβR) activates R-Smad-dependent pathways, such as Smad2/3, and R-Smad-independent pathways, such as ERK1/2. The mechanism of the TGFβ-TβRII-TβRI-Smad2/3 pathway is established; however, it is not known how TGFβ activates ERK1/2. We show here that although TGFβ equally activated Smad2/3 in all cells, it selectively activated ERK1/2 in dermal cells and inhibited ERK1/2 in epidermal cells. These opposite effects correlated with the distinct expression levels of TβRII, which are 7- to 18-fold higher in dermal cells than in epidermal cells. Reduction of TβRII expression in dermal cells abolished TGFβ-stimulated ERK1/2 activation. Upregulation of TβRII expression in epidermal cells to a similar level as that in dermal cells switched TGFβ-induced ERK1/2 inhibition to ERK1/2 activation. More intriguingly, in contrast to the equal importance of TβRII in mediating TGFβ signaling to both Smad2/3 and ERK1/2, knockdown of TβRI/Alk5 blocked activation of only Smad2/3, not ERK1/2, in dermal cells. Similarly, expression of the constitutively activated TβRI-TD kinase activated only Smad2/3 and not ERK1/2 in epidermal cells. This study provides an explanation for why TGFβ selectively activates ERK1/2 in certain cell types and direct evidence for TβRI-independent TβRII signaling to a R-Smad-independent pathway.
authors.affiliation: The Department of Dermatology and the USC-Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Balaji
authors.initials: B
authors.lastname: Bandyopadhyay
authors.forename: Arum
authors.initials: A
authors.lastname: Han
authors.forename: Jinyao
authors.initials: J
authors.lastname: Dai
authors.forename: Jianhua
authors.initials: J
authors.lastname: Fan
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.forename: David T
authors.initials: DT
authors.lastname: Woodley
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human