Endoglin differentially modulates antagonistic transforming growth factor-beta1 and BMP-7 signaling.
Transforming growth factor-beta1 (TGF-beta1) and BMP-7 (bone morphogenetic protein-7; OP-1) play central, antagonistic roles in kidney fibrosis, a setting in which the expression of endoglin (CD105), an accessory TGF-beta type III receptor, is increased. So far, endoglin is known as a negative regulator of TGF-beta/ALK-5 signaling. Here we analyzed the effect of BMP-7 on TGF-beta1 signaling and the role of endoglin for both pathways in endoglin-deficient L(6)E(9) cells. In this myoblastic cell line, TGF-beta1 and BMPs are opposing cytokines, interfering with myogenic differentiation. Both induce specific target genes of which Id1 (for BMPs) and collagen I (for TGF-beta1) are two examples. TGF-beta1 activated two distinct type I receptors, ALK-5 and ALK-1, in these cells. Although the ALK-5/Smad3 signaling pathway mediated collagen I expression, ALK-1/Smad1/Smad5 signaling mediated a transient Id1 up-regulation. In contrast, BMP-7 exclusively activated Smad1/Smad5 resulting in a more prolonged Id1 expression. Although BMP-7 had no impact on collagen I abundance, it antagonized TGF-beta1-induced collagen I expression and (CAGA)(12)-MLP-Luc activity, effects that are mediated by the ALK-5/Smad3 pathway. Finally, we found that the transient overexpression of endoglin, previously shown to inhibit TGF-beta1-induced ALK-5/Smad3 signaling, enhanced the BMP-7/Smad1/Smad5 pathway.
Scherner
Olaf
O
Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital, Aachen, Germany.
Meurer
Steffen K
SK
Tihaa
Lidia
L
Gressner
Axel M
AM
Weiskirchen
Ralf
R
D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D019556:COS Cells; D002454:Cell Differentiation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D024042:Collagen Type I / Q000378:metabolism; D000071063:Endoglin; D006801:Humans; D047468:Immunoprecipitation; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008156:Luciferases; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
C525819:BMP7 protein, human; C525821:Bmp7 protein, rat; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D024042:Collagen Type I; D000071063:Endoglin; C501740:Eng protein, rat; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta; D051898:Smad1 Protein; C497400:Smad1 protein, rat; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051902:Smad5 Protein; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; C000625843:Tgfbr1 protein, rat