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Endoglin differentially modulates antagonistic transforming growth factor-beta1 and BMP-7 signaling.

Abstract
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.
AuthorsOlaf Scherner, Steffen K Meurer, Lidia Tihaa, Axel M Gressner, Ralf Weiskirchen
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 19 Pg. 13934-43 (May 11 2007) ISSN: 0021-9258 [Print] United States
PMID17376778 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • BMP7 protein, human
  • Bmp7 protein, rat
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins
  • Collagen Type I
  • Endoglin
  • Eng protein, rat
  • Idb1 protein, mouse
  • Inhibitor of Differentiation Protein 1
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Transforming Growth Factor beta
  • Smad1 Protein
  • Smad1 protein, rat
  • Smad2 Protein
  • Smad2 protein, rat
  • Smad5 Protein
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Luciferases
  • Protein Serine-Threonine Kinases
  • ACVRL1 protein, human
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse
  • Tgfbr1 protein, rat
Topics
  • Activin Receptors, Type I (metabolism)
  • Activin Receptors, Type II (metabolism)
  • Animals
  • Blotting, Western
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins (metabolism)
  • COS Cells
  • Cell Differentiation
  • Cells, Cultured
  • Chlorocebus aethiops
  • Collagen Type I (metabolism)
  • Endoglin
  • Humans
  • Immunoprecipitation
  • Inhibitor of Differentiation Protein 1 (metabolism)
  • Intracellular Signaling Peptides and Proteins (pharmacology)
  • Liver (cytology, metabolism)
  • Luciferases
  • Mice
  • Myoblasts (cytology, metabolism)
  • Phosphorylation
  • Protein Serine-Threonine Kinases
  • Rats
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta (metabolism)
  • Signal Transduction
  • Smad1 Protein (metabolism)
  • Smad2 Protein (metabolism)
  • Smad5 Protein (metabolism)
  • Transforming Growth Factor beta (metabolism)
  • Transforming Growth Factor beta1 (antagonists & inhibitors, metabolism)

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