title: The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways.
abstract: Bone morphogenetic proteins (BMPs) are multifunctional proteins regulating cell growth, differentiation, and apoptosis. BMP-2 signals via two types of receptors (BRI and BRII) that are expressed at the cell surface as homomeric as well as heteromeric complexes. Prior to ligand binding, a low but measurable level of BMP-receptors is found in preformed hetero-oligomeric complexes. The major fraction of the receptors is recruited into hetero-oligomeric complexes only after ligand addition. For this, BMP-2 binds first to the high affinity receptor BRI and then recruits BRII into the signaling complex. However, ligand binding to the preformed complex composed of BRII and BRI is still required for signaling, suggesting that it may mediate activating conformational changes. Using several approaches we have addressed the following questions: (i) Are preformed complexes incompetent of signaling in the absence of BMP-2? (ii) Which domains of the BRII receptors are essential for this complex formation? (iii) Are there differences in signals sent from BMP-induced versus preformed receptor complexes? By measuring the activation of Smads, of p38 MAPK and of alkaline phosphatase, we show that the ability of kinase-deficient BRII receptor mutants to inhibit BMP signaling depends on their ability to form heteromeric complexes with BRI. Importantly, a BRII mutant that is incapable in forming preassembled receptor complexes but recruits into a BMP-induced receptor complex does not interfere with the Smad pathway but does inhibit the induction of alkaline phosphatase as well as p38 phosphorylation. These results indicate that signals induced by binding of BMP-2 to preformed receptor complexes activate the Smad pathway, whereas BMP-2-induced recruitment of receptors activates a different, Smad-independent pathway resulting in the induction of alkaline phosphatase activity via p38 MAPK.
authors.affiliation: Department of Physiological Chemistry, Biocenter, University of Würzburg, 97074 Würzburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Nohe
authors.forename: Sylke
authors.initials: S
authors.lastname: Hassel
authors.forename: Marcelo
authors.initials: M
authors.lastname: Ehrlich
authors.forename: Florian
authors.initials: F
authors.lastname: Neubauer
authors.forename: Walter
authors.initials: W
authors.lastname: Sebald
authors.forename: Yoav I
authors.initials: YI
authors.lastname: Henis
authors.forename: Petra
authors.initials: P
authors.lastname: Knaus
mesh_terms: D016475:3T3 Cells; D000469:Alkaline Phosphatase / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism*; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins; D051902:Smad5 Protein; D051904:Smad8 Protein; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D008024:Ligands; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; C497797:SMAD5 protein, human; C107514:SMAD9 protein, human; D051785:Smad Proteins; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D052004:Bone Morphogenetic Protein Receptors; D000469:Alkaline Phosphatase