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The Journal of Bone and Joint Surgery (American) 85:44-51 (2003)
© 2003 The Journal of Bone and Joint Surgery, Inc.

Basic Science

Initiation of Smad-Dependent and Smad-Independent Signaling via Distinct BMP-Receptor Complexes

Sylke Hassel, Dipl.Bio, Simone Schmitt, Anke Hartung, Dipl.Bio, Martin Roth, PhD, Anja Nohe, PhD, Nils Petersen, PhD, Marcelo Ehrlich, Dipl.Bio, Yoav I. Henis, PhD, Walter Sebald, PhD and Petra Knaus, PhD

Corresponding author: Petra Knaus, PhD
Biocenter, Physiological Chemistry II, University of Würzburg, 97074 Würzburg Germany. E-mail address: pknaus{at}biozentrum.uni-wuerzburg.de

In support of their research or preparation of this manuscript, P. Knaus received a grant from the Deutsche Forschungsgemeinschaft (DFG) (DFG Kn 332/8-1) and Y.I. Henis received Grant 414/01 from the Israel Science Foundation. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Abstract

Background: BMP-2 (bone morphogenetic protein-2) signals via two types of transmembrane serine/threonine kinase receptors (BRI and BRII), which form heteromeric complexes prior to and after ligand binding. Within a BMP-bound receptor complex, BRII transphosphorylates and activates BRI-a for further signaling. We investigated which signaling pathway is initiated by BMP-2 via preformed receptor complexes versus BMP-2-induced signaling receptor complexes.

Methods: Immunofluorescence co-patching was used to study the oligomerization of receptors at the surface of live cells. Binding and chemical cross-linking of iodinated BMP-2 followed by immunoprecipitation was used to show association of receptors in the presence of ligand. Western blots with use of anti-phospho-Smad1 antibodies and reporter gene assays with use of SBE-lux were employed to show activation of the Smad pathway. Phosphorylation of p38-MAPK was shown by Western blots. Induction of alkaline phosphatase was determined by staining the cells. The cluster density of receptors was determined with use of image correlation spectroscopy.

Results and Conclusion: We showed that the Smad pathway is induced by preformed receptor complexes, whereas BMP-2-induced signaling complexes result in the activation of p38-MAPK. We also found evidence that the clustering of BRI-a at the membrane is altered in the presence of BRII, suggesting that it associates with existing clusters of BRII to initiate efficient Smad signaling. These data clearly demonstrate that it is critical to fully understand receptor oligomerization in order to estimate signaling outcome for distinct receptor and ligand mutants.

Clinical Relevance: The development of BMP-2 antagonists is of special importance for a number of human disorders caused by several members of the BMP/TGF-ß (transforming growth factor-beta) superfamily. Since manipulation of BMP-signaling is complex, it is important to understand what influence it might have during the initiation of signaling—:i.e., the oligomerization of BMP receptors to form a signaling receptor complex. There might be cases where either the Smad or the p38 pathway should be targeted.


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