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J. Biol. Chem., Vol. 277, Issue 7, 5330-5338, February 15, 2002
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From the 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.
Department of Physiological Chemistry,
Biocenter, University of Würzburg, 97074 Würzburg,
Germany and the Department of Neurobiochemistry, The George
S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv
69978, Israel
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E. Wiater and W. Vale Inhibin Is an Antagonist of Bone Morphogenetic Protein Signaling J. Biol. Chem., February 28, 2003; 278(10): 7934 - 7941. [Abstract] [Full Text] [PDF]
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R. K. Moore, F. Otsuka, and S. Shimasaki Molecular Basis of Bone Morphogenetic Protein-15 Signaling in Granulosa Cells J. Biol. Chem., January 3, 2003; 278(1): 304 - 310. [Abstract] [Full Text] [PDF]
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