A new model for growth factor activation: type II receptors compete with the prodomain for BMP-7.
Bone morphogenetic proteins (BMPs) are morphogens with long-range signaling activities. BMP-7 is secreted as a stable complex consisting of a growth factor noncovalently associated with two propeptides. In other transforming growth factor-beta-like growth factor complexes, the prodomain (pd) confers latency to the complex. However, we detected no difference in signaling capabilities between the growth factor and the BMP-7 complex in multiple in vitro bioactivity assays. Biochemical and biophysical methods elucidated the interaction between the BMP-7 complex and the extracellular domains of its type I and type II receptors. Results showed that type II receptors, such as BMP receptor II, activin receptor IIA, and activin receptor IIB, competed with the pd for binding to the growth factor and displaced the pd from the complex. In contrast, type I receptors interacted with the complex without displacing the pd. These studies suggest a new model for growth factor activation in which proteases or other extracellular molecules are not required and provide a molecular mechanism consistent with a role for BMP receptors in the establishment of early morphogen gradients.
Sengle
Gerhard
G
Shriners Hospital for Children, Oregon Health & Science University, OR 97239, USA.
Ono
Robert N
RN
Lyons
Karen M
KM
Bächinger
Hans Peter
HP
Sakai
Lynn Y
LY
D030301:Activin Receptors, Type II / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D055419:Bone Morphogenetic Protein 7; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008970:Molecular Weight; D055435:Myostatin; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D016212:Transforming Growth Factor beta / Q000737:chemistry* / Q000378:metabolism*; D014461:Ultracentrifugation
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D036341:Intercellular Signaling Peptides and Proteins; C525911:MSTN protein, human; C525912:Mstn protein, mouse; D055435:Myostatin; D016212:Transforming Growth Factor beta; D030301:Activin Receptors, Type II; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; C425585:activin receptor type II-A