The pro-form of BMP-2 interferes with BMP-2 signalling by competing with BMP-2 for IA receptor binding.
Pro-forms of growth factors have received increasing attention since it was shown that they can affect both the maturation and functions of mature growth factors. Here, we assessed the biological function of the pro-form of bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor beta (TGFbeta)/BMP superfamily. The role of the 263 amino acids of the pro-peptide is currently unclear. In order to obtain an insight into the function of the pro-form (proBMP-2), the ability of proBMP-2 to induce alkaline phosphatase (AP), a marker enzyme for cells differentiating into osteoblasts, was tested. Interestingly, in contrast to mature BMP-2, proBMP-2 did not lead to induction of AP. Instead, proBMP-2 inhibited the induction of AP by BMP-2. This result raised the question of whether proBMP-2 may compete with mature BMP-2 for receptor binding. ProBMP-2 was found to bind to the purified extracellular ligand binding domain (ECD) of BMPR-IA, a high-affinity receptor for mature BMP-2, with a similar affinity as mature BMP-2. Binding of proBMP-2 to BMPR-IA was confirmed in cell culture by cross-linking proBMP-2 to BMPR-IA presented on the cell surface. In contrast to this finding, proBMP-2 did not bind to the ECD of BMPR-II. ProBMP-2 also differed from BMP-2 in its capacity to induce p38 and Smad phosphorylation. The data presented here suggest that the pro-domain of BMP-2 can alter the signalling properties of the growth factor by modulating the ability of the mature part to interact with the receptors.
Hauburger
Anja
A
Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, Germany.
von Einem
Sabrina
S
Schwaerzer
Gerburg K
GK
Buttstedt
Anja
A
Zebisch
Matthias
M
Schräml
Michael
M
Hortschansky
Peter
P
Knaus
Petra
P
Schwarz
Elisabeth
E
D000469:Alkaline Phosphatase / Q000096:biosynthesis; D000818:Animals; D001667:Binding, Competitive; D055396:Bone Morphogenetic Protein 2 / Q000502:physiology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D051379:Mice; D010766:Phosphorylation; D011498:Protein Precursors / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D055396:Bone Morphogenetic Protein 2; D011498:Protein Precursors; D051785:Smad Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D000469:Alkaline Phosphatase