Yêu cầu để loại bỏ thủy phân protein của prodomain cho hoạt động được hỗ trợ bằng cách phát hiện các hình thức phân cắt đột biến của BMP trong đó RXXR motif-đã bị gián đoạn không hoạt động và có thể dimerize với và ức chế sự phân cắt, tiết và bioactivity BMP bản địa (23 ). Một vài ngoại lệ cho quy tắc này không tồn tại, | Regulation of BMP Wnt and Hh Signaling 117 mature Nodal cleaved from its native precursor protein is highly unstable whereas that cleaved from a chimeric precursor containing the BMP-4 prodomain is stable 16 . The requirement for proteolytic removal of the prodomain for activity is supported by the finding that cleavage mutant forms of BMPs in which the -RXXR- motif has been disrupted are inactive and can dimerize with and inhibit the cleavage secretion and bioactivity of native BMPs 23 . A few exceptions to this rule do exist however in that precursor forms of inhibin A 24 lefty 25 and Xenopus nodal related-2 26 possess some bioactivity. The mechanism s by which the prodomain regulates the activity of mature BMPs is unknown and is likely to vary between individual family members. In the case of TGF-p which has been better studied than BMPs the prodomain remains noncovalently associated with the mature ligand forming an inactive latent complex that is stored in the extracellular matrix ECM in association with the latent TGF-p binding protein. The major regulatory step controlling TGF-p activity takes place outside of the cell when proteases or other agents either release the prodomain or induce a conformational change that exposes the receptor binding sites on TGF-p 27 . Analogous to TGF-p the prodomain of BMP-7 remains noncovalently associated with the mature region after cleavage but unlike TGF-p this complex can bind to and activate BMP receptors without further processing or alteration 28 . Recent genetic data support a functional interaction between BMP-7 and the latent TGF-p binding protein family member Fibrillin-2 and suggest that the bioactivity or availability of BMP-7 like that of TGF-p may be regulated by interactions with the ECM 29 . Processing of BMP-4 is more complex than that of BMP-7 in that the precursor is sequentially cleaved by furin at two sites and this ordered proteolysis regulates the activity and signaling range of mature BMP-4 14 15 . .
