The activity and signaling range of mature BMP-4 is regulated by sequential cleavage at two sites within the prodomain of the precursor.
Proteolytic maturation of proBMP-4 is required to generate an active signaling molecule. We show that proBMP-4 is cleaved by furin in a sequential manner. Cleavage at a consensus furin site adjacent to the mature ligand domain allows for subsequent cleavage at an upstream nonconsensus furin site within the prodomain. BMP-4 synthesized from precursor in which the upstream site is noncleavable is less active, signals at a shorter range, and accumulates at lower levels than does BMP-4 cleaved from native precursor. Conversely, BMP-4 cleaved from precursor in which both sites are rapidly cleaved is more active and signals over a greater range. Differential use of the upstream cleavage site could provide for tissue-specific regulation of BMP-4 activity and signaling range.
Cui
Y
Y
Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, Oregon 97201, USA.
Hackenmiller
R
R
Berg
L
L
Jean
F
F
Nakayama
T
T
Thomas
G
G
Christian
J L
JL
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D045683:Furin; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013381:Subtilisins / Q000737:chemistry; D013997:Time Factors; D014981:Xenopus / Q000378:metabolism; D029867:Xenopus Proteins; D001616:beta-Galactosidase / Q000378:metabolism
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D018076:DNA, Complementary; D008024:Ligands; D029867:Xenopus Proteins; C525812:bmp4 protein, Xenopus; D001616:beta-Galactosidase; D013381:Subtilisins; D045683:Furin