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Oganesian, A, Au, S, Horst, JA, Holzhausen, LC, Macy, AJ, Pace, JM and Bornstein, P (2006) The NH2-terminal propeptide of type I procollagen acts intracellularly to modulate cell function. J. Biol. Chem. 281:38507-18
The function of the NH(2)-terminal propeptide of type I procollagen (N-propeptide) is poorly understood. We now show that a recombinant trimeric N-propeptide interacts with transforming growth factor-beta1 and BMP2 and exhibits functional effects in stably transfected cells. The synthesis of N-propeptide by COS-7 cells results in an increase in phosphorylation of Akt and Smad3 and is associated with a marked reduction in type I procollagen synthesis and impairment in adhesion. In C2C12 cells, N-propeptide inhibits the osteoblastic differentiation induced by BMP2. Our data suggest that these effects are mediated by the interaction of N-propeptide with an intracellular receptor in the secretory pathway, because they are not observed when recombinant N-propeptide is added to the culture medium of either COS-7 or C2C12 cells. Both the binding of N-propeptide to cytokines and its functional properties are entirely dependent on the exon 2-encoded globular domain, and a mutation that substitutes a serine for a highly conserved cysteine in exon 2 abolishes its function. Our findings suggest that N-propeptide performs an important feedback regulatory function and provides a rationale for the prominence of a homotrimeric form of type I procollagen (alpha1 trimer) during vertebrate development.
Animals; Cell Adhesion; Cell Line; Collagen Type I/chemistry; Collagen Type I/genetics; Collagen Type I/physiology; Mice; Mutation; Osteogenesis Imperfecta/genetics; Phosphorylation; Proto-Oncogene Proteins c-akt/metabolism; Recombinant Proteins/chemistry; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Smad2 Protein/metabolism
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