The NH2-terminal propeptide of type I procollagen acts intracellularly to modulate cell function.
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.
Oganesian
Anush
A
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Au
Sandra
S
Horst
Jeremy A
JA
Holzhausen
Lars C
LC
Macy
Athena J
AJ
Pace
James M
JM
Bornstein
Paul
P
D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D024042:Collagen Type I / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism
D024042:Collagen Type I; D011994:Recombinant Proteins; D051899:Smad2 Protein; D051057:Proto-Oncogene Proteins c-akt