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J. Biol. Chem., Vol. 281, Issue 50, 38507-38518, December 15, 2006

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The NH₂-terminal Propeptide of Type I Procollagen Acts Intracellularly to Modulate Cell Function^*

Anush Oganesian, Sandra Au, Jeremy A. Horst, Lars C. Holzhausen, Athena J. Macy, James M. Pace, and Paul Bornstein^¶1

From the Departments of Biochemistry, ^¶Medicine, and Pathology, University of Washington, Seattle, Washington 98195

The function of the NH₂-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-1 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 (1 trimer) during vertebrate development.

Received for publication, August 8, 2006 , and in revised form, September 25, 2006.

^* This work was supported by National Institutes of Health Grant R01 AR 11248 and by National Science Foundation Grant EEC 95291161. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, Box 357350, University of Washington, Seattle WA 98195. Tel.: 206-543-1789; Fax: 206-685-4426; E-mail: bornsten{at}u.washington.edu.

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