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J. Biol. Chem., Vol. 281, Issue 9, 5341-5347, March 3, 2006

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Extracellular Matrix-mediated Signaling by Dentin Phosphophoryn Involves Activation of the Smad Pathway Independent of Bone Morphogenetic Protein^*

Julie A. Jadlowiec, Xiaoyuan Zhang, Jinhua Li, Phil G. Campbell^¶, and Charles Sfeir¹

From the Department of Oral Medicine and Pathology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, the Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, and the ^¶Institute for Complex Engineered Systems, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213

Cells have ingenious mechanisms for interpreting complex signals from their external microenvironment. Previously, we have shown that phosphophoryn (PP) regulates the expression of bone/dentin marker genes via the integrin/MAPK signaling pathway (Jadlowiec, J., Koch, H., Zhang, X., Campbell, P. G., Seyedain, M., and Sfeir, C. (2004) J. Biol. Chem. 279, 53323–53330). We hypothesize that other signaling pathways important for mineralized tissue morphogenesis such as the Smad pathway could be involved in PP signaling. We determined activation of the Smad pathway in human adult mesenchymal stem cells following treatment with recombinant PP (rPP). We observed that PP enhanced phosphorylation of Smad1 within 30 min and Smad1 translocation to the nucleus within 1 h. PP up-regulated the expression of Smad1 target genes, Smad6, Dlx5, and Runx2. The timing of PP activation of Smad1 implies this is a direct effect; however, we also investigated the possible involvement of bone morphogenetic proteins in PP stimulation of the Smad pathway. PP was shown to up-regulate Bmp-2 gene expression 12 h post-treatment with PP, which is much later than initial detection of Smad1 phosphorylation at 30 min. Furthermore, addition of Noggin did not block Smad1 phosphorylation by PP. We propose that PP could signal via the Smad pathway by either directly stimulating the phosphorylation of Smad1 via integrins or other mechanisms. These might include integrin/bone morphogenetic protein receptor interactions or involvement of PP with other growth factors leading to the modulation of intracellular signaling. It is noteworthy that a non-transforming growth factor- family member activates the Smad pathway. The role of PP in regulating the Smad pathway raises very interesting questions regarding the role of PP during bone and tooth development.

Received for publication, June 6, 2005 , and in revised form, October 12, 2005.

^* This work was supported in part by National Institutes of Health Grant DE016123-01 and by the University of Pittsburgh Central Research Development Fund (to C. S.) and by the Pennsylvania Infrastructure Technology Alliance (to P. G. C.). 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 Oral Medicine and Pathology, University of Pittsburgh; 693A Salk Hall, 3501 Terrace St., Pittsburgh, PA 15261-1964. Tel.: 412-648-1949, E-mail: csfeir{at}pitt.edu.

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