ECM-mediated signaling by dentin phosphophoryn involves activation of the Smad pathway independent of BMP

doi:10.1074/jbc.M506158200

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Papers In Press, published online ahead of print December 2, 2005
J. Biol. Chem, 10.1074/jbc.M506158200
Submitted on June 6, 2005
Accepted on December 2, 2005

ECM-mediated signaling by dentin phosphophoryn involves activation of the Smad pathway independent of BMP

Julie A. Jadlowiec, Xiaoyuan Zhang, Jinhua Li, Phil G. Campbell, and Charles Sfeir

Oral Medicine and Pathology, University of Pittsburgh, Pittsburgh, PA 15261

Corresponding Author: csfeir{at}pitt.edu

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 (1). 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 (hMSC) 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 hr. 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 BMPs in PP-stimulation of the Smad pathway. PP was shown to up-regulate Bmp-2 gene expression 12 hrs post-treatment with PP, which is much later than initial detection of Smad1 phosphorylation at 30 min. Further, 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/BMP receptor interactions or involvement of PP with other growth factors leading to the modulation of intracellular signaling. It is noteworthy that a non-TGF-beta 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.

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