title: Extracellular matrix-mediated signaling by dentin phosphophoryn involves activation of the Smad pathway independent of bone morphogenetic protein.
abstract: 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-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.
authors.affiliation: Department of Oral Medicine and Pathology, School of Dental Medicine, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA 15261, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Jadlowiec
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Jinhua
authors.initials: J
authors.lastname: Li
authors.forename: Phil G
authors.initials: PG
authors.lastname: Campbell
authors.forename: Charles
authors.initials: C
authors.lastname: Sfeir
mesh_terms: D021581:Active Transport, Cell Nucleus; D000328:Adult; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D000099176:Noggin Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D020928:Mitogen-Activated Protein Kinases; D010750:Phosphoproteins; D051898:Smad1 Protein; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525718:BMP2 protein, human; C497399:SMAD1 protein, human; C017630:phosphophoryn