Abstract
Dentin phosphoprotein (DPP), a major noncollagenous protein of the dentin matrix, is a highly acidic protein that binds Ca(2+) avidly and is thus linked to matrix mineralization. Here, we demonstrate that the RGD domain in DPP can bind to integrins on the cell surface of undifferentiated mesenchymal stem cells and pulp cells. This coupling generates intracellular signals that are channeled along cytoskeletal filaments and activate the non-receptor tyrosine kinase focal adhesion kinase, which plays a key role in signaling at sites of cellular adhesion. The putative focal adhesion kinase autophosphorylation site Tyr(397) is phosphorylated during focal adhesion assembly induced by DPP on the substrate. We further demonstrate that these intracellular signals propagate through the cytoplasm and activate anchorage-dependent ERK signaling. Activated ERK translocates to the nucleus and phosphorylates the transcription factor ELK-1, which in turn coordinates the expression of downstream target genes such as DMP1 and dentin sialoprotein (DSP). These studies suggest a novel paradigm demonstrating that extracellular DPP can induce intracellular signaling that can be propagated to the nucleus and thus alter gene activities.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism
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Active Transport, Cell Nucleus / drug effects
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Animals
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Cell Adhesion / drug effects
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Cell Differentiation / drug effects
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Cell Line
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cytoskeleton / drug effects
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Cytoskeleton / metabolism
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Dental Pulp / cytology
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / drug effects
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Embryonic Stem Cells / metabolism
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Enzyme Activation / drug effects
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Extracellular Matrix Proteins / chemistry
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Extracellular Matrix Proteins / pharmacology*
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Focal Adhesion Protein-Tyrosine Kinases / metabolism
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Focal Adhesions / drug effects
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Immobilized Proteins / chemistry
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Immobilized Proteins / pharmacology
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Integrins / metabolism*
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MAP Kinase Signaling System / drug effects
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Mesenchymal Stem Cells / cytology
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Mesenchymal Stem Cells / drug effects*
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Mesenchymal Stem Cells / metabolism*
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Mice
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Minerals / metabolism
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Odontoblasts / cytology
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Odontoblasts / drug effects
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Odontoblasts / metabolism
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Paxillin / metabolism
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Phosphoproteins / chemistry
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Phosphoproteins / pharmacology*
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Protein Structure, Tertiary
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Sialoglycoproteins / chemistry
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Sialoglycoproteins / pharmacology*
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Signal Transduction / drug effects*
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ets-Domain Protein Elk-1 / metabolism
Substances
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Actins
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Extracellular Matrix Proteins
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Immobilized Proteins
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Integrins
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Minerals
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Paxillin
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Phosphoproteins
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Sialoglycoproteins
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dentin sialophosphoprotein
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ets-Domain Protein Elk-1
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Focal Adhesion Protein-Tyrosine Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3