Dentin phosphophoryn (DPP) is an extracellular matrix protein synthesized by odontoblasts. It is highly acidic and the phosphorylated protein possesses a strong affinity for calcium ions. Therefore, DPP in the extracellular matrix can promote hydroxyapatite nucleation and can regulate the size of the growing crystal. Besides its calcium binding property, DPP can initiate signaling functions from the ECM (Extracellular matrix). The signals that promote the cytodifferentiation of preodontoblasts to fully functional odontoblasts are not known. In this study, we demonstrate that preodontoblasts on a DPP matrix, generates mechanical and biochemical signals. This is initiated by the ligation of the integrins with the RGD containing DPP. The downstream biochemical response observed is the activation of the AKT( protein kinase B) and mTOR (mammalian target of rapamycin) signaling pathways leading to the activation of the transcription factor NF- κB (Nuclear factor κB) . Terminal differentiation of the preodontoblasts was assessed by identifying phosphate and calcium deposits in the matrix using von Kossa and Alizarin red staining respectively. Identifying the signaling pathways initiated by DPP in the dentin matrix would help in devising strategies for dentin tissue engineering.