Article

Post-translational modifications of SIBLING proteins and their roles in osteogenesis and dentinogenesis

The Department of Endodontics and Periodontics, University of Texas-Houston Health Science Center, Dental Branch, Houston, TX 77030, USA.
Critical reviews in oral biology and medicine: an official publication of the American Association of Oral Biologists 02/2004; 15(3):126-36. DOI: 10.1177/154411130401500302
Source: PubMed

ABSTRACT The extracellular matrix (ECM) of bone and dentin contains several non-collagenous proteins. One category of non-collagenous protein is termed the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family, that includes osteopontin (OPN), bone sialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP), and matrix extracellular phosphoglycoprotein (MEPE). These polyanionic SIBLING proteins are believed to play key biological roles in the mineralization of bone and dentin. Although the specific mechanisms involved in controlling bone and dentin formation are still unknown, it is clear that some functions of the SIBLING family members are dependent on the nature and extent of post-translational modifications (PTMs), such as phosphorylation, glycosylation, and proteolytic processing, since these PTMs would have significant effects on their structure. OPN and BSP are present in the ECM of bone and dentin as full-length forms, whereas amino acid sequencing indicates that DMP1 and DSPP exist as proteolytically processed fragments that result from scission of X-Asp bonds. We hypothesized that the processing of DMP1 and DSPP is catalyzed by the PHEX enzyme, since this protein, an endopeptidase that is predominantly expressed in bone and tooth, has a strong preference for cleavage at the NH2-terminus of aspartyl residue. We envision that the proteolytic processing of DMP1 and DSPP may be an activation process that plays a significant, crucial role in osteogenesis and dentinogenesis, and that a failure in this processing would cause defective mineralization in bone and dentin, as observed in X-linked hypophosphatemic rickets.

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    • "DMP1, also called AG1 in the early literature, is an acidic non collagenous phosphoprotein originally found in teeth (George et al., 1993), but later also detected in bones (Hirst et al., 1997; MacDougall et al., 1998), where it is primarily expressed by osteocytes (Toyosawa et al., 2001). DMP1 is a multifunctional protein involved in the biomineralization of bones and dentin (Ling et al., 2005; Lu et al., 2007; Qin et al., 2004), phosphate homeostasis (Feng et al., 2006), and differentiation of odonto-and osteoblasts (Almushayt et al., 2006; Narayanan et al., 2001). Mutations in this gene cause autosomal recessive hypophosphatemic rickets syndrome , manifested by rickets and osteomalacia with isolated renal phosphate-wasting (Feng et al., 2006; Lorenz-Depiereux et al., 2006). "
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    • "Furthermore, SIBLINGs are overexpressed in many cancers. Cancer cells use them as molecular tools to facilitate their expansion [14] [15] [16] [17] [18] [19] [20] [21]. Thus, they were regarded as potentially valuable candidates for effective anticancer therapies. "
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    • "The large DMP1 region encoded by exon 6 contains several domains that are identified as being under strong functional pressure. They are the SG and RGD motifs, the cleavage site as defined by (Qin et al. 2004 ) and the two collagen-binding sites. The analysis of non-synonymous substitution rate (dN) allowed us to identify in a more precise manner, the functionally important regions (Fig. 3b). "
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