The Matrix Biochemistry Section focuses its research on the functions of five major noncollagenous proteins first found associated with the mineralized matrix of bones and teeth but that we later showed are also made by many metabolically active ductal epithelial cells. The five proteins are bone sialoprotein (BSP), osteopontin (OPN), dentin matrix protein-1 (DMP1), dentin sialophosphoprotein (DSPP), and matrix extracellular phosphoglycoprotein (MEPE). We have made a strong case for the genetic relatedness of these seemingly different proteins and there is increasing acceptance of the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family concept. The genes encoding these proteins are all clustered in a tandem fashion within a short (400,000 base pairs) region of human chromosome 4 and similarly on all other mammals studied to date. After comparing the intron-exon structures and conserved motifs of their respective protein-encoding exons, we proposed that the five genes might be the result of ancient gene duplication and subsequent divergence. This year we have looked more deeply into the evolution of the most acidic protein made by mammals, DSPP. We have presented evidence that DSPP was likely the result of a gene duplication of the DMP1 gene about the time that reptiles and mammals diverged from their shared ancestor more than 300 million years ago. Detailed analyses of representative mammalian and reptilian DSPP genes showed that different copies of the duplicated DMP1 genes independently amplified different serine-rich phosphorylation motifs resulting in the convergent evolution of a highly repetitive, phosphate-rich, calcium-binding DSPP-like proteins perhaps corresponding to their independent evolution of more sophisticated and complex enamel-covered dentin tooth structures. The evidence included the use of specific serine-encoding codons as well as the convergent use of different positively charged amino acids to interrupt the otherwise negatively charged repeat domain. Our current research involves a focus on the mechanism(s) causing the dominant negative affects of all DSPP mutations in both dentin dysplasia and dentinogenesis imperfecta.

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National Institute of Dental & Craniofacial Research
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Yin, Ying; Garcia, Mekka R; Novak, Alexander J et al. (2018) Surf4 (Erv29p) binds amino-terminal tripeptide motifs of soluble cargo proteins with different affinities, enabling prioritization of their exit from the endoplasmic reticulum. PLoS Biol 16:e2005140
Lamour, Virginie; Henry, Aurélie; Kroonen, Jérôme et al. (2015) Targeting osteopontin suppresses glioblastoma stem-like cell character and tumorigenicity in vivo. Int J Cancer :
Nam, Anna S; Yin, Ying; von Marschall, Zofia et al. (2014) Efficient trafficking of acidic proteins out of the endoplasmic reticulum involves a conserved amino terminal IleProVal (IPV)-like tripeptide motif. Connect Tissue Res 55 Suppl 1:138-41
von Marschall, Zofia; Mok, Seeun; Phillips, Matthew D et al. (2012) Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP. J Bone Miner Res 27:1309-21
Ogbureke, Kalu U E; Weinberger, Paul M; Looney, Stephen W et al. (2012) Expressions of matrix metalloproteinase-9 (MMP-9), dentin sialophosphoprotein (DSPP), and osteopontin (OPN) at histologically negative surgical margins may predict recurrence of oral squamous cell carcinoma. Oncotarget 3:286-98
Fisher, Larry W (2011) DMP1 and DSPP: evidence for duplication and convergent evolution of two SIBLING proteins. Cells Tissues Organs 194:113-8
Ogbureke, Kalu U E; Abdelsayed, Rafik A; Kushner, Harvey et al. (2010) Two members of the SIBLING family of proteins, DSPP and BSP, may predict the transition of oral epithelial dysplasia to oral squamous cell carcinoma. Cancer 116:1709-17
von Marschall, Zofia; Fisher, Larry W (2010) Dentin sialophosphoprotein (DSPP) is cleaved into its two natural dentin matrix products by three isoforms of bone morphogenetic protein-1 (BMP1). Matrix Biol 29:295-303
von Marschall, Zofia; Fisher, Larry W (2010) Decorin is processed by three isoforms of bone morphogenetic protein-1 (BMP1). Biochem Biophys Res Commun 391:1374-8
Inkson, Colette A; Ono, Mitsuaki; Bi, Yanming et al. (2009) The potential functional interaction of biglycan and WISP-1 in controlling differentiation and proliferation of osteogenic cells. Cells Tissues Organs 189:153-7

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