Extracellular matrices are the scaffoldings that give organs and bodies structure. Skeletal cells control the addition of highly ordered calcium phosphate crystals (hydroxyapatite) into the matrices of hard tissues (bone, dentin, enamel), while other fibroblasts (skin, cartilage, tendons, etc.) keep their similar matrices soft. Research is focused on the disordered, calcium-binding protein family called SIBLINGs (Small Integrin-Binding LIgands, N-linked Glycoproteins), which are uniquely abundant in mineralized matrices. Recent work shows that mutations in one SIBLING gene, DSPP (dentin sialophosphoprotein), causes all known cases of nonsyndromic Dentinogenesis Imperfecta, and the milder Dentin Dysplasia, by retaining the DSPP proteins within the first cellular compartment (endoplasmic reticulum) of secreted protein synthesis. These results expand the knowledge of transmembrane proteins called cargo receptors, which are essential for trafficking secreted proteins out of the cell before they can reassemble into damaging complexes within the cell.
Dr. Larry W. Fisher received his BS in Biology/Biochemistry from Cornell University, and then worked as a research assistant studying the reconstitution of both Ca2+ and Na+/K+ ion pumps in liposomes.in the laboratory of Dr. Efraim Racker Dr. Fisher received his PhD from Pennsylvania State University, where he studied the timing of sulfated matrix proteins made in the highly synchronous, estrogen-induced medullary bone in birds. These proteins later became known as biglycan, decorin, and bone sialoprotein. After a brief postdoctoral fellowship at Case Western University, he began his career at NIDCR; first with a Kroc Fellowship, and then with a Shriner’s Fellowship, before becoming a NIH Fellow. Dr. Fisher is now chief of the matrix biochemistry section of what is now the Craniofacial and Skeletal Diseases Branch.
- von Marschall Z, Mok S, Phillips MD, McKnight DA, Fisher. LW. 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. 2012 Jun;27(6):1309-21.
- McKnight DA, Suzanne Hart P, Hart TC, Hartsfield JK, Wilson A, Wright JT, Fisher LW. A comprehensive analysis of normal variation and disease-causing mutations in the human DSPP gene. Hum Mutat. 2008 Dec;29(12):1392-404.
- von Marschall Z, Fisher LW. Dentin matrix protein-1 isoforms promote differential cell attachment and migration. J Biol Chem. 2008 Nov 21;283(47):32730-40.
- Bellahcène A, Castronovo V, Ogbureke KU, Fisher LW, Fedarko NS. Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Nat Rev Cancer. 2008 Mar;8(3):212-26.
- Ogbureke KU, Nikitakis NG, Warburton G, Ord RA, Sauk JJ, Waller JL, Fisher LW. Up-regulation of SIBLING proteins and correlation with cognate MMP expression in oral cancer. Oral Oncol. 2007 Oct;43(9):920-32.
- Ogbureke KU, Fisher LW. J Histochem. SIBLING expression patterns in duct epithelia reflect the degree of metabolic activity. Cytochem. 2007 Apr;55(4):403-9.
- Fedarko NS, Jain A, Karadag A, Fisher LW. Three small integrin binding ligand N-linked glycoproteins (SIBLINGs) bind and activate specific matrix metalloproteinases. FASEB J. 2004
- Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, Shi S. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5807-12.
- Fisher LW, Torchia DA, Fohr B, Young MF, Fedarko NS. Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem Biophys Res Commun. 2001 Jan 19;280(2):460-5.
- Fedarko NS, Fohr B, Robey PG, Young MF, Fisher LW. Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complement-mediated attack. J Biol Chem. 2000 Jun 2;275(22):16666-72.