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Larry W. Fisher, Ph.D.

Senior InvestigatorLarry Fisher, Ph.D.
Chief, Matrix Biochemistry Section

BETHESDA MD 20892-4320

Phone: (301) 496-5769
Fax: (301) 402-0824
E-mail: Larry W. Fisher


After receiving my B.S. in biology/biochemistry from Cornell University in 1974, I remained for one year working as a research assistant in the laboratory of Dr. Efraim Racker on the reconstitution of both Ca2+ and Na+/K+ ion pumps in liposomes. My Ph.D. thesis project at Pennsylvania State University (1980) was studying the timing of sulfated proteins made in the highly synchronous, estrogen-induced medullary bone in birds. These proteins were later called biglycan, decorin, and bone sialoprotein.  After a brief postdoctoral fellowship at Case Western University, I began my career at NIDCR in 1981. I received tenure in 1990 and became chief of the Matrix Biochemistry Section of what is now the Craniofacial & Skeletal Diseases Branch, NIDCR, in 2000.

Research Focus/Scientific Interests

I am interested in the evolution, function, and genetic diseases of the five members of the Small Integrin-Binding Llgand, N-Linked Glycoprotein (SIBLING) family of secreted phosphoproteins. The five proteins are Bone Sialoprotein (BSP), Dentin Matrix Protein-1 (DMP1), Dentin Sialophosphoprotein (DSPP), Matrix Extracellular Protein (MEPE), and Osteopontin (OPN). The proteins’ respective genes (IBSP, DMP1, DSPP, MEPE and SPP1) are always found in tandem on a single chromosome and are conserved in all mammals although the (toothless) anteaters have only vestigial remnants of their DSPP gene. Shared exon-intron structures, protein motifs (ex. the integrin-binding tripeptide, RGD) and post translational modifications (including phosphorylation, attachment of glycosaminoglycan chains and specific protease cleavage) all suggest that they are the result of ancient gene duplication and divergent evolution from a single gene hundreds of millions of years ago. We’ve shown by NMR that BSP and OPN are disordered proteins.  Computer modeling as well as the rapid genetic drift of all other SIBLINGS suggest that they likely disordered also. Reptiles and mammals appear to have used different copies of a duplicated DMP1 gene to co-evolve different but chemically similar DSPP proteins. Evolution has generally retained the integrin-binding RGD tripeptide in most SIBLINGs back through the common ancestors of mammals and reptiles.  Half of the mammals species studied,however, have lost their RGD motif in DSPP suggesting that this protein's critical function may no longer require binding to the cell surface via RGD-integrins. Three SIBLINGs, BSP, OPN and DMP1, have been shown to specifically bind and activate proMMP2, proMMP3, and proMMP9 respectively.  On an equimolar basis, tissue inhibitors of metalloproteinases (TIMPs) lose their ability to inhibit active MMP2, MMP3, and MMP9 in the presence of their SIBLING partners.  In each case, complement Factor H inactivates the SIBLINGs’ ability to interact with their partner proMMP and active MMPs and has been shown to interfere with the detection of SIBLING proteins in serum assays. SIBLINGs have been shown to be up-regulated by a variety of cancers including oral, prostate, breast, thyroid, and lung.  Recently we have shown that surgically removed oral precancerous lesions that expressed DSPP (but not BSP) were associated with those patients that tended to progress to local frank oral cancer within four years of the "successful" surgery.

Our most recent work has defined the mechanisms leading to the dominant negative effects of all but one (Y6D) of the many mutations in DSPP (discovered by this laboratory and by others) that cause all nonsyndromic forms of Dentin Dysplasia (DD-II) and Dentinogenesis Imperfecta (DGI-II and III).  We propose that all of the many and diverse 5’ mutations in the DSPP gene (including a proposed nonsense mutation) ultimately result in changes in the first three amino acids of the mature DSPP protein. Mutations in this tripeptide (isoleucine-proline-valine, IPV) result in inefficient trafficking of the defective DSPP out of the rough endoplasmic reticulum (rER).  We hypothesize that an “IPV” receptor in the rER is responsible for trafficking and/or packaging of DSPP (and other acidic proteins) into the ER exit vesicles.  A second class of mutations we discovered, loss of one or four DNA bases in the ~ 2000 basepair 3’ repeat domain (encoding ~ 700 tandem copies of the nominal tripeptide, serine-serine-aspartic acid, SSD), causes the mutant DSPP protein to become very hydrophobic, to insert into the membrane, and therefore also be retained in the rER.  Mutant DSPP retained in the rER cause their dominant negative effects by then capturing the normal DSPP protein encoded by the patients’ second (normal) allele thereby further decreasing the amount of DSPP secreted into the dentin matrix.  We showed that the milder DD was likely caused by the subset of mutations in the DSPP proteins that were less effective at capturing the normal DSPP protein thereby permitting more of the normal allele’s DSPP to be secreted into the dentin matrix.

Selected Publications

  1. DMP1 and DSPP: evidence for duplication and convergent evolution of two SIBLING proteins. Fisher LW. Cells Tissues Organs. 2011;194(2-4):113-8.
  2. Modulation of canonical Wnt signaling by the extracellular matrix component biglycan. Berendsen AD, Fisher LW, Kilts TM, Owens RT, Robey PG, Gutkind JS, Young MF. Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17022-7.
  3. Two members of the SIBLING family of proteins, DSPP and BSP, may predict the transition of oral epithelial dysplasia to oral squamous cell carcinoma. Ogbureke KU, Abdelsayed RA, Kushner H, Li L, Fisher LW. Cancer. 2010 Apr 1;116(7):1709-17.PMID: 20186700
  4. Secreted Frizzled-related protein-2 (sFRP2) augments canonical Wnt3a-induced signaling. von Marschall Z, Fisher LW. Biochem Biophys Res Commun. 2010 Sep 24;400(3):299-304.
  5. Dentin sialophosphoprotein (DSPP) is cleaved into its two natural dentin matrix products by three isoforms of bone morphogenetic protein-1 (BMP1). von Marschall Z, Fisher LW. Matrix Biol. 2010 May;29(4):295-303. Epub 2010 Jan 15.PMID: 20079836
  6. Decorin is processed by three isoforms of bone morphogenetic protein-1 (BMP1). von Marschall Z, Fisher LW. Biochem Biophys Res Commun. 2010 Jan 15;391(3):1374-8. Epub 2009 Dec 22.PMID: 20026052
  7. Molecular evolution of dentin phosphoprotein among toothed and toothless animals. McKnight DA, Fisher LW. BMC Evol Biol. 2009 Dec 23;9:299.PMID: 20030824
  8. Small integrin-binding proteins as serum markers for prostate cancer detection. Jain A, McKnight DA, Fisher LW, Humphreys EB, Mangold LA, Partin AW, Fedarko NS. Clin Cancer Res. 2009 Aug 15;15(16):5199-207. Epub 2009 Aug 11.PMID: 19671866
  9. Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Bellahcène A, Castronovo V, Ogbureke KU, Fisher LW, Fedarko NS. Nat Rev Cancer. 2008 Mar;8(3):212-26. Review.PMID: 18292776
  10. Overlapping DSPP mutations cause dentin dysplasia and dentinogenesis imperfecta. McKnight DA, Simmer JP, Hart PS, Hart TC, Fisher LW. J Dent Res. 2008 Dec;87(12):1108-11. Erratum in: J Dent Res. 2009 Jan;88(1):95. PMID: 19029076
  11. Dentin matrix protein-1 isoforms promote differential cell attachment and migration. von Marschall Z, Fisher LW. J Biol Chem. 2008 Nov 21;283(47):32730-40. Epub 2008 Sep 25.PMID: 18819913
  12. Structural requirements for bone sialoprotein binding and modulation of matrix metalloproteinase-2. Jain A, Karadag A, Fisher LW, Fedarko NS. Biochemistry. 2008 Sep 23;47(38):10162-70. Epub 2008 Aug 26.PMID: 18729384
  13. A comprehensive analysis of normal variation and disease-causing mutations in the human DSPP gene. McKnight DA, Suzanne Hart P, Hart TC, Hartsfield JK, Wilson A, Wright JT, Fisher LW. Hum Mutat. 2008 Dec;29(12):1392-404.PMID: 18521831
  14. Bone sialoprotein binding to matrix metalloproteinase-2 alters enzyme inhibition kinetics. Jain A, Fisher LW, Fedarko NS. Biochemistry. 2008 Jun 3;47(22):5986-95. Epub 2008 May 8.PMID: 18465841
  15. Molecular energy dissipation in nanoscale networks of Dentin Matrix Protein 1 is strongly dependent on ion valence. Adams J, Fantner GE, Fisher LW, Hansma PK. Nanotechnology. 2008 Sep 24;19(38):384008.PMID: 18843380


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This page last updated: May 28, 2014