Stuart Kornfeld, M.D.
- Professor
- Department of Medicine
- Hematology Division
- Department of Biochemistry & Molecular Biophysics
- Department of Medicine
- Clinical interests
- General hematology
- Research interests
- Intracellular protein trafficking
- Lysosomes
- Glycoproteins
Research
We are studying the biochemical and molecular basis for protein trafficking in mammalian cells, focusing on the biogenesis of lysosomes. The targeting of lysosomal enzymes from their site of synthesis in the rough endoplasmic reticulum to their final destination in lysosomes is a multistep process that utilizes a series of recognition signals that must be deciphered by cellular components that mediate the sorting, packaging and transport of the lysosomal enzymes. A key step in this pathway is the selective phosphorylation of mannose residues on the lysosomal enzymes. These residues allow binding to Man-6-P receptors in the Golgi and transport to lysosomes via clathrin-coated vesicles.
The goal of our work is to understand this complex sorting system at the molecular level. Currently we are studying how the enzyme that mediates mannose phosphorylation recognizes lysosomal enzymes as specific substrates and how the Man-6-P receptors bind their ligands, enter clathrin-coated pits, and traffic between various cellular compartments. We are using an in vitro assay to dissect the steps involved in the formation of clathrin-coated vesicles on Golgi membranes and liposomes.
Recently we discovered that a newly described coat protein termed GGA binds the acidic cluster/dileucine sorting motif on the cytoplasmic tail of the Man-6-P receptors. This implicates GGA in the packaging of the receptor in the Golgi. As GGA also binds clathrin, we are examining whether GGA nucleates clathrin-coated vesicles that contain Man-6-P receptors.
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A schematic representation of the subcellular localization and trafficking itinerary of the MPRs Mannose 6-phosphate receptors (MPRs) bind to their cargo (acid hydrolases) in the trans-Golgi network (TGN), and are packaged into transport carriers that deliver the receptor with its bound ligand to early endosomes (EE). The low pH within the endosomes facilitates the dissociation of the acid hydrolases from the MPRs. Dynamic fusion/fission between the late endosomal and lysosomal compartments results in selective delivery of the hydrolases to the lysosome (L) (the 'kiss-and-run' theory77). TIP47/Rab9 prevent the MPRs from reaching the lysosomes, in which they would otherwise be degraded. The return pathway from the early endosomal compartment to the Golgi is probably mediated by PACS-1-assisted packaging into AP1-containing clathrin-coated vesicles (CCVs), whereas that from the late endosomal (LE) compartments is mediated by TIP47 and Rab9. Some of the MPRs go to the cell surface either from early or late endosomes through the recycling endosome (RE), or from proximal TGN cisternae as a consequence of mis-sorting. The cell-surface receptors are internalized in AP2 CCVs and delivered back to the endosomes.
From: Ghosh P, Dahms NM, Kornfeld S
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Biographical Sketch
Education
| 1958 | AB, Dartmouth College, Hanover, NH |
| 1962 | MD, Washington University School of Medicine, St. Louis, MO |
Post-graduate Training
| 1962-1963 | Intern in Ward Medicine, Barnes Hospital, St. Louis, MO |
| 1963-1965 | Research Associate, National Institute of Arthritis and Metabolic Diseases, NIH |
| 1965-1966 | Assistant Resident in Ward Medicine, Barnes Hosital, St. Louis, MO |
Academic Positions & Employment
| 1966-1967 | Instructor in Medicine, Washington University School of Medicine, St. Louis, MO |
| 1967-1970 | Assistant Professor of Medicine, Washington University School of Medicine |
| 1968-1976 | Assistant Professor of Biochemistry, Washington University School of Medicine |
| 1970-1972 | Associate Professor of Medicine, Washington University School of Medicine |
| 1972-present | Professor of Medicine, Washington University School of Medicine |
| 1973-1976 | Director, Division of Oncology, Washington University School of Medicine |
| 1976-1992 | Co-Director, Division of Hematology-Oncology, Washington University School of Medicine |
| 1993-present | Co-Director, Division of Hematology, Washington University School of Medicine |
| 2000-present | David C. and Betty Farrell Distinguished Professor of Medicine |
Appointments & Committees
| 1991-1997 | Director, Medical Scientist Training Program, Washington University School of Medicine |
| 2000-present | Co-Director, Physician Scientist Training Program, Washington University School of Medicine |
Honors & Awards
| 1959 | Biochemistry Award, Washington University School of Medicine |
| 1962 | Bordon Award for Outstanding Undergraduate Research |
| 1966-1971 | American Cancer Society Faculty Research Associate |
| 1971-1976 | Research Career Development Award, National Institutes of Health |
| 1982 | National Academy of Sciences |
| 1983 | Institute of Medicine |
| 1984 | American Academy of Arts and Sciences |
| 1987 | Alumni/Faculty Award, Washington University School of Medicine |
| 1989 | Jubilee Lecturer and Harden Medallist, The Biochemical Society |
| 1991 | Passano Award (with William Sly) |
| 1992 | E. Donnall Thomas Lectureship and Prize |
| 1999 | Karl Meyer Award, Society for Glycobiology |
| 2002 | UCSD/Nature Medicine "Mentorship Award" |
| 2002 | Gerty & Carl Cori Faculty Recognition Award, Washington University |
| 2002 | Second Century Award, Washington University |
Editorial Responsibilities
| 1972-1996 | Editorial Board, Archives of Biochemistry and Biophysics |
| 1976-1981 | Editorial Board, Journal of Biological Chemistry |
| 1977-1981 | Associate Editor, Journal of Clinical Investigation |
| 1981-1982 | Editor, Journal of Clinical Investigation |
| 1982-1987 | Associate Editor, Journal of Biological Chemistry |
| 1985-1991 | Editorial Board, Proceedings of the National Academy of Sciences |
| 1988-1991 | Editorial Board, Journal of Cell Biology |
| 1992-2004 | Editorial Board, Molecular Biology of the Cell |
| 1997-2007 | Consulting Editor, Journal of Clinical Investigation |
| 1998-2003 | Editorial Board, Journal of Biological Chemistry |
Professional Societies
| American Society for Clinical Investigation | |
| American Society of Biological Chemists | |
| American Society of Hematolgy | |
| Association of American Physicians | |
| Foreign Member, Finnish Society of Sciences and Letters |
Board Memberships
| 1972-1975 | Councillor, American Society for Clinical Investigation |
| 1974-1977 | Member, NIH Cell Biology Study Section |
| 1983-1987 | Member, NIADDK Board of Scientific Counselors |
| 1986-1991 | Secretary, Association of American Physicians |
| 1991-1997 | Councillor, Associaton of American Physicians |
| 1986-1994 | Member, Scientific Review Board, Howard Hughes Medical Institute |
| 1987-1995 | Member, Board of Scientific Advisors, Jane Coffin Childs Memorial Fund for Medical Research |
| 1995-2000 | Medical Advisory Board, Howard Hughes Medical Institute |
| 1997-1998 | President, Association of American Physicians |
| 1998-present | Albert Lasker Medical Research Awards Jury |
Updated: March 21, 2008
