Yair Argon, PhD
Emeritus Professor of Pathology and Laboratory MedicinePerelman School of Medicine at the University of Pennsylvania
Contact Information816B Abramson Research Center
3615 Civic Center Boulevard
Philadelphia, PA, 19104-4318
Office: (267) 426-5131
Fax: (267) 426-5165
Email: yargon@pennmedicine.upenn.edu
Research Expertise
Research Interests: Functions of molecular chaperones in modulating cell surface receptors and secreted proteins
Key words: Chaperones, BiP, GRP94, HSP90, calreticulin, Amyloid, Light Chain, Heavy Chain, B Cell Receptor, Insulin-like growth factors, Peptide, Stress Response, Development.
Description of Research
Communication among cells through secreted ligands and their receptors underlies the organization of tissues. The proper expression of receptors and secretion of protein ligands are dependent on accessory proteins, molecular chaperones, which regulate their biosynthesis and minimize their misfolding. Our work focuses on the molecular chaperones in the endoplasmic reticulum, where membrane and secreted proteins are synthesized.
BiP is a peptide binding protein that controls folding of antigen receptors by binding selectively to some peptides in the newly synthesized proteins. Because of this ability, BiP provides an important quality control function in screening somatically mutated molecules. One project in the lab concerns how BiP recognizes normal Ig sequences and distinguishes them from aggregation-prone somatic mutants. A second project examines the use of BiP as an inhibitor of the pathologic polymerization of antibodies into amyloid fibers.
GRP94 has a different mode of action and therefore biological activity. Although it binds peptides, its specificity is different from BiP. We use combinatorial genetic and biochemical techniques to characterize its preferred binder peptides and identify the features that it recognizes in client proteins. We developed the first cell-based assay for the chaperone function of GRP94, relying on the discovery that GRP94 is needed for production of Insulin-like growth factors, which are needed for cultured cells to cope with stress. We assay variants of GRP94 by expressing them in stressed chaperone-deficient cells. The more functional the variant chaperone, the higher the level of growth factor that is produced and the higher the survival of the cells under stress. This assay enables us to dissect the biochemical mode of action of GRP94.
Another project explores the GRP94-IGF axis in muscle physiology, using mice with targeted deletion of GRP94 in skeletal muscle. We use this model to understand what are the major client proteins of the chaperone in myocytes and to ask how modulation of GRP94 expression affect the recovery of muscle from injury.
A third project utilizes proteomic approaches to identify the interactions among ER chaperones as well as their co-factors, to understand the dynamic nature of the chaperone network and the changes in it during physiological ER stress.
Rotation Projects
1. Structure-function analysis of chaperones using cell-based assays
2. Analysis of GRP94-deficient mice
3. Proteomic analyses of chaperone-deficient cells
4. Analysis of an amyloid LC-expressing transgenic mouse
5. The GRP94-IGF axis in growth control
6. Genetic analysis of chaperone action in C. elegans
Lab personnel:
Ostrovsky, O - Research Associate
Eletto, D - Postdoctoral Fellow
Dersh, D - Graduate Student
James, J - Technician
Penn IMIG Expertise
Research:
B and T lymphocytes, dendritic cells and macrophages sense their environment using a number of cell-surface receptors, and respond to environmental signals by secreting proteins that bind to infectious agents or to other immune system cells. Both the specificity of immune cells and their ability to act depend on proper expression of these membrane receptors and secreted proteins. All are multi-subunit proteins that fold and assemble in the endoplasmic reticulum and then traffic to their site of action. The control of folding, assembly and proper expression of proteins in immune cells is dependent on accessory proteins termed molecular chaperones. The roles of molecular chaperones, in particular, the role of GRP94, an essential ER stress protein, during the production of growth factors and differentiation of B cells is a major focus of research in the Argon lab. The lab uses microscopy to track antigen uptake by lymphoid cells, expression of surface proteins as well as ER dynamics under normal and stress conditions.
Lab expertise and resources:
Live cell imaging of fluorescent fusion proteins
Cells with depleted or increased expression of chaperones
Chaperone knockout mice
Molecular biology
RNAi using viral vectors
Biochemical analysis of proteins
Proteomic methods
Fluorescent ER stress reporters
IMIG Collaborations:
Argon and Burkhardt: antigen presentation by dendritic cells
Lab members:
Devin Dersh - Graduate student
ER quality control
dcdersh@gmail.com
Yina Dong - Research Associate
IGF processing and signaling
dongy@email.chop.edu
Davide Eletto - Post-doctoral Fellow
Cell-based assays, RNAi
davide.laptop@gmail.com
Jose James - Technician
jamesjk@email.chop.edu
Michal Marcez - Senior Research Associate
IGF signaling, tumor progression
mimarzec73@gmail.com
Olga Ostrovsky - Research Associate
md88olga@yahoo.com
Graduate Groups
Biochemistry and Molecular Biophysics
Cell and Molecular Biology
Immunology
Education
B.S. (Biology), The Hebrew University Medical School, Jerusalem, Israel , 1974
Ph.D. (Biochemistry), Harvard Medical School, 1980
Fellow (Molecular Biology), Medical Research Council Lab of Molecular Biol., Cambridge, UK, 1984
Specialty Certification
Postgraduate Training
Research Associate, Carnegie Institution of Washington, 1977-1979
Visiting Scientist, MRC Laboratory of Molecular Biology, Cambridge, England, 1980-1984
Visiting Scientist, Basel Institute for Immunology, Switzerland, 1991-1992
Visiting Scientist, Technion, Israel Institute for Technology, 2001-2002
Awards and Honors
Albert Ryan Predoctoral Fellow, Harvard Medical School, 1975-1976
Leukemia Society of America Postdoctoral Fellow, 1980-1981
European Molecular Biology Organization Postdoctoral Fellow, 1981-1982
Muscular Dystrophy Association Postdoctoral Fellow, 1982-1984
Young Investigator Award, the Arthritis Foundation, 1986-1989
Junior Faculty Research Award, American Cancer Society, 1988-1991
Roche International Fellow, Basel, 1991-1992
Fogarty International Fellow, Technion, Israel, 2001-2002
Memberships and Professional Organizations
American Cancer Society Tumor Immunology Study Section, - Present
American Association of Immunologists, - Present
American Society for Cell Biology, - Present
Sigma Xi, - Present
National Institutes of Health, - Present
Web Links
Selected Publications
An essential role for ATP binding and hydrolysis in the chaperone activity of GRP94 in cells
Ostrovsky O, Makarewich CA, Snapp EL, Argon Y., Proc. Nat. Acad. Sci 106(28): 11600-5, 2009 PMCID: PMC2710619
The chaperone activity of GRP94 toward insulin-like growth factor II is necessary for the stress response to serum deprivation
Ostrovsky O, Ahmed NT, Argon Y, Mol. Biol. Cell 20(6): 1855-64, 2009 PMCID: PMC2655248
The peptide binding activity of GRP94 is regulated by calcium
Biswas C, Ostrovsky O, Makarewich CA, Wanderling S, Gidalevitz T, Argon Y., Biochem. J 405(2): 233-41, 2007
GRP94 is essential for mesoderm induction and muscle development because it regulates IGF-II
Wanderling S, Simen BB, Ostrovsky O, Ahmed NT, Vogen SM, Gidalevitz T, Argon Y., Mol. Biol. Cell 18(10): 3764-75, 2007
Cysteines in the CH1 domain underlie retention of unassembled Ig heavy chains
Elkabetz Y, Argon Y, Bar-Nun S., J. Biol. Chem 280(15): 14402-12, 2005
Both the environment and somatic mutations govern the aggregation pathway of pathogenic immunoglobulin light chain
Davis DP1, Gallo G, Vogen SM, Dul JL, Sciarretta KL, Kumar A, Raffen R, Stevens FJ, Argon Y., J. Mol. Biol 313(5): 1023-1036, 2001
Identification of the N-terminal peptide binding site of glucose-regulated protein 94
Gidalevitz T, Biswas C, Ding H, Schneidman-Duhovny D, Wolfson HJ, Stevens F, Radford S, Argon Y., J. Biol. Chem. 279(16): 16543-52, 2004
Radicicol-sensitive peptide binding to the N-terminal portion of GRP94
Vogen S, Gidalevitz T, Biswas C, Simen BB, Stein E, Gulmen F, Argon Y., J. Biol. Chem 277(43): 40742-50, 2002
Inhibition of amyloid fiber assembly by both BiP and its target peptide
Davis PD, Raffen R, Dul LJ, Vogen MS, Williamson KE, Stevens JF, Argon Y., Immunity 13(4): 433-442, 2000
Hsp70 and antifibrillogenic peptides promote degradation and inhibit intracellular aggregation of amyloidogenic light chains
Dul JL1, Davis DP, Williamson EK, Stevens FJ, Argon Y., J. Cell. Biol 152(4): 705-16, 2001
