Faculty Appointments: 
Professor of Pathology and Laboratory Medicine at University of Pennsylvania School of Medicine (2002– present)
(267) 426-5131
Office Location: 
816 Abramson Research Center 3615 Civic Center Boulevard

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

Yina Dong - Research associate

IGF processing and signaling

Davide Eletto - Post-doctoral fellow

Cell-based assays, RNAi

Jose James
- Technician


Michal Marcez - Senior research associate

IGF signaling, tumor progression

Olga Ostrovsky - Research associate


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

Fellow, Molecular Biology, Medical Research Council Lab of Molecular Biol., Cambridge, UK (1984)
Ph.D., Biochemistry, Harvard Medical School (1980)
B.S., Biology, The Hebrew University Medical School, Jerusalem, Israel (1974)
Selected Publications
Ostrovsky, O,C. Makarewich, E.L. Snapp. and Y. Argon. An essential role for ATP binding and hydrolysis in the chaperone activity of GRP94 in cells. Proc. Nat. Acad. Sci.. 2009:106(28):11600-5. PMC2710619.
Ostrovsky O, Ahmed NT, Argon Y. The Chaperone Activity of GRP94 Towards Insulin-like Growth Factor II Is Necessary for the Stress Response to Serum Deprivation. Mol. Biol. Cell.. Vol 20(6) . 2009:20(6):1855-64. PMC2655248.
Biswas, C., Ostrovsky, o., Makarewich, C.A., Wanderling, S., Gidalevitz, T., and Argon, Y.. The peptide binding activity of GRP94 is regulated by Calcium. Biochem. J.. 2007:405(2):233-41..
Wanderling, S., Simen, B.B., Ostrovsky,O., Ahmed,N.T., Vogent, S.M., R. Gidalevitz, and Y. Argon. GRP94 is essential for mesoderm induction and muscle development because it regulates IGF-II. Mol. Biol. Cell.. 2007:18(10):3764-75.
Elkabetz, Y., Argon, Y., Bar-Nun, S.. Cysteines in the CH1 domain underlie retention of unassembled Ig heavy chains. J. Biol. Chem.. 2005:280(15):14402-12.
Davis, P.D., Raffen, R., Dul, J. L., Vogen, S., Williamson, E.K., Stevens, F.J., Argon, Y.. Inhibition of amyloid fiber assembly by both BiP and its target peptide. Immunity. 2000:13(4):433-442.
Dul, J.L., Davis, P. D., Williamson, E.K., Stevens, F.J., Argon, Y.. Hsp70 and antifibrillogenic peptides promote degradation and inhibit intracellular aggregation of amyloidogenic light chains.. J. Cell. Biol.. 2001:152(4):705-16..
Davis, D.P., Gallo, G., Vogen, S.M., Dul, J.L., Sciarretta, K.L., Kumar, A., Raffen, R., Stevens, F.J., Argon, Y.. Both the environment and somatic mutations govern the aggregation pathway of pathogenic immunoglobulin light chain. J. Mol. Biol.. Vol 313. 2001:313(5):1023-1036.
Vogen, S.M., Gidalevitz, T., Biswas, C., Simen, B.S., Stein, E., Gulmen, F., Argon, Y.. Radicicol-sensitive peptide binding to the N-terminal portion of GRP94. J. Biol. Chem.. 2002:277(43):40742-50.
Gidalevitz, T., Biswas, C., Ding, H., Schneidman-Duhovny, D., Wolfson, H.J., Stevens, F., Radford, R., and Argon, Y.. Identification of the N-terminal peptide binding site of glucose-regulated protein 94.. J. Biol. Chem.. 2004:279(16):16543-52.