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Yair Argon, Ph.D.
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Emeritus Professor of Pathology and Laboratory Medicine
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Department: Pathology and Laboratory Medicine
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Graduate Group Affiliations
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- Pharmacology 6b
- Cell and Molecular Biology 5c
- Immunology e
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Contact information
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816B Abramson Research Center
43 3615 Civic Center Boulevard
Philadelphia, PA 19104-4318
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43 3615 Civic Center Boulevard
Philadelphia, PA 19104-4318
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Office: (267) 426-5131
34 Fax: (267) 426-5165
34 Lab: (267) 426-5130
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34 Fax: (267) 426-5165
34 Lab: (267) 426-5130
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Publications
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Education:
21 9 B.S. 14 (Biology) c
52 The Hebrew University Medical School, Jerusalem, Israel , 1974.
21 a Ph.D. 19 (Biochemistry) c
2f Harvard Medical School, 1980.
21 b Fellow 1e (Molecular Biology) c
57 Medical Research Council Lab of Molecular Biol., Cambridge, UK, 1984.
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Permanent link21 9 B.S. 14 (Biology) c
52 The Hebrew University Medical School, Jerusalem, Israel , 1974.
21 a Ph.D. 19 (Biochemistry) c
2f Harvard Medical School, 1980.
21 b Fellow 1e (Molecular Biology) c
57 Medical Research Council Lab of Molecular Biol., Cambridge, UK, 1984.
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65 Functions of molecular chaperones in modulating cell surface receptors and secreted proteins
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be Key words: Chaperones, BiP, GRP94, HSP90, calreticulin, Amyloid, Light Chain, Heavy Chain, B Cell Receptor, Insulin-like growth factors, Peptide, Stress Response, Development.
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26 Description of Research
8
1b6 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.
8
219 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.
8
355 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.
141 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.
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f3 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.
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20 Rotation Projects
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4d 1. Structure-function analysis of chaperones using cell-based assays
2c 2. Analysis of GRP94-deficient mice
3b 3. Proteomic analyses of chaperone-deficient cells
41 4. Analysis of an amyloid LC-expressing transgenic mouse
30 5. The GRP94-IGF axis in growth control
3d 6. Genetic analysis of chaperone action in C. elegans
8
1e Lab personnel:
29 Ostrovsky, O - Research Associate
27 Eletto, D - Postdoctoral Fellow
23 Dersh, D - Graduate Student
1c James, J - Technician
26 29
27
Description of Research Expertise
2b Research Interests8
65 Functions of molecular chaperones in modulating cell surface receptors and secreted proteins
8
be Key words: Chaperones, BiP, GRP94, HSP90, calreticulin, Amyloid, Light Chain, Heavy Chain, B Cell Receptor, Insulin-like growth factors, Peptide, Stress Response, Development.
8
26 Description of Research
8
1b6 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.
8
219 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.
8
355 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.
141 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.
8
f3 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.
8
20 Rotation Projects
8
4d 1. Structure-function analysis of chaperones using cell-based assays
2c 2. Analysis of GRP94-deficient mice
3b 3. Proteomic analyses of chaperone-deficient cells
41 4. Analysis of an amyloid LC-expressing transgenic mouse
30 5. The GRP94-IGF axis in growth control
3d 6. Genetic analysis of chaperone action in C. elegans
8
1e Lab personnel:
29 Ostrovsky, O - Research Associate
27 Eletto, D - Postdoctoral Fellow
23 Dersh, D - Graduate Student
1c James, J - Technician
26 29
23
120 Ostrovsky O, Ahmed NT, Argon Y: The chaperone activity of GRP94 toward insulin-like growth factor II is necessary for the stress response to serum deprivation. Mol. Biol. Cell 20(6): 1855-64, 2009 PMCID: PMC2655248.
f4 Biswas C, Ostrovsky O, Makarewich CA, Wanderling S, Gidalevitz T, Argon Y.: The peptide binding activity of GRP94 is regulated by calcium Biochem. J 405(2): 233-41, 2007.
11e Wanderling S, Simen BB, Ostrovsky O, Ahmed NT, Vogen SM, Gidalevitz T, Argon Y.: GRP94 is essential for mesoderm induction and muscle development because it regulates IGF-II. Mol. Biol. Cell 18(10): 3764-75, 2007.
df Elkabetz Y, Argon Y, Bar-Nun S.: Cysteines in the CH1 domain underlie retention of unassembled Ig heavy chains. J. Biol. Chem 280(15): 14402-12, 2005.
fb Davis PD, Raffen R, Dul LJ, Vogen MS, Williamson KE, Stevens JF, Argon Y.: Inhibition of amyloid fiber assembly by both BiP and its target peptide. Immunity 13(4): 433-442, 2000.
122 Dul JL1, Davis DP, Williamson EK, Stevens FJ, Argon Y.: Hsp70 and antifibrillogenic peptides promote degradation and inhibit intracellular aggregation of amyloidogenic light chains. J. Cell. Biol 152(4): 705-16, 2001.
140 Davis DP1, Gallo G, Vogen SM, Dul JL, Sciarretta KL, Kumar A, Raffen R, Stevens FJ, Argon Y.: Both the environment and somatic mutations govern the aggregation pathway of pathogenic immunoglobulin light chain. J. Mol. Biol 313(5): 1023-1036, 2001.
ff Vogen S, Gidalevitz T, Biswas C, Simen BB, Stein E, Gulmen F, Argon Y.: Radicicol-sensitive peptide binding to the N-terminal portion of GRP94. J. Biol. Chem 277(43): 40742-50, 2002.
129 Gidalevitz T, Biswas C, Ding H, Schneidman-Duhovny D, Wolfson HJ, Stevens F, Radford S, Argon Y.: Identification of the N-terminal peptide binding site of glucose-regulated protein 94. J. Biol. Chem. 279(16): 16543-52, 2004.
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Selected Publications
115 Ostrovsky O, Makarewich CA, Snapp EL, Argon Y.: An essential role for ATP binding and hydrolysis in the chaperone activity of GRP94 in cells. Proc. Nat. Acad. Sci 106(28): 11600-5, 2009 PMCID: PMC2710619.120 Ostrovsky O, Ahmed NT, Argon Y: The chaperone activity of GRP94 toward insulin-like growth factor II is necessary for the stress response to serum deprivation. Mol. Biol. Cell 20(6): 1855-64, 2009 PMCID: PMC2655248.
f4 Biswas C, Ostrovsky O, Makarewich CA, Wanderling S, Gidalevitz T, Argon Y.: The peptide binding activity of GRP94 is regulated by calcium Biochem. J 405(2): 233-41, 2007.
11e Wanderling S, Simen BB, Ostrovsky O, Ahmed NT, Vogen SM, Gidalevitz T, Argon Y.: GRP94 is essential for mesoderm induction and muscle development because it regulates IGF-II. Mol. Biol. Cell 18(10): 3764-75, 2007.
df Elkabetz Y, Argon Y, Bar-Nun S.: Cysteines in the CH1 domain underlie retention of unassembled Ig heavy chains. J. Biol. Chem 280(15): 14402-12, 2005.
fb Davis PD, Raffen R, Dul LJ, Vogen MS, Williamson KE, Stevens JF, Argon Y.: Inhibition of amyloid fiber assembly by both BiP and its target peptide. Immunity 13(4): 433-442, 2000.
122 Dul JL1, Davis DP, Williamson EK, Stevens FJ, Argon Y.: Hsp70 and antifibrillogenic peptides promote degradation and inhibit intracellular aggregation of amyloidogenic light chains. J. Cell. Biol 152(4): 705-16, 2001.
140 Davis DP1, Gallo G, Vogen SM, Dul JL, Sciarretta KL, Kumar A, Raffen R, Stevens FJ, Argon Y.: Both the environment and somatic mutations govern the aggregation pathway of pathogenic immunoglobulin light chain. J. Mol. Biol 313(5): 1023-1036, 2001.
ff Vogen S, Gidalevitz T, Biswas C, Simen BB, Stein E, Gulmen F, Argon Y.: Radicicol-sensitive peptide binding to the N-terminal portion of GRP94. J. Biol. Chem 277(43): 40742-50, 2002.
129 Gidalevitz T, Biswas C, Ding H, Schneidman-Duhovny D, Wolfson HJ, Stevens F, Radford S, Argon Y.: Identification of the N-terminal peptide binding site of glucose-regulated protein 94. J. Biol. Chem. 279(16): 16543-52, 2004.
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