- LECTURER Pharmacology and Systems Therapeutics
Excellence in Teaching Award
Mount Sinai School of Medicine
Dr. Caplan is a PF Applicant for the Mount Sinai Liver Diseases Research Center.
Molecular chaperone proteins in signal transduction processes
My laboratory studies the role of molecular chaperone proteins in signal transduction processes. This new field brings together the study of protein folding with the familiar problem of how signals are transmitted in biological systems. Our case study is the human androgen receptor: a major target of drugs used to control prostate cancer. We are characterizing how the androgen receptor is regulated by proteins that have been traditionally thought to participate in protein folding events - the so-called molecular chaperones. These proteins, called Hsp90, Hsp70, and dnaJ, regulate the conformation of the androgen receptor to maintain it in an inactive conformation prior to hormone binding. Upon hormone binding, the receptor is "activated" to become a transcription factor that controls the activity of its target genes. We study how the Hsp90, Hsp70, and dnaJ molecular chaperones maintain the inactive conformation and how androgens transform it to the active conformation.
In these studies, we use a combination of genetics and biochemistry. For the genetics, the yeast Saccharomyces cerevisiae is used to understand how mutations in different molecular chaperone genes alter androgen receptor function. The biochemical studies use in vitro translation systems to characterize molecular details of the assembly and disassembly processes between molecular chaperones and the androgen receptor.
Caplan A, Ma'ayan A, Willis IM. Multiple Kinases and System Robustness: A Link Between Cdc37 and Genome Integrity. Cell Cycle 2007 Dec; 6(24): 3145-7.
Caplan AJ, Mandal AK, Theodoraki MA. Molecular chaperones and protein kinase quality control. Trends Cell Biol 2007 Feb ; 17(2): 87-92.
Mandal AK, Lee P, Chen JA, Nillegoda N, Heller A, Distasio S, Oen H, Victor J, Nair DM, Brodsky JL, Caplan AJ. Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation.. J Cell Biol 2007 Jan 29; 176(3): 319-328.
Robzyk K, Oen H, Buchanan G, Butler LM, Tilley WD, Mandal AK, Rosen N, Caplan AJ. Uncoupling of hormone-dependence from chaperone-dependence in the L701H mutation of the androgen receptor.. Mol Cell Endocrinol 2007 March 30; 268(1-2): 67-74.
Fan CY, Ren HY, Lee P, Caplan AJ, Cyr DM. The type I Hsp40 zinc finger-like region is required for Hsp70 to capture non-native polypeptides from Ydj1. J Biol Chem 2005 Jan 7; 280(1): 695-702.
Shabbir A, Distasio S, Zhao J, Cardozo CP, Wolff MS, Caplan AJ. Differential effects of the organochlorine pesticide DDT and its metabolite p,p'-DDE on p-glycoprotein activity and expression. Toxicol Appl Pharmacol 2005 Mar 1; 203(2): 91-98.
Zhao Q, Boschelli F, Caplan AJ, Arndt K. Identification of a Conserved Sequence Motif that Promotes Cdc37 and Cyclin D1 Binding to Cdk4. J Biol Chem 2004; 279: 12560-12564.
Lee P, Shabbir A, Cardozo C, Caplan AJ. Sti1 stabilizes Cdc37 and Hsp90 in chaperone complexes with a protein kinase. Mol Biol Cell 2004; 15(4): 1785-1792.
Zhao J, Bauman WA, Huang R, Caplan A, Cardozo C. Oxandrolone blocks glucocorticoid receptor signaling in an androgen receptor dependent manner. Steroids 2004; 69(5): 357-366.
Cardozo CP, Michaud C, Ost MC, Fliss AE, Yang E, Patterson C, Hall SJ, Caplan AJ. Chip reduces the rate of androgen receptor synthesis. Arch Biochem Biophys 2003; 410: 134-140.
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