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Avrom Caplan
P | 212.650.8614
E | acaplan@sci.ccny.cuny.edu
Dr. Caplan is currently serving as the CUNY Associate University Dean for Research
Education
BSc. University of Sussex, 1978
MSc. University of London, 1983
PhD. University of London, 1987
Research interests
Protein quality control and cellular systems robustness
Quality control processes regulate protein homeostasis by promoting polypeptide folding, degradation and in some cases controlled aggregation. Polypeptide folding is mediated by molecular chaperones that interact with exposed hydrophobic surfaces. This reduces aggregation but can also result in targeting towards the ubiquitin/proteasome machinery for degradation. As humans age there is down-regulation of quality control systems that inversely correlates with onset of neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease. In addition, molecular chaperones buffer phenotypic change during development, regulate the onset of tumorigenesis and appear to have a general role in cellular robustness.
Our studies utilize a yeast model system to analyze the fate of newly made polypeptides; to determine the mechanisms underlying whether they will fold or be targeted towards the degradation machinery. We will also determine consequences of this fate determination to cellular systems robustness as defined by the ability of cells to withstand stressful change. These studies utilize genetics as a primary tool including whole genome screens and also biochemical approaches. We anticipate being able to expand into metazoan models such as C. elegans or D. melanogaster in the future.
A second approach is the study of Hsp90 molecular chaperone inhibitors in the treatment of cancer. These inhibitors are currently in clinical trials because of their ability to stimulate degradation of several different oncogenic protein kinases. Our studies analyze the mechanisms underlying this effect and investigate how such inhibitors come to be more effective in cancer cells than in cells from healthy tissue. We use mammalian cell culture models for these studies.
Publications (since 2007):
Mandal, A., Nair, D. and Caplan, A. J. (2007). Role of Cdc37 in protein kinase folding. In Cell Stress Proteins, edited by S. Calderwood. Springer press, 326-337.
Caplan, A. J., Mandal, A., and Theodoraki, M. (2007). Molecular chaperones and protein kinase quality control. Trends in Cell Biology, 17, 87-92.
Mandal, A. K., Lee, P., Chen, J. A., Nillegoda, N., Heller, A., DiStasio, S., Oen, H., Victor, J., Nair, D. M. and Caplan, A. J. (2007). Cdc37 has distinct roles in protein kinase quality control that protects nascent chains from degradation and promotes post-translational maturation. J. Cell Biol. 176, 319-328
Robzyk, K., Oen, H., Mandal, A. K.,Tilley, W., Rosen, N. and Caplan A. J. (2007). Uncoupling of Hormone-dependence from chaperone-dependence in the L701H mutation of the androgen receptor. Mol. Cell Endocrinology 268, 67-74.
Ren, R., Santhanam, A., Lee, P., Caplan, A. J. and Garrett, S. (2007) Alteration of the Putative Protein Kinase Binding Domain Enhances Function of the Yeast Chaperone Cdc37. Eukaryotic Cell, 6, 1363-1372.
Theodoraki, M., Kunjappu, M., Sternberg, D. and Caplan, A. J. (2007). Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context. Experimental Cell Research, 313, 3851-3858.
Caplan, A. J., Ma’Ayaan, A. Willis, I. M. (2007). Multiple kinases and system robustness: a link between Cdc37 and genome integrity. Cell Cycle 6, 3145-7.
Matts, R. and Caplan, A. J. (2007). Cdc37 and protein kinase folding. In Heat Shock proteins in cancer. Edited by Stuart K Calderwood, Daniel Ciocca and Michael Sherman. Springer press. Chapter 16, pp. 331-350
Mandal, A. K., Nillegoda, N. B., Chen, J. A. and Caplan, A. J. (2008). Ydj1 protects nascent protein kinases from degradation and controls the rate of their maturation. Mol. Cell Biol. 28, 4434-4444. Recommended pick by the Faculty of 1000 (Biology)
Mandal, A. K., Gibney, P. A., Nillegoda, N. B., Theordoraki, M. A., Caplan, A. J. and Morano, K. A. (2010). Hsp110 chaperones control differential fate determination of clients of the Hsp70/Hsp90 chaperone system. Mol. Biol. Cell. 21, 1439-1448.
Nillegoda, N. B., Theodoraki, M. A., Mandal, A. K., Mayo, K. J. Ren, H. Y., Sultana, R., Wu, K., Johnson, J., Cyr, D. M. and Caplan, A. J. (2010). Ubr1 and Ubr2 function in a quality control pathway for degradation of unfolded cytosolic proteins. Mol. Biol. Cell, 21, 2102-2116
Mandal, A. K., Theodoraki, M. A., Nillegoda, N. B. and Caplan, A. J. (2010). Role of Molecular Chaperones in Biogenesis of the Protein Kinome. Methods in Molecular Biology. Submitted.
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