Professor CUNY Associate University Dean For Research
Dr. Caplan investigates how protein homeostasis is regulated by promoting polypeptide folding or protein degradation or aggregation. His studies utilize a yeast model system to analyze the fate of newly made polypeptides and to determine the mechanisms underlying whether they will fold or be targeted towards the degradation machinery. His research also uses mammalian cell culture models to examine how molecular chaperone inhibitors can be used in the treatment of cancer.
Ph.D. in Biochemistry, King's College, University of London, 1987
M.Sc. in Biochemistry, University College, University of London, 1983
B.Sc. in Biology, University of Sussex, 1978
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.
Sultana, R., Theodoraki, M. and Caplan, A. J. (2011). UBR1 promotes protein kinase quality control and sensitizes cells to Hsp90 inhibition. Experimental Cell Research. In Press.
Theodoraki, M. A. and Caplan, A. J. (2011). Quality Control and Fate Determination of Hsp90 Client Proteins. Biochemica et Biophyscia Acta. In press.
Mandal, A. K., Theodoraki, M. A., Nillegoda, N. B. and Caplan, A. J. (2011). Role of Molecular Chaperones in Biogenesis of the Protein Kinome. Methods in Molecular Biology. 787, 75-81.
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., 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.
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).