Avrom Caplan

program: Molecular cellular and developmental biology
office: Marshak J713, 212-650 8614
lab: Marshak J719/J723
Laboratory personnel
Postdocs: Atin K. Mandal PhD, Maria Theokoraki PhD
Graduate student: Nadinath Nillegoda
Undergraduate student: Daniel Nekola

Research
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.

Recent publications
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-transla tional maturation. J. Cell Biol. 176, 319-328.
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.

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.