Ph.D., Indiana University
Tel: (617) 552-2781
E-mail: annette.parks.1@bc.edu
Fields of Interest
Cell-cell signaling during development. Role of subcellular trafficking during signal transduction.
Academic Profile
Understanding the mechanisms underlying cell fate specification is a principal goal of developmental biology and something that has fascinated me throughout most of my scientific career. Working with Dr. Marc Muskavitch, I am currently investigating the regulation and function of the Notch signaling pathway. Activation of this pathway occurs when a transmembrane signal protein, Delta, expressed on one cell, binds to a transmembrane receptor protein, Notch, on the surfaces of neighboring cells. The result is signaling within the Notch cell that controls numerous cell fate decisions during the development of most multicellular organisms, including mammals. Perturbations in Notch signaling in humans has been associated with several cancers, including T-cell leukemia and breast cancer, as well as a number of genetic disorders such as congenital heart disease. Understanding how this pathway is regulated may therefore help in understanding and treating certain human cancers and diseases.
Our recent work has focused on the role of subcellular trafficking in regulation and activation of Notch signaling. Previous work by myself and others has shown that Notch signaling is extraordinarily sensitive to perturbations in subcellular trafficking and, in particular, disruption of the endocytic machinery. Several lines of evidence suggest that Delta is normally transported to the cell surface and is then efficiently removed by endocytosis. Intriguingly, during normal signaling, the Notch protein dissociates and the Notch extracellular domain is taken up into neighboring Delta-expressing cells where it co-localizes with Delta in vesicles. Disruption of Delta endocytosis in Drosophila resulting from mutations in Delta itself, mutations in endocytic genes, or mutations in genes that probably modify and target Delta for endocytosis, all result in loss of Notch signaling and, at least in some cases, loss of Notch dissociation. Endocytosis has now been implicated in Notch signaling in several organisms; however, the role that endocytosis plays in Delta-Notch signaling still eludes us. We have hypothesized that endocytosis is required during signaling, while Delta is bound to Notch, to generate a change in Notch or other Notch-bound proteins that then makes Notch competent for the next step in the signaling process (proteolysis). Others have postulated that endocytosis is required prior to signaling to transport Delta to, or through, a special intracellular compartment where it is activated.
We are using a variety of techniques to define the roles of endocytosis in the Notch pathway, including the use of genetic screens, molecular biology, immunochemistry, and cell biological techniques in whole organisms (Drosophila) and in insect and mammalian cell culture systems. We hope that determining the means by which subcellular trafficking contributes to regulation and activation of Notch signaling will advance not only our understanding of the mechanisms of the Delta-Notch interaction, but will also help to elucidate how cells regulate signals used in intercellular communication during normal development and in disease states.
Representative Publications
Parks, A. L., Shalaby, N. A., and Muskavitch, M. A. T. 2008. Notch and suppressor of Hairless regulate levels but not patterns of Delta expression in Drosophila. Genesis 46: 265–275.
Parks, A. L., and Curtis, D. 2007. Presenilin diversifies its portfolio. Trends in Genetics 23(3): 140.
Parks, A. L., Stout, J. R., Shepard, S. B., Klueg, K. M., Dos Santos, A. A., Parody, T. R., Vaskova, M., and Muskavitch, M. A. T. 2006. Structure-function analysis of Delta trafficking, receptor binding, and signaling in Drosophila. Genetics 174: 1947–1961.
Mahoney, M. B., A. L. Parks, D. A. Ruddy, S. Y. K. Tiong, H. Esengil, A. C. Phan, P. Philandrinos, C.G. Winter, R. Chatterjee, K. Huppert, W. W. Fisher, L. L’Archeveque, F. A. Mapa, W. Woo, M. C. Ellis, and D. Curtis. 2006. Presenilin-based genetic screens in Drosophila melangaster identify novel Notch pathway modifiers. Genetics 172: 2309.
Edgar, K. A., Belvin, M., Parks, A. L., Whittaker, K., Mahoney, M. B., Nicoll, M., Park, C., Winter, C. G., Chen, F., Lickteig, K., Tabios, M., Ahmad, F., Esengil, H., Lorenzi, M. V., Norton, A., Rupnow, B. A., Shayesteh, L., Young, L. M., Carroll, P., Kopczynski, C., Plowman, G., Friedman, L. S., Francis-Lang, H. L. 2005. Synthetic lethality of retinoblastoma mutant cells in the Drosophila eye by mutation of a novel peptidyl prolyl isomerase gene. Genetics 170: 161.
Parks, A. L., Cook, K. R., Belvin, M., Dompe, N. A., Fawcett, R, Huppert, K, Tan, L. R., Winter, C. G., Bogart, K. P., Deal, J. E., Deal-Herr, M. E., Grant, D., Marcinko, M., Miyazaki, W. Y., Robertson, S., Shaw, K. J., Tabios, M., Vysotskaia, V., Zhao, L., Andrade, R. S., Edgar, K. A., Howie, E., Killpack, K., Milash, B., Norton, A., Thao, D., Whittaker, K., Winner, M. A., Friedman, L., Margolis, J., Singer, M. A., Kopczynski, C., Curtis, D., Kaufman, T. C., Plowman, G. D., Duyk, G., Francis-Lang, H. L. 2004. Systematic generation of high-resolution deletion coverage of the Drosophila genome. Nature Genetics 36: 288.
Francis, R., McGrath, G., Zhang, J., Ruddy, D.A., Sym, M., Apfeld, J., Nicoll, M., Maxwell, M., Hai, B., Ellis, M.C., Parks, A.L., Xu, W., Li, J., Gurney, M., Myers, R.L., Himes, C.S., Hiebsch, R., Ruble, C., Nye, J.S., and Curtis, D. 2002. aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and Presenilin protein accumulation. Developmental Cell 3: 85–97.
Parks, A. L., Klueg, K. M., Stout, J. R., and Muskavitch, M. A. T. 2000. Ligand endocytosis drives receptor dissociation and activation in the Notch pathway. Development 127: 1373–1385.
Helms, W., Hyung, L., Ammerman, M., Parks, A. L., Muskavitch, M. A. T., and Yedvobnick, B. 1999. Engineered truncations in the Drosophila Mastermind protein disrupt Notch pathway function. Developmental Biology 215(2): 358–374.
Parks, A. L., Huppert, S. S., and Muskavitch, M. A. T. 1997. The dynamics of neurogenic signaling underlying bristle development in Drosophila melanogaster. Mechanisms of Development 63: 61–74.
Parks, A. L., Turner, F. R., and Muskavitch, M. A. T. 1995. Relationships between complex Delta expression and the specification of retinal cell fates during Drosophila eye development. Mechanisms of Development 50: 201–216.
Parks, A. L., and Muskavitch, M. A. T. 1993. Delta function is required for bristle organ determination and morphogenesis in Drosophila. Developmental Biology 157: 484–496.
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