Research Interests

Ese Proteins are novel regulators of the Endocytosis/Signaling.
The strength, duration and mechanism of signaling from growth factor receptors are controlled through regulation of endocytosis and recycling. We have recently identified a novel and complex family of endocytic proteins. These Ese proteins possess up to 11 protein-protein interaction domains including two EH domains, a coiled-coil domain, up to five SH3 domains, a DBL domain, a PH domain and a C2 domain.

We have also found that Ese proteins can bind to Eps15(R), Dynamin, and Epsin to regulate endocytosis through clathrin coated pits. We are currently investigating the role of Ese proteins in endocytosis, signaling and development using cultured cells and Ese mutant mice.

Analysis of the Fringe/Notch signaling system.
The Notch family receptors have been implicated in development of most tissues in complex animals. We are interested in how the Notch receptors are activated. To this end we identified mammalian Fringe proteins (Lunatic, Manic and Radical Fringe) which control Notch activation in response to Delta and Serrate family ligands. The biochemical mechanism by which Fringes regulate Notch activation is under investigation.

The role of Notch activation and signaling in mammary development/cancer.
We are studying how the Notch system is activated during mouse mammary gland development, and what role the Notch receptor system plays in regulation of growth and differentiation of mammary epithelial cells in vivo. We have recently determined that Notch activation regulates organization and differentiation of mammary alveoli during pregnancy.

Publications

Adams JR, Xu K, Liu JC, Agamez NM, Loch AJ, Wong RG, Wang W, Wright KL, Lane TF, Zacksenhaus E, Egan SE. Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation. Cancer Res. 71:2706-2717, 2011.

Xu K, Nieuwenhuis E, Cohen BL, Wang W, Canty AJ, Danska JS, Coultas L, Rossant J, Wu MY, Piscione TD, Nagy A, Gossler A, Hicks GG, Hui CC, Henkelman RM, Yu LX, Sled JG, Gridley T, Egan SE. Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis. Am J Physiol Lung Cell Mol Physiol. 298(1):L45-56, 2010.

Tan JB, Xu K, Cretegny K, Visan I, Yuan JS, Egan SE and Guidos CJ. Lunatic and manic fringe cooperatively enhance marginal zone B cell precursor competition for delta-like 1 in splenic endothelial niches. Immunity 30:254-63, 2009.

Reedijk M, Odorcic S, Zhang H, Chetty R, Tennert C, Dickson BC, Lockwood G, Gallinger S, and Egan SE. Activation of Notch signaling in human colon adenocarcinoma. International Journal of Oncology 33:1223-1229, 2008.

Wang W, Bouhours M, Gracheva EO, Liao EH, Xu K, Sengar AS, Xin X, Roder J, Boone C, Richmond JE, Zhen M, Egan SE. ITSN-1 controls vesicle recycling at the neuromuscular junction and functions in parallel with DAB-1. Traffic. 9:742-754, 2008.

Reedijk M, Pinnaduwage D, Dickson BC, Mulligan A-M, Zhang H, Bull SB, O’Malley FP, Egan SE* and Andrulis IL*. JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer. Breast Cancer Research and Treatment. 111:439-448, 2008. * Co-corresponding authors.

Egan SE and Sengar AS Intersectin2 AfCS-Nature Molecule Pages (doi:10.1038/mp.a000881.01), 2006.

Reedijk M, Odorcic S, Chang L, Zhang H, Miller N, McCready D, Lockwood G, Egan SE. High-level co-expression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Research. 65:8530-8537, 2005.

Egan SE and Sengar AS. Intersectin1 AfCS-Nature Molecule Pages (doi:10.1038/mp.a000086.01), 2005.

Koch U, Lacombe TA, Holland D, Bowman JL, Cohen BL, Egan SE, Guidos CJ. Subversion of the T/B lineage decision in the thymus by Lunatic Fringe-mediated inhibition of Notch1. Immunity. 15:225-236, 2001.

Sengar AS, Wang W, Cohen S, Bishay J, Egan SE. The EH and SH3 domain Ese proteins regulate endocytosis by linking to dynamin and Eps15. EMBO Journal, 18: 1159-1171, 1999.

Cohen B, Bashirullah A, Dagnino L, Campbell C, Fisher WW, Leow CC, Whiting E, Ryan D, Zinyk D, Boulianne G, Hui C-c, Gallie B, Phillips RA, Lipshitz HD, Egan SE. Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila. Nature Genetics, 16: 283-288, 1997.

Wang W, Fisher EMC, Jia C, Dunn J, Porfiri J, Downward J, Egan SE. The Grb2 binding domain of mSos1 is not required for downstream signal transduction. Nature Genetics, 10: 294-300, 1995.

Review Articles:

Hinck L, Lewis MT, Egan SE. (Editors). Milking biological diversity for all its worth – What do other model systems teach us about mammary gland development and function. Journal of Mammary Gland Biology and Neoplasia. Volume 11:183-185, 2006.

Callahan R and Egan SE. Notch Signaling in Mammary Development and Oncogenesis. Journal of Mammary Gland Biology and Neoplasia. 9(2):145-63. 2004