A DUAL FUNCTIONAL SWITCH IN REPRODUCTIVE BIOLOGY

The two subtypes of estrogen receptor, ERa and ERb, carry out non-overlapping functions inreproductive biology. ERb is capable of both interfering with ERa function and exerting its biological activityindependent of ERa. It remains unclear how the ERa-independent and ERa-competing functions of ERb areregulated. We recently made the pioneering discovery of an ERb-specific phosphotyrosine switch thatregulates ERb function in reproductive organs. Based on our preliminary work, we hypothesize that a singlephosphotyrosine switch toggles between two different ERb functions: while phosphorylated ERb is activein its ERa-independent function in ovarian folliculogenesis, unphosphorylated ERb is more potent in its ERa-competing function in mammary gland development. With a repertoire of unique tools including a phospho-specific antibody and a knockin animal model, we are ideally positioned to test this novel hypothesis byinvestigating how the phosphotyrosine switch differentially regulates two distinct ERb activities. The concept ofa molecular toggle between two distinct activities of ERb represents a previously unappreciated mechanismthat integrates control of two subtype-specific ERb activities through a single signaling switch. In addition, theunique technical tools and experimental models developed in our work will greatly promote in-depth studies ofendocrine functions in reproductive biology.