A Dual Functional Switch in Reproductive Biology

摘要 雌激素受体的两种亚型ER a和ER b在乳腺癌中发挥非重叠的功能。 生殖生物学ERb既能干扰ERa的功能，又能发挥其生物学活性 独立于ER。目前尚不清楚ERb的ERa独立功能和ERa竞争功能是如何发挥作用的。 监管.我们最近开创性地发现了ERb特异性磷酸酪氨酸开关， 调节生殖器官中的ERb功能。根据我们的初步工作，我们假设一个单一的 磷酸酪氨酸开关在两种不同的ERb功能之间切换：而磷酸化的ERb是活跃的 在卵巢卵泡发生中，非磷酸化的ERb在其ERa-依赖性功能中更有效， 在乳腺发育中的竞争功能。有一整套独特的工具，包括一个磷酸- 特异性抗体和敲入动物模型，我们理想地定位于测试这一新的假设， 研究磷酸酪氨酸开关如何差异调节两种不同的ERb活性。的概念 ERb的两种不同活性之间的分子切换代表了一种以前未被认识的机制， 其通过单个信号转导开关整合了对两种亚型特异性ERb活性的控制。此外该 在我们的工作中开发的独特的技术工具和实验模型将极大地促进对 生殖生物学中的内分泌功能。

ABSTRACT The two subtypes of estrogen receptor, ERa and ERb, carry out non-overlapping functions in reproductive biology. ERb is capable of both interfering with ERa function and exerting its biological activity independent of ERa. It remains unclear how the ERa-independent and ERa-competing functions of ERb are regulated. We recently made the pioneering discovery of an ERb-specific phosphotyrosine switch that regulates ERb function in reproductive organs. Based on our preliminary work, we hypothesize that a single phosphotyrosine switch toggles between two different ERb functions: while phosphorylated ERb is active in 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 by investigating how the phosphotyrosine switch differentially regulates two distinct ERb activities. The concept of a molecular toggle between two distinct activities of ERb represents a previously unappreciated mechanism that integrates control of two subtype-specific ERb activities through a single signaling switch. In addition, the unique technical tools and experimental models developed in our work will greatly promote in-depth studies of endocrine functions in reproductive biology.