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Molecular mechanism of a cross-talk between oestrogen and growth factor signalling pathways
S Kato1, Y Masuhiro, M Watanabe
1The Institute of Molecular and Celluar Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. uskato@mail.ecc.u-tokyo.ac.jp
Abstract:
Oestrogen (E2) plays significant roles in variety of biological events such as the development and maintenance of female reproductive organs, bone and lipid metabolisms. More recently, from study of knock-out mice deficient in oestrogen receptor (ER) alpha and ERbeta it turned out that normal spermatogenesis requires the E2 actions. Furthermore, this female steroid hormone is also well known to be deeply involved in many pathophysiological events such as osteoporosis and cancer development in female reproductive organs. It is particularly well known that most breast cancer is dependent on E2 in its development. Such E2 actions are thought to be mediated through two subtypes of ERs. Growth factors have been shown to synergize in this E2 signalling pathway, although the actual molecular mechanism largely remains unknown. Recently, we found that the MAP kinase activated by growth factors phosphorylates the Ser118 residue of the human ERalpha A/B domain and this phosphorylation potentiates the N-terminal transactivation function (AF-1) of human ERalpha, indicating the possible molecular mechanism of a novel cross-talk between E2 and growth factor signalling pathways. More recently, we have identified a coactivator associating with the hERalpha AF-1 in a MAPK-mediated phosphorylation-dependent manner. In this review, the molecular mechanism of this cross-talk is discussed in terms of the transactivation function of ERs, and their coactivators.
Insights
Oestrogen (E2) signaling, crucial for reproduction and metabolism, involves oestrogen receptors (ERs). Growth factors enhance E2 pathways by phosphorylating ERalpha, revealing a novel cross-talk mechanism.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Signaling
Background:
- Oestrogen (E2) is vital for female reproductive health, bone, and lipid metabolism.
- E2 actions are mediated by oestrogen receptors (ERs), with roles extending to spermatogenesis and diseases like breast cancer.
- Growth factors are known to interact with E2 signaling, but the molecular basis remains unclear.
Purpose of the Study:
- To elucidate the molecular mechanism of cross-talk between oestrogen and growth factor signaling pathways.
- To investigate the role of MAP kinase in phosphorylating oestrogen receptor alpha (ERalpha).
- To identify coactivators involved in the ERalpha signaling pathway.
Main Methods:
- Studies involving knock-out mice deficient in ERalpha and ERbeta.
- Analysis of MAP kinase-mediated phosphorylation of the human ERalpha A/B domain at Ser118.
- Identification of coactivators associating with hERalpha AF-1.
Main Results:
- MAP kinase phosphorylates Ser118 on human ERalpha, enhancing its N-terminal transactivation function (AF-1).
- This phosphorylation establishes a molecular link between E2 and growth factor signaling pathways.
- A novel coactivator has been identified that interacts with hERalpha AF-1 in a phosphorylation-dependent manner.
Conclusions:
- The findings reveal a novel cross-talk mechanism between oestrogen and growth factor signaling.
- MAPK-mediated phosphorylation of ERalpha is a key event in potentiating its transactivation function.
- This research sheds light on the intricate regulation of ERalpha activity and its coactivator interactions.