Human Progesterone Receptor Crosstalk with Cytoplasmic Signaling Molecules Through Direct SH3 Domain Interaction

Abstract

Progesterone (PG) exerts its biological effects through the nuclear progesterone receptor (PR) which binds DNA to directly regulate gene transcription (1). However, not all effects of PG can be explained by the well-established roles of PR as transcription factor. There is increasing evidence that PG has rapid effects independent of gene transcription to alter cytoplasmic signaling pathways and ion channels. Rapid non-genomic actions of progesterone include PG-induced acceleration of Xenopus oocyte maturation(2, 3), stimulation of acrosome reaction in sperm, modulation of neurotransmitter and neural excitability (4) and activation of Src/Ras/MAPK pathway in breast cancer cells (5) . Surprisingly, some of these rapid non-genomic effects of PG have been shown to be mediated, at least in part, by the same nuclear PR that regulates gene transcription (5, 6) . However, mechanisms of how nuclear PR mediates these rapid non-genomic effects of PG are not well characterized. What has been missing is an understanding of how a nuclear receptor can activate signaling pathways, and a mechanistic basis for protein-interaction with signaling molecules.