A new link in a mysterious signalling chain

Abstract

Progesterone, the steroid hormone affecting multiple tissues and reproductive functions in mammals through its prowess as a transcription activator, has a mechanistically different effect on Xenopus oocytes. It interacts with an unidentified receptor to set off a cascade of transcription-independent events culminating in the translational activation of many mRNAs, the most crucial being the polyadenylation and translation of c-Mos. As a MAP kinase kinase kinase, c-Mos is required for MAP kinase activation and the subsequent activation of the universal M-phase-promoting factor (MPF). Although the mechanisms of translation regulation in this system and in others are becoming well understood, uncovering the pathway that leads from progesterone stimulation to c-Mos translation has been slow going. Recently, Mendez1xPhosphorylation of CPE binding factors by Eg2 regulates translation of c-mos mRNA. Mendez, R. et al. Nature. 2000; 404: 302–307Crossref | PubMed | Scopus (240)See all References1 and colleagues closed the gap between the signalling pathway and translational activation by showing that Eg2, a kinase activated early after progesterone stimulation, phosphorylates CPEB, the factor directly responsible for c-Mos polyadenylation and translation.Earlier studies demonstrated that CPEB is phosphorylated, as detected by mobility shift on western blotting, after MPF activation and hence after c-Mos translation. In this study, they demonstrate that 32P is incorporated into CPEB before c-Mos translation (this phosphorylation does not correspond to a mobility shift, explaining why it was missed previously). The early phosphorylation pattern of CPEB is different from the later pattern, and, when a phosphorylated serine in the early phosphorylation site is changed to alanine, this mutant CPEB functions as a dominant negative, blocking both progesterone-stimulated c-Mos translation and MPF activation. The observations that Eg2 kinase activation occurs at about the same time that the CEB is phosphorylated (on the ‘early sites’) and Eg2 overexpression accelerates c-Mos translation suggested that there might be a link between Eg2 and CPEB- mediated c-Mos translation. This link is indeed real: in a colossal figure, the authors show that Eg2 binds CPEB, phosphorylating it on the very serine identified as required for c-Mos translation, and elimination of this association blocks polyadenylation and maturation.Identification of CPEB as an in vivo substrate for Eg2 provides the first link between the still sketchy progesterone-stimulated signalling pathway and the better-understood translational activation that is required for cell cycle re-entry in this system. This is, however, only the first step. The Eg2 activator remains unidentified, as does the progesterone receptor itself, and we await forthcoming studies to fill in these missing links.