Relevance of c-Src and protein phosphatase 2A to aromatase activity: Evidence of an acute self-regulating oestrogenic signalling complex in rat central nervous system.

Abstract

We previously reported that aromatase protein levels do not parallel aromatase enzyme activity. This suggests that oestrogenic signalling may be modulated via post-translational modification of aromatase protein. The tyrosine and serine phosphorylation state of aromatase are known to influence its activity. To investigate the possible relevance of aromatase phosphorylation to the incongruity observed between aromatase protein and its activity, we explored interactions between aromatase and the tyrosine kinase c-Src and the serine protein phosphatases 2A and 5 (PP2A and PP5), as well as the relationship between levels of tyrosine-phosphorylated aromatase and the extrapolated aromatase activity. We found that (a) hypothalamic aromatase was significantly more heavily tyrosine-phosphorylated than spinal aromatase; (b) aromatase was oligomerized with c-Src and PP2A/PP5, potentially activating aromatase via tyrosine-phosphorylation and serine-dephosphorylation; (c) the associations of c-Src and PP2A/PP5 with hypothalamic aromatase were substantially greater than with spinal aromatase; and (d) aromatase, oestrogen receptor α, PP2A, and c-Src were present in a common membrane oligomer. The existence of c-Src and PP2A in an oligomer that also contains aromatase and membrane oestrogen receptor α (and presumably other signalling molecules) indicates the presence in the CNS of a potentially self-regulating oestrogenic signalling unit. The degree to which such a complex operates autonomously and the regulatory factors thereof are likely to have substantial physiological implications and clinical relevance.