Cross-talk between tuberin, calmodulin, and estrogen signaling pathways

Lymphangioleiomyomatosis (LAM) is a rare disease that occurs primarily in women and has been linked to both estrogen-mediated signaling events and mutations associated with the tuberous sclerosis complex 2 gene product tuberin. These two observations fostered the hypothesis that tuberin's impact on estrogen-mediated signaling might be through a direct interaction with the intracellular receptor for estrogen, estrogen receptor alpha (ER alpha). In the study presented here, tuberin was shown to co-immunoprecipitate and directly bind ER alpha through a domain localized within the carboxyl 73 amino acids of tuberin. This domain had previously been shown to serve as a binding domain for the intracellular calcium signaling molecule calmodulin (CaM). Competition binding studies identified a potential competitive relationship for binding of tuberin by ER alpha and CaM. Additionally, tuberin-ER alpha interactions were found to be modulated by the presence of tuberin's predominant intracellular binding partner hamartin, suggesting that tuberin-hamartin interactions negatively impact the ability of tuberin to modulate ER alpha-mediated gene transcription events. Cumulatively, data presented here support the hypothesis that interactions between tuberin, ER alpha, and CaM may play a critical role in the pathology of LAM disease.