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

FASEB J. 2005 Jul;19(9):1202-4. doi: 10.1096/fj.04-3142fje. Epub 2005 Apr 25.


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 (ERalpha). In the study presented here, tuberin was shown to co-immunoprecipitate and directly bind ERalpha 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 ERalpha and CaM. Additionally, tuberin-ERalpha 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 ERalpha-mediated gene transcription events. Cumulatively, data presented here support the hypothesis that interactions between tuberin, ERalpha, and CaM may play a critical role in the pathology of LAM disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding, Competitive
  • Calmodulin / metabolism*
  • DNA / metabolism
  • Estrogen Receptor alpha / physiology*
  • Estrogens / physiology*
  • Female
  • Humans
  • Lymphangioleiomyomatosis / etiology*
  • Signal Transduction / physiology*
  • Transcription, Genetic
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • Calmodulin
  • Estrogen Receptor alpha
  • Estrogens
  • TSC1 protein, human
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • DNA