Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis Academic Article uri icon


MeSH Major

  • Estradiol
  • Lymphangioleiomyomatosis
  • Mitogen-Activated Protein Kinase 1
  • TOR Serine-Threonine Kinases


  • Lymphangioleiomyomatosis (LAM) is a destructive lung disease of women associated with the metastasis of tuberin-null cells with hyperactive mammalian target of rapamycin complex 1 (mTORC1) activity. Clinical trials with the mTORC1 inhibitor rapamycin have revealed partial efficacy but are not curative. Pregnancy appears to exacerbate LAM, suggesting that estrogen (E2) may play a role in the unique features of LAM. Using a LAM patient-derived cell line (bearing biallelic Tuberin inactivation), we demonstrate that E2 stimulates a robust and biphasic activation of ERK2 and transcription of the late response-gene Fra1 associated with epithelial-to-mesenchymal transition. In a carefully orchestrated collaboration, activated mTORC1/S6K1 signaling enhances the efficiency of Fra1 translation of Fra1 mRNA transcribed by the E2-ERK2 pathway, through the phosphorylation of the S6K1-dependent eukaryotic translation initiation factor 4B. Our results indicate that targeting the E2-ERK pathway in combination with the mTORC1 pathway may be an effective combination therapy for LAM.

publication date

  • September 10, 2013



  • Academic Article



  • eng

PubMed Central ID

  • PMC3773757

Digital Object Identifier (DOI)

  • 10.1073/pnas.1309110110

PubMed ID

  • 23983265

Additional Document Info

start page

  • 14960

end page

  • 5


  • 110


  • 37