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EGF potentiated oncogenesis requires a tissue transglutaminase-dependent signaling pathway leading to Src activation

Bo Li1, Marc A Antonyak, Joseph E Druso

  • 1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 19, 2010
PubMed

Insights

Epidermal Growth Factor Receptor (EGFR) signaling drives cancer growth by up-regulating tissue transglutaminase (tTG). Inhibiting tTG blocks EGFR-promoted breast cancer cell growth, revealing a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Epidermal Growth Factor Receptor (EGFR) signaling is critical for human cancer progression.
  • Identifying downstream proteins regulated by EGFR is key to developing targeted cancer therapies.

Purpose of the Study:

  • To identify proteins regulated by EGFR signaling in human cancers.
  • To investigate the role of tissue transglutaminase (tTG) in EGFR-mediated tumor growth.

Main Methods:

  • Investigated EGF-induced changes in protein expression in breast cancer cells.
  • Utilized gene knock-down and pharmacological inhibition of tTG.
  • Analyzed signaling pathways including Ras, Cdc42, PI 3-kinase, NFkappaB, and Src tyrosine kinase.
  • Examined the interaction between tTG and keratin-19.

Main Results:

  • EGF up-regulates tTG expression in human breast cancer cells.
  • tTG knock-down or inhibition blocks EGF-stimulated anchorage-independent growth.
  • EGF up-regulates tTG via Ras/Cdc42 activation of PI 3-kinase and NFkappaB.
  • Overexpression of wild-type tTG mimics EGF-induced growth advantages.
  • tTG-promoted growth depends on Src tyrosine kinase activation via a tTG-keratin-19 complex.

Conclusions:

  • Tissue transglutaminase (tTG) is a key mediator of EGFR-promoted breast cancer cell growth.
  • tTG acts downstream of EGFR and upstream of Src tyrosine kinase in a novel signaling pathway.
  • tTG represents a potential therapeutic target for inhibiting EGFR-driven tumor progression.

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