The tyrosine phosphorylated pro-survival form of Fas intensifies the EGF-induced signal in colorectal cancer cells through the nuclear EGFR/STAT3-mediated pathway

Sci Rep. 2018 Aug 20;8(1):12424. doi: 10.1038/s41598-018-30804-z.

Abstract

Tyrosine phosphorylation of Fas (TNFRSF6/CD95) in its death domain turns off Fas-mediated apoptosis, turns on the pro-survival signal, and has implications in different cancers types. We show here that Fas in its pro-survival state, phosphorylated at Y291 (pY291-Fas), functionally interacts with the epidermal growth factor receptor (EGFR), a key cancer-driving protein and major therapeutic target. Using an evolution-guided pY291-Fas proxy, RNA interference, and site-specific phospho-protein detection, we show that pY291-Fas significantly intensifies EGFR signaling in anti-EGFR-resistant colorectal cancer cells via the Yes-1/STAT3-mediated pathway. The pY291-Fas is essential for the EGF-induced formation of the Fas-mediated nuclear EGFR/STAT3 signaling complex consisting of Fas, EGFR, Yes-1, Src, and STAT3. The pY291-Fas accumulates in the nucleus upon EGF treatment and promotes the nuclear localization of phospho-EGFR and phospho-STAT3, the expression of cyclin D1, the activation of STAT3-mediated Akt and MAPK pathways, and cell proliferation and migration. This novel cancer-promoting function of phosphorylated Fas in the nuclear EGFR signaling constitutes the foundation for developing pro-survival-Fas targeted anti-cancer therapies to overcome disease recurrence in patients with anti-EGFR resistant cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Cell Nucleus / metabolism
  • Cell Proliferation / physiology
  • Colorectal Neoplasms / metabolism*
  • Cyclin D1 / metabolism
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / metabolism
  • HCT116 Cells
  • Humans
  • Neoplasm Recurrence, Local / metabolism
  • Phosphorylation / physiology*
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / physiology
  • Tyrosine / metabolism*
  • fas Receptor / metabolism*

Substances

  • FAS protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • fas Receptor
  • Cyclin D1
  • Tyrosine
  • Epidermal Growth Factor
  • EGFR protein, human
  • ErbB Receptors