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.
Ta NL1,2, Chakrabandhu K3, Huault S1, Hueber AO4.
Author information
1. Université Côte d’Azur, CNRS, Inserm, iBV, Côte d’Azur, France.
2. The University of Da-Nang, University of Science and Technology, Da-Nang, Vietnam.
3. Université Côte d’Azur, CNRS, Inserm, iBV, Côte d’Azur, France. chakraba@unice.fr.
4. Université Côte d’Azur, CNRS, Inserm, iBV, Côte d’Azur, France. hueber@unice.fr.
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.