title: An Evolution-Guided Analysis Reveals a Multi-Signaling Regulation of Fas by Tyrosine Phosphorylation and its Implication in Human Cancers.
abstract: Demonstrations of both pro-apoptotic and pro-survival abilities of Fas (TNFRSF6/CD95/APO-1) have led to a shift from the exclusive "Fas apoptosis" to "Fas multisignals" paradigm and the acceptance that Fas-related therapies face a major challenge, as it remains unclear what determines the mode of Fas signaling. Through protein evolution analysis, which reveals unconventional substitutions of Fas tyrosine during divergent evolution, evolution-guided tyrosine-phosphorylated Fas proxy, and site-specific phosphorylation detection, we show that the Fas signaling outcome is determined by the tyrosine phosphorylation status of its death domain. The phosphorylation dominantly turns off the Fas-mediated apoptotic signal, while turning on the pro-survival signal. We show that while phosphorylations at Y232 and Y291 share some common functions, their contributions to Fas signaling differ at several levels. The findings that Fas tyrosine phosphorylation is regulated by Src family kinases (SFKs) and the phosphatase SHP-1 and that Y291 phosphorylation primes clathrin-dependent Fas endocytosis, which contributes to Fas pro-survival signaling, reveals for the first time the mechanistic link between SFK/SHP-1-dependent Fas tyrosine phosphorylation, internalization route, and signaling choice. We also demonstrate that levels of phosphorylated Y232 and Y291 differ among human cancer types and differentially respond to anticancer therapy, suggesting context-dependent involvement of Fas phosphorylation in cancer. This report provides a new insight into the control of TNF receptor multisignaling by receptor phosphorylation and its implication in cancer biology, which brings us a step closer to overcoming the challenge in handling Fas signaling in treatments of cancer as well as other pathologies such as autoimmune and degenerative diseases.
authors.affiliation: Univ. Nice Sophia Antipolis, CNRS, Inserm, iBV, 06100 Nice, France.
authors.forename: Krittalak
authors.initials: K
authors.lastname: Chakrabandhu
authors.affiliation: Univ. Nice Sophia Antipolis, CNRS, Inserm, iBV, 06100 Nice, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Huault
authors.affiliation: Univ. Nice Sophia Antipolis, CNRS, Inserm, iBV, 06100 Nice, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Durivault
authors.affiliation: Univ. Nice Sophia Antipolis, CNRS, Inserm, iBV, 06100 Nice, France.
authors.forename: Kévin
authors.initials: K
authors.lastname: Lang
authors.affiliation: Univ. Nice Sophia Antipolis, CNRS, Inserm, iBV, 06100 Nice, France.
authors.forename: Ly
authors.initials: L
authors.lastname: Ta Ngoc
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Marseille, France, INSERM, U1104, Marseille, France, and CNRS, UMR 7280, Marseille, France.
authors.forename: Angelique
authors.initials: A
authors.lastname: Bole
authors.affiliation: Univ. Nice Sophia Antipolis, CNRS, Inserm, iBV, 06100 Nice, France.
authors.forename: Eszter
authors.initials: E
authors.lastname: Doma
authors.affiliation: Univ. Nice Sophia Antipolis, CNRS, Inserm, iBV, 06100 Nice, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Dérijard
authors.affiliation: Service de radiothérapie, Centre Antoine Lacassagne, Nice, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gérard
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Marseille, France, INSERM, U1104, Marseille, France, and CNRS, UMR 7280, Marseille, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Pierres
authors.affiliation: Univ. Nice Sophia Antipolis, CNRS, Inserm, iBV, 06100 Nice, France.
authors.forename: Anne-Odile
authors.initials: AO
authors.lastname: Hueber
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D004705:Endocytosis; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D019014:fas Receptor; D019061:src-Family Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6