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.
Highlights
Fas (CD95/APO-1/TNFRSF6), a tumor necrosis factor (TNF) receptor superfamily member, is a well-known apoptosis activator
We demonstrate here that the outcome of Fas signaling is determined by the phosphorylation status of two tyrosine residues (Y232 and Y291) within the death domain
Dephosphorylation of Fas tyrosines by SHP-1 tyrosine phosphatase turns on the pro-apoptotic signal whereas the tyrosine phosphorylation by Src family kinases (SFKs) turns off the pro-apoptotic signal and turns on the pro-survival signal
Summary
Fas (CD95/APO-1/TNFRSF6), a tumor necrosis factor (TNF) receptor superfamily member, is a well-known apoptosis activator. The binding with Fas ligand (FasL) can lead to the recruitment of Fas-associated protein with death domain (FADD) and procaspase-8, forming the death-inducing signaling complex (DISC). This results in the activation of the caspase cascade and, apoptosis [1]. Accumulating evidence supports a significant role of Fas in the alternative non-death signaling leading to cell survival, proliferation, motility, epithelial-mesenchymal transition, cancer growth, and metastasis in some contexts [2]. While such conditional multisignaling of Fas has been well demonstrated in several cancer models, including colon cancer [3,4,5], the mechanism controlling these multisignals is unclear
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