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Review
. 2016 Oct 17:7:429.
doi: 10.3389/fimmu.2016.00429. eCollection 2016.

Fas Versatile Signaling and Beyond: Pivotal Role of Tyrosine Phosphorylation in Context-Dependent Signaling and Diseases

Krittalak Chakrabandhu  1 , Anne-Odile Hueber  1
Affiliations
Review

Fas Versatile Signaling and Beyond: Pivotal Role of Tyrosine Phosphorylation in Context-Dependent Signaling and Diseases

Krittalak Chakrabandhu et al. Front Immunol. .

Abstract

The Fas/FasL system is known, first and foremost, as a potent apoptosis activator. While its proapoptotic features have been studied extensively, evidence that the Fas/FasL system can elicit non-death signals has also accumulated. These non-death signals can promote survival, proliferation, migration, and invasion of cells. The key molecular mechanism that determines the shift from cell death to non-death signals had remained unclear until the recent identification of the tyrosine phosphorylation in the death domain of Fas as the reversible signaling switch. In this review, we present the connection between the recent findings regarding the control of Fas multi-signals and the context-dependent signaling choices. This information can help explain variable roles of Fas signaling pathway in different pathologies.

Keywords: Fas/CD95; apoptosis; disease; survival signals; tyrosine phosphorylation.

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Figures

Figure 1
Figure 1
Regulation of Fas multi-signaling by death domain tyrosine phosphorylation and pathologies. (A) Fas death domain structural model demonstrating six antiparallel α-helices (PDB: 1DDF) (19) with the side chains of Y232 and Y291 indicated (left) and amino acid sequences of human Fas and rat Fas encompassing the death domain with positions of each helix indicated (right; α, α-helix). Tyrosine phosphorylation sites in hFas and corresponding residues in rat Fas are highlighted. Amino acid numbering is according to UniProt entries P25445 and Q63199. (B) A diagram depicting different states of Fas, with respect to its ability to transmit apoptotic signal, as affected by its death domain phosphorylation [adapted from Ref. (27)]. The proapoptotic state is allowed when both DD tyrosines are dephosphorylated. The dominant proapoptotic state takes place when Y232 and/or Y291 is phosphorylated (some examples of possible dominant-negative scenarios are given). (C) A simplified illustration of Fas multi-signaling regulation by tyrosine phosphorylation switch. The non-death signaling triggered by activators such as soluble FasL (sFasL) is mediated by Src or Yes phosphorylation of the death domain tyrosines. The death signaling triggered by activators such as cross-linked FasL (cFasL) or membrane FasL (mFasL) is permitted by the dephosphorylation of the death domain tyrosines by SHP-1. (D) A diagram outlining pathologically relevant parameters leading to contexts that define the role of Fas signaling in human diseases (see text).
See this image and copyright information in PMC

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