Fas receptor

The Fas receptor (FasR), also known as Fas or as CD95 (Cluster of differentiation 95), belongs to the TNF receptor family, which triggers apoptosis of the cell concerned after binding to its ligand(Fas ligand, FasL). FasR is a so-called type I transmembrane protein with 335 amino acids and a molecular weight of 45 kDa. It consists of three cysteine-rich repeat units (trimers) in the extracellular protein domain. The trimer structure is essential for the function of the receptor and typical for TNF receptors.

FasR is the most intensively studied member of the death receptor family. In humans, the gene is located on chromosome 10 (10q24.1). Seven isoforms of the protein are known to date. Many of these isoforms are rare haplotypes that are normally associated with a disease state. The apoptosis-inducing Fas receptor is referred to as isoform 1.

The physiological ligand of the Fas receptor is the Fas ligand (FasL, CD95L, CD178, TNFSF6). As a type II transmembrane glycoprotein, it belongs to the TNF superfamily of cytokines. Like all members of this family, the Fas ligand has a characteristic TNF homology domain (THD) that enables it to bind to the cysteine-rich domains (CRD) of the Fas receptor.

After binding to its receptor-specific ligand, a cytotoxic signal leading to apoptosis is transmitted into the cell. The signal transmission is made possible by the specific recruitment of the corresponding adaptor proteins TRADD (TNF receptor-associated protein with death domain) and FADD (Fas-associated protein with death domain). Depending on the receptor type, the interaction of TRADD/FADD (for TNF-R1) or only FADD with the binding domain of the death receptor (DD=death domains) causes the recruitment of initiator caspase 8 and 10 (aspartate-specific cysteine proteases). This leads to the formation of a cell death-inducing signaling complex (DISC) and the induction of a proteolytic cascade.

In addition to apoptosis induction, FasR can mediate signals that contribute to cell proliferation and differentiation through the activation of NF-B (nuclear factor-B) and MAPK (mitogen-activated protein kinase).

The decision between a pro- or anti-apoptotic signaling pathway is due to a variety of different regulatory mechanisms. In addition to the intrinsic regulation of adaptor proteins and the targeted inhibition of pro-apoptotic proteins, the subcellular localization of the receptor is also of great importance. Although the Fas receptor can be detected in almost all tissues of the human body, it is particularly prevalent in the kidneys, heart, liver, pancreas, brain, thymus and in activated T lymphocytes. Tumor cells can also express the Fas receptor on their surface in varying densities.

FasR (CD95) can also be induced by various endogenous and exogenous factors. These include TNF-alpha (tumor-necrosis-factor-alpha), IFN-gamma, IL-1 (interleukin-1), IL-6, IL-7, infectious agents, nitric oxide (NO), chemotherapy and radiation.

In addition to a membrane-bound form, FasR can occur as a soluble protein through alternative splicing or through matrix metalloprotease-mediated shedding. Through competitive binding and neutralization of the ligand specific for the receptor, the soluble FasR probably has an anti-apoptotic function.

Furthermore, FasL/FasR interactions play an important role in the regulation of the immune system and the progression of malignant cells. Tumor cells can prove to be resistant to FasL-mediated apoptosis. This may be due to the downregulation of Fas receptor expression. However, resistance can also occur if a large number of Fas receptors are present on the cell surface. In this case, the apoptotic signal is interrupted at the level of the death-inducing signaling complex (DISC), which prevents the activation of the initiator caspases. Due to this resistance, recombinant FasL is not a useful antitumor strategy.

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