FAS

Official Full Name

Fas cell surface death receptor

Organism

Homo sapiens

GeneID

355

Background

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]

Synonyms

APT1; CD95; FAS1; APO-1; FASTM; ALPS1A; TNFRSF6;

Bio Chemical Class

mRNA target

Protein Sequence

MLGIWTLLPLVLTSVARLSSKSVNAQVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKEEGSRSNLGWLCLLLLPIPLIVWVKRKEVQKTCRKHRKENQGSHESPTLNPETVAINLSDVDLSKYITTIAGVMTLSQVKGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCTLAEKIQTIILKDITSDSENSNFRNEIQSLV

Open

Approved Drug

Clinical Trial Drug

4 +

Discontinued Drug

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Detailed Information

Fas is a member of the tumor necrosis factor receptor and nerve growth factor receptor superfamily, and is a type I transmembrane glycoprotein. The extramembrane region is a signal peptide composed of 157 amino acid residues, which has the characteristics of membrane receptors, and its amino acid sequence is relatively conservative. When combined with FasL, it initiates the transmembrane transmission of apoptosis signals. The transmembrane region is located in the middle of the molecular structure and consists of 17 amino acid residues. A section of 80-100 amino acid sequence of the cytoplasmic region is highly homologous to the cytoplasmic region of tumor necrosis factor receptor, mediates apoptosis and plays a key role in transmitting apoptosis signals, so this region is called the death domain. Therefore, Fas molecules are also called "death molecules". The other two structural sequences of the death domain, the death effect domain and the caspase recruitment domain, have similar structural features and belong to the death domain superfamily. They can perform biological functions through the interaction between homologous protein domains.

Figure 1. Immune effector cells induce tumor cell death through apoptosis and necrotic-like cell lysis. (Reilly, E. O., et al. 2016)

After the cell receives the apoptosis signal transmitted by Fas, there are two main ways to induce cell apoptosis, namely, the exogenous apoptotic pathway (death receptor pathway) and the endogenous apoptotic pathway (mitochondrial pathway). Based on this, the cells that are sensitive to Fas-mediated apoptosis are divided into two types: Fas type I cells and Fas type II cells. Type I cells (such as thymocytes) induce apoptotic signals through the caspase pathway, while type II cells (such as hepatocytes) induce the caspase cascade through the disappearance of mitochondrial membrane potential, increased mitochondrial membrane permeability, and the release of cytochrome C, leading to apoptosis.

The Effect of Fas on Tumor Occurrence and Development

Under normal circumstances, Fas is highly expressed in various tissue cells, and the development of human tumors is often accompanied by loss of Fas expression or loss of function of tumor cells, but FasL expression increases. The role of the Fas /FasL system in the pathological process of tumors has always been a hot topic of research. One of the important mechanisms for tumor cells to evade the immune system is due to the existence of the Fas/FasL system. On the one hand, cancer cell Fas expression is down-regulated to resist the immune attack of tumor infiltrating cells and cytotoxic T lymphocytes caused by FasL expression. On the other hand, the expression of FasL in cancer cells can interact with Fas + tumor infiltrating cells and Fas + cytotoxic T lymphocytes. It stimulates apoptotic signals through the Fas system, kills tumor infiltrating cells and cytotoxic T lymphocytes, enables tumor cells to evade immune surveillance and counterattack. However, studies have shown that Fas/FasL can not only induce cell apoptosis, but also promote multiple signaling pathways to inhibit cell apoptosis. Its abnormal expression is closely related to tumor occurrence, development and autoimmune diseases.

Application of Fas in Tumor Treatment

Tumor targeted therapy for Fas/FasL is mainly used to promote or block apoptosis. Therapies that promote apoptosis by activating Fas/FasL include: recombinant soluble FasL or Fas excitatory antibody, FasL fusion protein, FasL prodrugs, etc. As early as the 1990s, people expected to use Fas antibodies to activate Fas-mediated apoptosis. But after injecting anti-Fas antibody into the abdominal cavity of mice, it quickly caused massive necrosis of mouse liver cells, and the mice died due to liver failure.

In recent years, a new recombinant FasL-APO010 has been proven to induce apoptosis of glioma cells in vitro and in vivo. Phase I clinical trials have shown good results. The researchers used recombinant soluble FasL in combination with adriamycin, which showed a significant synergistic anti-apoptotic effect on hepatocellular carcinoma. This effect can also be observed in transplanted tumor models in vivo; FasL gene therapy. Fas/FasL signal transduction caused by chemotherapeutics. Studies have shown that the anti-tumor mechanism of a variety of chemotherapeutic drugs may be to induce the up-regulation of Fas or FasL expression and cause tumor cell apoptosis.

References:

Reilly, E. O., Tirincsi, A., Logue, S. E., & Szegezdi, E. (2016). The Janus Face of Death Receptor Signaling during Tumor Immunoediting. Frontiers in Immunology.
Guégan, J. P., & Legembre, P. (2018). Nonapoptotic functions of Fas/CD95 in the immune response. The FEBS journal, 285(5), 809–827.
Modiano, J. F., & Bellgrau, D. (2016). Fas ligand based immunotherapy: A potent and effective neoadjuvant with checkpoint inhibitor properties, or a systemically toxic promoter of tumor growth? Discovery medicine, 21(114), 109–116.

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