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FLASH GENE

Symbol

FAS

contributors: mct/ - updated : 05-03-2016

HGNC name	Fas (TNF receptor superfamily, member 6)
HGNC id	11920

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CSS1 Canale-Smith syndrome 1 TAL4 childhood acute lymphoblastic leukemia (T cell)
Location	10q23.31      Physical location : 90.750.287 - 90.775.541
Synonym name	cell differentiation antigen CD95
	Fas antigen mediating apoptosis
	FASLG receptor
	APO-1 antigen
	tumor necrosis factor receptor superfamily, member 6
	CD95 antigen
	Fas AMA
Synonym symbol(s)	APO1, CD95, APT1, FASTM, TNR6, TNFRSF6, FAS1, LFG, ALPS1A, FAIM2, NMP35

DNA

TYPE	functioning gene
STRUCTURE	25.25 kb     9 Exon(s)

regulatory sequence	Promoter
	Binding site   transcription factor
motif	repetitive sequence   other
text structure	SNP in the promoter playing a role in Alzheimer
	G to A substitution at -1377 bp and an A to G substitution at -670 bp, which occur within SP1 and signal transducers and activators of transcription 1(variation in the promoter may affect gene expression and modulate apoptotic signaling)
	one TP53 responsive-element within the first intron of the gene and 3 REs within the promoter

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000043 9 splicing 2755 NP_000034 37.7 335 - 2002 12359741 NM_152871 8 splicing 2692 NP_690610 33.7 314 - 2002 12359741 lacking an in frame coding segment precursor NM_152872 8 splicing 2730 NP_690611 23.1 220 - 2002 12359741 lacking a codin segment leading to a translation fameshift precursor

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver           pharynx         Endocrine adrenal gland         Lymphoid/Immune thymus       highly Reproductive female system uterus       Respiratory lung         Urinary bladder           kidney         Visual eye       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     highly

cell lineage
cell lines
fluid/secretion	blood

at STAGE

physiological period

fetal

Text

muscle

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	three extracytoplasmic cysteine-rich pseudo-repeats CRD1, CRD2, CRD3 typical for the TNFR superfamily
	a preligand assembly domain (PLAD) in CRD1 mediating ligand-independent receptor assembly and signaling
	a small cytoplasmic domain
	a DEATH domain, associating under activation with the DEATH domain of FADD and CASP8

conjugated

GlycoP

mono polymer

homomer , trimer

HOMOLOGY

Homologene

FAMILY

tumor necrosis factor receptor superfamily

CATEGORY

antigen , receptor membrane

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
text	isoforms lacking the transmembrane domain are secreted

basic FUNCTION	mediating apoptosis of inactivated T cells for instance in negative regulation of erythropoiesis through sequential activation of ICE-like (CASP4, CASP5 and CPP32-like (CASP3)) caspases
	blocking after stimulation T lymphocyte calcium channels through the activation of acidic sphingomyelinase (SMPD1) and ceramide release
	involved in extra-thymic self-tolerance and tumor immune escape
	playing a central role in the physiological regulation of programmed cell death, and involved in the pathogenesis of various malignancies and diseases of the immune system
	activating 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
	isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform
	its stimulation results in the formation of a novel death effector domain protein-containing complex
	death receptor whose stimulation by either the physiologic ligand FASL or the agonistic antibodies leads to the formation of a multi-molecular complex termed DISC (death-inducing signaling complex)
	death receptor that regulates tissue homeostasis mainly in the immune system through the induction of apoptosis
	could actually promote the growth of tumours through its non-apoptotic activities
	having a role in the tumorigenesis of ovarian cancer
	induces a potent apoptotic signal
	promotes apoptosis through well-defined signalling pathway
	FAS/FASLG system plays a central role in maintaining peripheral immune tolerance
	the site-specific FAS mRNA editing mutation may play a critical role in human immune responses and in the pathogenesis of human chronic inflammatory diseases
	plays a pivotal role in immune surveillance and immune tolerance
	induces invasion by stimulating the expression of extracellular matrix (ECM)-degrading proteases, and by stimulating the formation of actin-driven cell protrusions through Rac and the cofilin pathway
	FAS-stimulation triggers localized Ca2+ influx through the redistribution of STIM1/ORAI1 into the FAS-Cap, and this influx inhibits the initial steps of the FAS signaling pathway
	FAS-mediated Ca2+ response controls the initial steps in the receptor signaling pathway to promote the transmission of nonapoptotic signals
	rotative stress has a significant effect on CA2, FAS, FASLG, OSCAR, and TRAP gene expression in osteoclasts
	FAS and NFKB play a role in the initiation and development of breast cancer, while VEGFC appears to promote lymph node metastasis

CELLULAR PROCESS	cell life, proliferation/growth
	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

immunity/defense

PATHWAY

metabolism

signaling

signal transduction

a component	trimerization may be dependent of TNFSF6 or independent
	FAS/FASLG induces erythroblast apoptosis
	FAS/FADD/caspase-8 complex is known as the death-inducing signaling complex (DISC)

INTERACTION

DNA

RNA

small molecule

protein	binding DAXX, RIPK1, FAIM2
	interacting with HIPK3, BRE
	interacting with CASP8AP2
	interacting with CFL1 (cofilin activation is required for FAS-stimulated formation of membrane protrusions and increased tumour cell invasion)
	biological role of Ca2+ and the ORAI1 channel that drives a transient negative feedback loop, introducing a lag phase in the early steps of the FAS signal (
	hyperoxia-induced MAP1LC3B activation regulates the FAS apoptotic pathway and thus confers cytoprotection in lung epithelial cells (interaction of MAP1LC3B and FAS pathways requires CAV1)
	LAT is proteolytically cleaved following FAS engagement in a tyrosine phosphorylation-dependent fashion
	FAS-CALM1 interactions, and CALM1 antagonists greatly inhibit FAS-CALM1 interactions by blocking the FAS-binding site on CALM1
	identification of ZDHHC7 as a FAS-palmitoylating enzyme
	role for MOAP1 in FAS signaling in the liver by promoting MTCH2-mediated BID recruitment to mitochondria
	FAS, a mediator of extrinsic apoptotic pathway, is a novel CERS6 binding partner

cell & other

REGULATION

activated by

its natural ligand FASL (leads to the formation of the death-inducing signaling complex)

induced by

TP53-responsive elements, and TP63, TP73

ASSOCIATED DISORDERS

corresponding disease(s)

CSS1 , TAL4

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral fusion       fusion with ESR1 in several cancer lines (prostate, breast cervical, bladder) tumoral somatic mutation       mutated in the death domain in the non small cell lung cancer, in non lymphoid malignancie, T cell lymphoma and Hodgkin's disease, thyroid lymphoma, nasal NK/T cell lymphoma tumoral       loss of function retention of intron 5 and encodes a dysfunctional protein impairment of Fas-induced apoptosis resulting from aberrant splicing potentially contributes to the development and progression of cutaneous T-cell lymphoma tumoral somatic mutation       in nodal diffuse large B-cell lymphoma tumoral     --over   in epithelial ovarian cancer

Susceptibility

implicated early-onset Alzheimer with inconsistant results to autoimmune diabetes systemic lupus erythematous with loss of regulation of B lymphocytes to acute myeloid leukemia (AML) to myocardial infarction (MI)

Variant & Polymorphism SNP , other	promoter playing a role in Alzheimer disease
	increased risk of AML associated with heterozygotes (GA) and homozygote variants (AA) at position -1377 bp
	SNP (-670G/A), may be a risk factor of MI occurrence

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer     locking FAS in apoptosis-mode may be a more promising anti-cancer strategy than simply inhibiting or stimulating FAS

ANIMAL & CELL MODELS