O35732 (CFLAR_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
CASP8 and FADD-like apoptosis regulator

Alternative name(s):
Caspase homolog
Short name=CASH
Caspase-eight-related protein
Short name=Casper
Caspase-like apoptosis regulatory protein
Short name=CLARP
Cellular FLICE-like inhibitory protein
Short name=c-FLIP
FADD-like antiapoptotic molecule 1
Short name=FLAME-1
Inhibitor of FLICE
Short name=I-FLICE
MACH-related inducer of toxicity
Short name=MRIT
Usurpin

Cleaved into the following 2 chains:

1. CASP8 and FADD-like apoptosis regulator subunit p43
2. CASP8 and FADD-like apoptosis regulator subunit p12

Gene names

Name:	Cflar
Synonyms:	Cash

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	484 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at transcript level

General annotation (Comments)

Function	Apoptosis regulator protein which may function as a crucial link between cell survival and cell death pathways in mammalian cells. Acts as an inhibitor of TNFRSF6 mediated apoptosis. A proteolytic fragment (p43) is likely retained in the death-inducing signaling complex (DISC) thereby blocking further recruitment and processing of caspase-8 at the complex. Full length and shorter isoforms have been shown either to induce apoptosis or to reduce TNFRSF-triggered apoptosis. Lacks enzymatic (caspase) activity By similarity. Ref.4 Ref.5
Subunit structure	TNFRSF6 stimulation triggers recruitment to the death-inducing signaling complex (DISC) formed by TNFRSF6, FADD and caspase-8. A proteolytic fragment (p43) stays associated with the DISC By similarity.
Tissue specificity	Highly expressed in heart.
Developmental stage	At embryonic days E9.5 and E10.5 highest expression in developing heart.
Induction	Isoform 1 but not isoform 2 is activated by BCR cross-linking in primary B-cells.
Domain	The caspase domain lacks the active sites residues involved in catalysis.
Post-translational modification	Proteolytically processed; probably by caspase-8. Processing likely occurs at the DISC and generates subunit p43 and p12 By similarity.
Sequence similarities	Belongs to the peptidase C14A family. Contains 2 DED (death effector) domains.

Ontologies

Keywords
Biological process	Apoptosis
Coding sequence diversity	Alternative splicing
Domain	Repeat
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of myoblast fusion Inferred from mutant phenotype PubMed 21364645. Source: BHF-UCL positive regulation of NF-kappaB transcription factor activity Inferred from mutant phenotype PubMed 21364645. Source: BHF-UCL proteolysis Inferred from electronic annotation. Source: InterPro regulation of apoptotic process Inferred from electronic annotation. Source: InterPro regulation of satellite cell proliferation Inferred from mutant phenotype PubMed 21364645. Source: BHF-UCL skeletal muscle atrophy Inferred from mutant phenotype PubMed 21364645. Source: BHF-UCL skeletal muscle tissue development Inferred from mutant phenotype PubMed 21364645. Source: BHF-UCL skeletal muscle tissue regeneration Inferred from mutant phenotype PubMed 21364645. Source: BHF-UCL skeletal myofibril assembly Inferred from mutant phenotype PubMed 21364645. Source: BHF-UCL
Molecular_function	cysteine-type endopeptidase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O35732-1)

Also known as: FLIP-L; CASH alpha;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O35732-2)

Also known as: FLIP-S; CASH beta;

The sequence of this isoform differs from the canonical sequence as follows:
     208-218: LQNGRSKEPRF → VSLEPVYGVPA
     219-484: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 380	380	CASP8 and FADD-like apoptosis regulator subunit p43 By similarity		PRO_0000004680
	Chain	381 – 484	104	CASP8 and FADD-like apoptosis regulator subunit p12 By similarity		PRO_0000004681
Regions
	Domain	6 – 78	73	DED 1
	Domain	97 – 172	76	DED 2
	Region	268 – 363	96	Caspase
	Compositional bias	421 – 425	5	Poly-Ser
Natural variations
	Alternative sequence	208 – 218	11	LQNGRSKEPRF → VSLEPVYGVPA in isoform 2.		VSP_000842
	Alternative sequence	219 – 484	266	Missing in isoform 2.		VSP_000843
Experimental info
	Sequence conflict	121	1	T → TRIT in CAA74369. Ref.1
	Sequence conflict	121	1	T → TRIT in CAA74368. Ref.1
	Sequence conflict	201 – 207	7	PSVLYLK → YNSR in CAA74368. Ref.1
	Sequence conflict	201 – 207	7	PSVLYLK → YNSR in AAC53281. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (FLIP-L) (CASH alpha) [UniParc]. Last modified October 3, 2012. Version 2. Checksum: B272DE6DB2861C86	FASTA	484	55,155
	10 20 30 40 50 60 MAQSPVSAEV IHQVEECLDE DEKEMMLFLC RDVTENLAAP NVRDLLDSLS ERGQLSFATL 70 80 90 100 110 120 AELLYRVRRF DLLKRILKTD KATVEDHLRR NPHLVSDYRV LLMEIGESLD QNDVSSLVFL 130 140 150 160 170 180 TRDYTGRGKI AKDKSFLDLV IELEKLNLIA SDQLNLLEKC LKNIHRIDLN TKIQKYTQSS 190 200 210 220 230 240 QGARSNMNTL QASLPKLSIK PSVLYLKLQN GRSKEPRFVE YRDSQRTLVK TSIQESGAFL 250 260 270 280 290 300 PPHIREETYR MQSKPLGICL IIDCIGNDTK YLQETFTSLG YHIQLFLFPK SHDITQIVRR 310 320 330 340 350 360 YASMAQHQDY DSFACVLVSL GGSQSMMGRD QVHSGFSLDH VKNMFTGDTC PSLRGKPKLF 370 380 390 400 410 420 FIQNYESLGS QLEDSSLEVD GPSIKNVDSK PLQPRHCTTH PEADIFWSLC TADVSHLEKP 430 440 450 460 470 480 SSSSSVYLQK LSQQLKQGRR RPLVDLHVEL MDKVYAWNSG VSSKEKYSLS LQHTLRKKLI LAPT
	Isoform 2 (FLIP-S) (CASH beta) [UniParc]. Checksum: E42F32F27C66C337	FASTA	218	24,815
	10 20 30 40 50 60 MAQSPVSAEV IHQVEECLDE DEKEMMLFLC RDVTENLAAP NVRDLLDSLS ERGQLSFATL 70 80 90 100 110 120 AELLYRVRRF DLLKRILKTD KATVEDHLRR NPHLVSDYRV LLMEIGESLD QNDVSSLVFL 130 140 150 160 170 180 TRDYTGRGKI AKDKSFLDLV IELEKLNLIA SDQLNLLEKC LKNIHRIDLN TKIQKYTQSS 190 200 210 QGARSNMNTL QASLPKLSIK PSVLYLKVSL EPVYGVPA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"CASH, a novel caspase homologue with death effector domains." Goltsev Y.V., Kovalenko A.V., Arnold E., Varfolomeev E.E., Brodianskii V.M., Wallach D. J. Biol. Chem. 272:19641-19644(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). Tissue: Liver.
[2]	"Inhibition of death receptor signals by cellular FLIP." Irmler M., Thome M., Hahne M., Schneider P., Hofmann K., Steiner V., Bodmer J.-L., Schroeter M., Burns K., Mattmann C., Rimoldi D., French L.E., Tschopp J. Nature 388:190-195(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Heart.
[3]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6J.
[4]	"Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development." Yeh W.-C., Itie A., Elia A.J., Ng M., Shu H.-B., Wakeham A., Mirtsos C., Suzuki N., Bonnard M., Goeddel D.V., Mak T.W. Immunity 12:633-642(2000) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[5]	"Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c-FLIP." Wang J., Lobito A.A., Shen F., Hornung F., Winoto A., Lenardo M.J. Eur. J. Immunol. 30:155-163(2000) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	Y14041 mRNA. Translation: CAA74368.1. Y14042 mRNA. Translation: CAA74369.1. U97076 mRNA. Translation: AAC53281.1. AC112968 Genomic DNA. No translation available.
IPI	IPI00133915. IPI00230112. IPI00830184.
RefSeq	NP_997536.1. NM_207653.3.
UniGene	Mm.336848. Mm.486313.
3D structure databases
ProteinModelPortal	O35732.
SMR	O35732. Positions 12-182, 244-484.
ModBase	Search...
Protein-protein interaction databases
IntAct	O35732. 2 interactions.
Protein family/group databases
MEROPS	C14.974.
PTM databases
PhosphoSite	O35732.
Proteomic databases
PRIDE	O35732.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000097722; ENSMUSP00000095329; ENSMUSG00000026031.
GeneID	12633.
KEGG	mmu:12633.
Organism-specific databases
CTD	8837.
MGI	MGI:1336166. Cflar.
Phylogenomic databases
eggNOG	NOG331323.
GeneTree	ENSGT00530000064199.
HOGENOM	HOG000069972.
HOVERGEN	HBG050918.
KO	K04724.
OMA	YDWNSRV.
Gene expression databases
ArrayExpress	O35732.
Bgee	O35732.
CleanEx	MM_CFLAR.
Genevestigator	O35732.
GermOnline	ENSMUSG00000026031. Mus musculus.
Family and domain databases
Gene3D	1.10.533.10. 3 hits.
InterPro	IPR011029. DEATH-like_dom. IPR001875. DED. IPR011600. Pept_C14_cat. IPR001309. Pept_C14_ICE_p20. IPR002398. Pept_C14_p45. IPR015917. Pept_C14_p45_core. [Graphical view]
PANTHER	PTHR10454. PTHR10454. 1 hit.
Pfam	PF01335. DED. 2 hits. PF00656. Peptidase_C14. 1 hit. [Graphical view]
SMART	SM00115. CASc. 1 hit. SM00031. DED. 2 hits. [Graphical view]
SUPFAM	SSF47986. DEATH_like. 2 hits.
PROSITE	PS50208. CASPASE_P20. 1 hit. PS50168. DED. 2 hits. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	CFLAR. mouse.
NextBio	281824.
SOURCE	Search...

Entry information

Entry name

CFLAR_MOUSE

Accession

Primary (citable) accession number: O35732
Secondary accession number(s): D3Z0W6, O35707, O35733

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	October 3, 2012
Last modified:	May 1, 2013
This is version 122 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program