Reviewed, UniProtKB/Swiss-Prot Q14790 (CASP8_HUMAN)

Names and origin

Protein names

Recommended name:
    Caspase-8
      Short name=CASP-8
    EC=3.4.22.61
Alternative name(s):
    ICE-like apoptotic protease 5
    MORT1-associated CED-3 homolog
      Short name=MACH
    FADD-homologous ICE/CED-3-like protease
    FADD-like ICE
      Short name=FLICE
    Apoptotic cysteine protease
    Apoptotic protease Mch-5
    CAP4
Cleaved into the following 2 chains:
    1- Recommended name:
            Caspase-8 subunit p18
    2- Recommended name:
            Caspase-8 subunit p10

Gene names

Name:	CASP8
Synonyms:	MCH5

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	479 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. Ref.7 Ref.13
Catalytic activity	Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).
Subunit structure	Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit. Interacts with FADD, CFLAR and PEA15. Isoform 9 interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. Interacts with TNFAIP8L2 By similarity. Ref.8 Ref.16 Ref.17 Ref.23
Subcellular location	Cytoplasm.
Tissue specificity	Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle.
Domain	Isoform 9 contains a N-terminal extension that is required for interaction with the BCAP31 complex.
Post-translational modification	Generation of the subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events. Phosphorylated upon DNA damage, probably by ATM or ATR. Ref.19 Ref.21
Polymorphism	Genetic vaiations in CASP8 are associated with reduced risk of lung cancer [MIM:211980] in a population of Han Chinese subjects. Genetic vaiations are also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner.
Involvement in disease	Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:607271]. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. Ref.24
Sequence similarities	Belongs to the peptidase C14A family. Contains 2 DED (death effector) domains.
Sequence caution	The sequence CAA66858.1 differs from that shown. Reason: Miscellaneous discrepancy. The sequence CAA66859.1 differs from that shown. Reason: Miscellaneous discrepancy.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Repeat
Molecular function	Hydrolase Protease Thiol protease
PTM	Phosphoprotein Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	activation of pro-apoptotic gene products Inferred from Experiment. Source: Reactome induction of apoptosis by extracellular signals Inferred from mutant phenotype. Source: UniProtKB positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from expression pattern. Source: UniProtKB proteolysis involved in cellular protein catabolic process Inferred from mutant phenotype. Source: UniProtKB response to tumor necrosis factor Inferred from mutant phenotype. Source: UniProtKB
Cellular component	cytoplasm Inferred from direct assay. Source: HPA cytoskeleton Traceable author statement. Source: ProtInc cytosol Ref.1 Inferred from Experiment. Source: Reactome death-inducing signaling complex Inferred from direct assay. Source: UniProtKB mitochondrial outer membrane Inferred from Experiment. Source: Reactome nucleus Inferred from direct assay. Source: HPA
Molecular function	cysteine-type endopeptidase activity Ref.1 Inferred from Experiment. Source: Reactome identical protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		2	EBI-78060,EBI-78060
BCAP31	P51572	1	EBI-288343,EBI-77683
BCAP31	P51572	1	EBI-78060,EBI-77683
BCL2	Q9JJV8	1	EBI-78060,EBI-1749099	From a different organism.
CASP10	Q92851	2	EBI-78060,EBI-495095
ced-4	P30429	1	EBI-78060,EBI-494118	From a different organism.
CUL3	Q13618	3	EBI-78060,EBI-456129
EDA2R	Q9HAV5	1	EBI-288343,EBI-526033
FADD	Q13158	1	EBI-288326,EBI-494804
FADD	Q13158	3	EBI-78060,EBI-494804
FAS	P25445	3	EBI-78060,EBI-494743
ILK	Q13418	1	EBI-78060,EBI-747644
NOL3	O60936	3	EBI-78060,EBI-740992
OTUD7B	Q6GQQ9	1	EBI-78060,EBI-527784
P35	P08160	1	EBI-78060,EBI-1030934	From a different organism.
RIPK1	Q13546	1	EBI-78060,EBI-358507
SQSTM1	Q13501	1	EBI-78060,EBI-307104
Tnfaip8l2	Q9D8Y7	1	EBI-78060,EBI-1781612	From a different organism.

Alternative products

This entry describes 9 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q14790-1)

Also known as: Alpha-1;

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: Q14790-2)

Also known as: Alpha-2; MCH5-beta;

The sequence of this isoform differs from the canonical sequence as follows:
     184-198: Missing.

Isoform 3 (identifier: Q14790-3)

Also known as: Alpha-3;

The sequence of this isoform differs from the canonical sequence as follows:
     184-267: Missing.

Isoform 4 (identifier: Q14790-4)

Also known as: Alpha-4;

The sequence of this isoform differs from the canonical sequence as follows:
     102-102: R → RFHFCRMSWAEANSQCQTQSVPFWRRVDHLLIR
     184-198: Missing.

Isoform 5 (identifier: Q14790-5)

Also known as: Beta-1;

The sequence of this isoform differs from the canonical sequence as follows:
     199-235: GEELCGVMTISDSPREQDSESQTLDKVYQMKSKPRGY → DFGQSLPNEKQTSGILSDHQQSQFCKSTGESAQTSQH
     236-479: Missing.

Isoform 6 (identifier: Q14790-6)

Also known as: Beta-2;

The sequence of this isoform differs from the canonical sequence as follows:
     184-220: ERSSSLEGSPDEFSNGEELCGVMTISDSPREQDSESQ → DFGQSLPNEKQTSGILSDHQQSQFCKSTGESAQTSQH
     221-479: Missing.

Isoform 7 (identifier: Q14790-7)

Also known as: Beta-3; 8L;

The sequence of this isoform differs from the canonical sequence as follows:
     269-276: ALTTTFEE → TVEPKREK
     277-479: Missing.

Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoform 8 (identifier: Q14790-8)

Also known as: Beta-4;

The sequence of this isoform differs from the canonical sequence as follows:
     184-198: Missing.
     269-276: ALTTTFEE → TVEPKREK
     277-479: Missing.

Isoform 9 (identifier: Q14790-9)

Also known as: 8L;

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MEGGRRARVVIESRRNFFLGAFPTPFPAEHVELGRLGDSETAMVPGKGGADYILLPFKKM

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Propeptide

1 – 216

216

PRO_0000004628

Chain

217 – 374

158

Caspase-8 subunit p18

PRO_0000004629

Propeptide

375 – 384

10

PRO_0000004630

Chain

385 – 479

95

Caspase-8 subunit p10

PRO_0000004631

Regions

Domain

2 – 80

79

DED 1

Domain

100 – 177

78

DED 2

Sites

Active site

317

1

Active site

360

1

Amino acid modifications

Modified residue

188

1

Phosphoserine By similarity

Modified residue

219

1

Phosphoserine Ref.21

Modified residue

334

1

Phosphotyrosine Ref.19

Natural variations

Alternative sequence

1

1

M → MEGGRRARVVIESRRNFFLG AFPTPFPAEHVELGRLGDSE TAMVPGKGGADYILLPFKKM in isoform 9.

VSP_000808

Alternative sequence

102

1

R → RFHFCRMSWAEANSQCQTQS VPFWRRVDHLLIR in isoform 4.

VSP_000809

Alternative sequence

184 – 267

84

Missing in isoform 3.

VSP_000813

Alternative sequence

184 – 220

37

ERSSS…DSESQ → DFGQSLPNEKQTSGILSDHQ QSQFCKSTGESAQTSQH in isoform 6.

VSP_000811

Alternative sequence

184 – 198

15

Missing in isoform 2, isoform 4 and isoform 8.

VSP_000810

Alternative sequence

199 – 235

37

GEELC…KPRGY → DFGQSLPNEKQTSGILSDHQ QSQFCKSTGESAQTSQH in isoform 5.

VSP_000814

Alternative sequence

221 – 479

259

Missing in isoform 6.

VSP_000812

Alternative sequence

236 – 479

244

Missing in isoform 5.

VSP_000815

Alternative sequence

269 – 276

8

ALTTTFEE → TVEPKREK in isoform 7 and isoform 8.

VSP_000816

Alternative sequence

277 – 479

203

Missing in isoform 7 and isoform 8.

VSP_000817

Natural variant

219

1

S → T: dbSNP rs35976359. Ref.9

VAR_025816

Natural variant

248

1

R → W in CASP8D. dbSNP rs17860424. Ref.24

VAR_014204

Natural variant

285

1

D → H Associated with protection against breast cancer; also associated with a lower risk of cutaneous melanoma. dbSNP rs1045485. Ref.9 Ref.3 Ref.4 Ref.6 Ref.25 Ref.26 Ref.29

VAR_020127

Experimental info

Mutagenesis

73

1

D → A: Abolishes binding to FLASH. Induces NF-kappa-B activation. Ref.20

Sequence conflict

294

1

E → D in AAD24962. Ref.5

Sequence conflict

331

1

A → P Ref.2

Sequence conflict

331

1

A → P Ref.5

Sequence conflict

343 – 344

2

LK → FG in AAL87631. Ref.8

Secondary structure

1

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479

Helix Strand Turn

Details...

Beta strand

235 – 240

6

Helix

245 – 250

6

Helix

252 – 254

3

Helix

263 – 276

14

Beta strand

280 – 286

7

Helix

289 – 301

13

Beta strand

310 – 316

7

Beta strand

322 – 324

3

Beta strand

330 – 332

3

Helix

333 – 337

5

Helix

338 – 340

3

Turn

342 – 344

3

Helix

346 – 348

3

Beta strand

353 – 359

7

Beta strand

361 – 364

4

Beta strand

368 – 371

4

Beta strand

391 – 394

4

Beta strand

398 – 405

8

Beta strand

412 – 414

3

Turn

415 – 417

3

Helix

420 – 432

13

Helix

433 – 435

3

Helix

439 – 452

14

Turn

456 – 459

4

Beta strand

465 – 468

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Alpha-1) [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 7A5FEAA6B39B582F	FASTA	479	55,391
	10 20 30 40 50 60 MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS 70 80 90 100 110 120 FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRVMLYQISE EVSRSELRSF 130 140 150 160 170 180 KFLLQEEISK CKLDDDMNLL DIFIEMEKRV ILGEGKLDIL KRVCAQINKS LLKIINDYEE 190 200 210 220 230 240 FSKERSSSLE GSPDEFSNGE ELCGVMTISD SPREQDSESQ TLDKVYQMKS KPRGYCLIIN 250 260 270 280 290 300 NHNFAKAREK VPKLHSIRDR NGTHLDAGAL TTTFEELHFE IKPHDDCTVE QIYEILKIYQ 310 320 330 340 350 360 LMDHSNMDCF ICCILSHGDK GIIYGTDGQE APIYELTSQF TGLKCPSLAG KPKVFFIQAC 370 380 390 400 410 420 QGDNYQKGIP VETDSEEQPY LEMDLSSPQT RYIPDEADFL LGMATVNNCV SYRNPAEGTW 430 440 450 460 470 YIQSLCQSLR ERCPRGDDIL TILTEVNYEV SNKDDKKNMG KQMPQPTFTL RKKLVFPSD
	Isoform 2 (Alpha-2) (MCH5-beta). Checksum: 7F52F14ADE6A02B6	FASTA	464	53,768
	10 20 30 40 50 60 MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS 70 80 90 100 110 120 FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRVMLYQISE EVSRSELRSF 130 140 150 160 170 180 KFLLQEEISK CKLDDDMNLL DIFIEMEKRV ILGEGKLDIL KRVCAQINKS LLKIINDYEE 190 200 210 220 230 240 FSKGEELCGV MTISDSPREQ DSESQTLDKV YQMKSKPRGY CLIINNHNFA KAREKVPKLH 250 260 270 280 290 300 SIRDRNGTHL DAGALTTTFE ELHFEIKPHD DCTVEQIYEI LKIYQLMDHS NMDCFICCIL 310 320 330 340 350 360 SHGDKGIIYG TDGQEAPIYE LTSQFTGLKC PSLAGKPKVF FIQACQGDNY QKGIPVETDS 370 380 390 400 410 420 EEQPYLEMDL SSPQTRYIPD EADFLLGMAT VNNCVSYRNP AEGTWYIQSL CQSLRERCPR 430 440 450 460 GDDILTILTE VNYEVSNKDD KKNMGKQMPQ PTFTLRKKLV FPSD
	Isoform 3 (Alpha-3). Checksum: 2787AE831A2B36EF	FASTA	395	45,929
	10 20 30 40 50 60 MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS 70 80 90 100 110 120 FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRVMLYQISE EVSRSELRSF 130 140 150 160 170 180 KFLLQEEISK CKLDDDMNLL DIFIEMEKRV ILGEGKLDIL KRVCAQINKS LLKIINDYEE 190 200 210 220 230 240 FSKGALTTTF EELHFEIKPH DDCTVEQIYE ILKIYQLMDH SNMDCFICCI LSHGDKGIIY 250 260 270 280 290 300 GTDGQEAPIY ELTSQFTGLK CPSLAGKPKV FFIQACQGDN YQKGIPVETD SEEQPYLEMD 310 320 330 340 350 360 LSSPQTRYIP DEADFLLGMA TVNNCVSYRN PAEGTWYIQS LCQSLRERCP RGDDILTILT 370 380 390 EVNYEVSNKD DKKNMGKQMP QPTFTLRKKL VFPSD
	Isoform 4 (Alpha-4). Checksum: 68136650A49159D9	FASTA	496	57,701
	10 20 30 40 50 60 MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS 70 80 90 100 110 120 FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRFHFCRMSW AEANSQCQTQ 130 140 150 160 170 180 SVPFWRRVDH LLIRVMLYQI SEEVSRSELR SFKFLLQEEI SKCKLDDDMN LLDIFIEMEK 190 200 210 220 230 240 RVILGEGKLD ILKRVCAQIN KSLLKIINDY EEFSKGEELC GVMTISDSPR EQDSESQTLD 250 260 270 280 290 300 KVYQMKSKPR GYCLIINNHN FAKAREKVPK LHSIRDRNGT HLDAGALTTT FEELHFEIKP 310 320 330 340 350 360 HDDCTVEQIY EILKIYQLMD HSNMDCFICC ILSHGDKGII YGTDGQEAPI YELTSQFTGL 370 380 390 400 410 420 KCPSLAGKPK VFFIQACQGD NYQKGIPVET DSEEQPYLEM DLSSPQTRYI PDEADFLLGM 430 440 450 460 470 480 ATVNNCVSYR NPAEGTWYIQ SLCQSLRERC PRGDDILTIL TEVNYEVSNK DDKKNMGKQM 490 PQPTFTLRKK LVFPSD
	Isoform 5 (Beta-1). Checksum: 7C9013CEA85A77DE	FASTA	235	27,484
	10 20 30 40 50 60 MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS 70 80 90 100 110 120 FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRVMLYQISE EVSRSELRSF 130 140 150 160 170 180 KFLLQEEISK CKLDDDMNLL DIFIEMEKRV ILGEGKLDIL KRVCAQINKS LLKIINDYEE 190 200 210 220 230 FSKERSSSLE GSPDEFSNDF GQSLPNEKQT SGILSDHQQS QFCKSTGESA QTSQH
	Isoform 6 (Beta-2). Checksum: F3DA0380D12006C7	FASTA	220	25,862
	10 20 30 40 50 60 MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS 70 80 90 100 110 120 FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRVMLYQISE EVSRSELRSF 130 140 150 160 170 180 KFLLQEEISK CKLDDDMNLL DIFIEMEKRV ILGEGKLDIL KRVCAQINKS LLKIINDYEE 190 200 210 220 FSKDFGQSLP NEKQTSGILS DHQQSQFCKS TGESAQTSQH
	Isoform 7 (Beta-3) (8L). Checksum: 227ED77718788F92	FASTA	276	32,330
	10 20 30 40 50 60 MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS 70 80 90 100 110 120 FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRVMLYQISE EVSRSELRSF 130 140 150 160 170 180 KFLLQEEISK CKLDDDMNLL DIFIEMEKRV ILGEGKLDIL KRVCAQINKS LLKIINDYEE 190 200 210 220 230 240 FSKERSSSLE GSPDEFSNGE ELCGVMTISD SPREQDSESQ TLDKVYQMKS KPRGYCLIIN 250 260 270 NHNFAKAREK VPKLHSIRDR NGTHLDAGTV EPKREK
	Isoform 8 (Beta-4). Checksum: 19ACAE80171E0572	FASTA	261	30,707
	10 20 30 40 50 60 MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS 70 80 90 100 110 120 FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRVMLYQISE EVSRSELRSF 130 140 150 160 170 180 KFLLQEEISK CKLDDDMNLL DIFIEMEKRV ILGEGKLDIL KRVCAQINKS LLKIINDYEE 190 200 210 220 230 240 FSKGEELCGV MTISDSPREQ DSESQTLDKV YQMKSKPRGY CLIINNHNFA KAREKVPKLH 250 260 SIRDRNGTHL DAGTVEPKRE K
	Isoform 9 (8L). Checksum: 54402ECFACF9F6C9	FASTA	538	61,864
	10 20 30 40 50 60 MEGGRRARVV IESRRNFFLG AFPTPFPAEH VELGRLGDSE TAMVPGKGGA DYILLPFKKM 70 80 90 100 110 120 DFSRNLYDIG EQLDSEDLAS LKFLSLDYIP QRKQEPIKDA LMLFQRLQEK RMLEESNLSF 130 140 150 160 170 180 LKELLFRINR LDLLITYLNT RKEEMERELQ TPGRAQISAY RVMLYQISEE VSRSELRSFK 190 200 210 220 230 240 FLLQEEISKC KLDDDMNLLD IFIEMEKRVI LGEGKLDILK RVCAQINKSL LKIINDYEEF 250 260 270 280 290 300 SKERSSSLEG SPDEFSNGEE LCGVMTISDS PREQDSESQT LDKVYQMKSK PRGYCLIINN 310 320 330 340 350 360 HNFAKAREKV PKLHSIRDRN GTHLDAGALT TTFEELHFEI KPHDDCTVEQ IYEILKIYQL 370 380 390 400 410 420 MDHSNMDCFI CCILSHGDKG IIYGTDGQEA PIYELTSQFT GLKCPSLAGK PKVFFIQACQ 430 440 450 460 470 480 GDNYQKGIPV ETDSEEQPYL EMDLSSPQTR YIPDEADFLL GMATVNNCVS YRNPAEGTWY 490 500 510 520 530 IQSLCQSLRE RCPRGDDILT ILTEVNYEVS NKDDKKNMGK QMPQPTFTLR KKLVFPSD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death." Boldin M.P., Goncharov T.M., Goltsev Y.V., Wallach D. Cell 85:803-815(1996) [PubMed: 8681376] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 5; 6; 7 AND 8). Tissue: B-cell and Thymus.
[2]	"FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex." Muzio M., Chinnaiyan A.M., Kischkel F.C., O'Rourke K., Shevchenko A., Ni J., Scaffidi C., Bretz J.D., Zhang M., Gentz R., Mann M., Krammer P.H., Peter M.E., Dixit V.M. Cell 85:817-827(1996) [PubMed: 8681377] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE.
[3]	"In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains." Fernandes-Alnemri T., Armstrong R.C., Krebs J.F., Srinivasula S.M., Wang L., Bullrich F., Fritz L.C., Trapani J.A., Tomaselli K.J., Litwack G., Alnemri E.S. Proc. Natl. Acad. Sci. U.S.A. 93:7464-7469(1996) [PubMed: 8755496] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), VARIANT HIS-285. Tissue: T-cell.
[4]	"FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis." Srinivasula S.M., Ahmad M., Ottilie S., Bullrich F., Banks S., Wang Y., Fernandes-Alnemri T., Croce C.M., Litwack G., Tomaselli K.J., Armstrong R.C., Alnemri E.S. J. Biol. Chem. 272:18542-18545(1997) [PubMed: 9228018] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), VARIANT HIS-285.
[5]	"Structure and chromosome localization of the human CASP8 gene." Grenet J., Teitz T., Wei T., Valentine V., Kidd V.J. Gene 226:225-232(1999) [PubMed: 9931493] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]	"Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical region at chromosome 2q33-q34: candidate genes for ALS2." Hadano S., Yanagisawa Y., Skaug J., Fichter K., Nasir J., Martindale D., Koop B.F., Scherer S.W., Nicholson D.W., Rouleau G.A., Ikeda J.-E., Hayden M.R. Genomics 71:200-213(2001) [PubMed: 11161814] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT HIS-285.
[7]	"Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade." Himeji D., Horiuchi T., Tsukamoto H., Hayashi K., Watanabe T., Harada M. Blood 99:4070-4078(2002) [PubMed: 12010809] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7), FUNCTION (ISOFORM 7). Tissue: Leukocyte.
[8]	"The procaspase-8 isoform, procaspase-8L, recruited to the BAP31 complex at the endoplasmic reticulum." Breckenridge D.G., Nguyen M., Kuppig S., Reth M., Shore G.C. Proc. Natl. Acad. Sci. U.S.A. 99:4331-4336(2002) [PubMed: 11917123] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 9), INTERACTION OF ISOFORM 9 WITH BCAP31 AT THE ENDOPLASMIC RETICULUM.
[9]	NIEHS SNPs program Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS THR-219 AND HIS-285.
[10]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[11]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7). Tissue: Leukocyte.
[12]	"Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases." Srinivasula S.M., Ahmad M., Fernandes-Alnemri T., Litwack G., Alnemri E.S. Proc. Natl. Acad. Sci. U.S.A. 93:14486-14491(1996) [PubMed: 8962078] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE, PROTEOLYTIC PROCESSING.
[13]	"FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens." Muzio M., Salvesen G.S., Dixit V.M. J. Biol. Chem. 272:2952-2956(1997) [PubMed: 9006941] [Abstract] Cited for: FUNCTION.
[14]	"FLICE is activated by association with the CD95 death-inducing signaling complex (DISC)." Medema J.P., Scaffidi C., Kischkel F.C., Shevchenko A., Mann M., Krammer P.H., Peter M.E. EMBO J. 16:2794-2804(1997) [PubMed: 9184224] [Abstract] Cited for: PROTEOLYTIC PROCESSING.
[15]	"Dominant expression of a novel splice variant of caspase-8 in human peripheral blood lymphocytes." Horiuchi T., Himeji D., Tsukamoto H., Harashima S., Hashimura C., Hayashi K. Biochem. Biophys. Res. Commun. 272:877-881(2000) [PubMed: 10860845] [Abstract] Cited for: CHARACTERIZATION (ISOFORM 7).
[16]	"p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum." Ng F.W.H., Nguyen M., Kwan T., Branton P.E., Nicholson D.W., Cromlish J.A., Shore G.C. J. Cell Biol. 139:327-338(1997) [PubMed: 9334338] [Abstract] Cited for: INTERACTION WITH BCL2; BCL2L1 AND BCAP31.
[17]	"PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis." Condorelli G., Vigliotta G., Cafieri A., Trencia A., Andalo P., Oriente F., Miele C., Caruso M., Formisano P., Beguinot F. Oncogene 18:4409-4415(1999) [PubMed: 10442631] [Abstract] Cited for: INTERACTION WITH PEA15.
[18]	"An unappreciated role for RNA surveillance." Hillman R.T., Green R.E., Brenner S.E. Genome Biol. 5:R8.1-R8.16(2004) [PubMed: 14759258] [Abstract] Cited for: SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
[19]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed: 15592455] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-334, MASS SPECTROMETRY.
[20]	"Role of FLASH in caspase-8-mediated activation of NF-kappaB: dominant-negative function of FLASH mutant in NF-kappaB signaling pathway." Jun J.-I., Chung C.-W., Lee H.-J., Pyo J.-O., Lee K.N., Kim N.-S., Kim Y.S., Yoo H.-S., Lee T.-H., Kim E., Jung Y.-K. Oncogene 24:688-696(2005) [PubMed: 15592525] [Abstract] Cited for: MUTAGENESIS OF ASP-73.
[21]	"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage." Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J. Science 316:1160-1166(2007) [PubMed: 17525332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-219, MASS SPECTROMETRY.
[22]	"The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis." Blanchard H., Kodandapani L., Mittl P.R.E., Di Marco S., Krebs J.F., Wu J.C., Tomaselli K.J., Gruetter M.G. Structure 7:1125-1133(1999) [PubMed: 10508784] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS).
[23]	"The atomic-resolution structure of human caspase-8, a key activator of apoptosis." Watt W., Koeplinger K.A., Mildner A.M., Heinrikson R.L., Tomasselli A.G., Watenpaugh K.D. Structure 7:1135-1143(1999) [PubMed: 10508785] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS) OF 211-479, SUBUNIT.
[24]	"Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency." Chun H.J., Zheng L., Ahmad M., Wang J., Speirs C.K., Siegel R.M., Dale J.K., Puck J., Davis J., Hall C.G., Skoda-Smith S., Atkinson T.P., Straus S.E., Lenardo M.J. Nature 419:395-399(2002) [PubMed: 12353035] [Abstract] Cited for: VARIANT CASP8D TRP-248.
[25]	"Association of a common variant of the CASP8 gene with reduced risk of breast cancer." MacPherson G., Healey C.S., Teare M.D., Balasubramanian S.P., Reed M.W.R., Pharoah P.D., Ponder B.A.J., Meuth M., Bhattacharyya N.P., Cox A. J. Natl. Cancer Inst. 96:1866-1869(2004) [PubMed: 15601643] [Abstract] Cited for: VARIANT HIS-285, PROTECTION AGAINST BREAST CANCER.
[26]	"A common coding variant in CASP8 is associated with breast cancer risk." The Kathleen Cunningham foundation consortium for research into familial breast cancer, Breast cancer association consortium Cox A., Dunning A.M., Garcia-Closas M., Balasubramanian S., Reed M.W.R., Pooley K.A., Scollen S., Baynes C., Ponder B.A.J., Chanock S., Lissowska J., Brinton L., Peplonska B., Southey M.C., Hopper J.L., McCredie M.R.E., Giles G.G., Fletcher O. , Johnson N., dos Santos Silva I., Gibson L., Bojesen S.E., Nordestgaard B.G., Axelsson C.K., Torres D., Hamann U., Justenhoven C., Brauch H., Chang-Claude J., Kropp S., Risch A., Wang-Gohrke S., Schuermann P., Bogdanova N., Doerk T., Fagerholm R., Aaltonen K., Blomqvist C., Nevanlinna H., Seal S., Renwick A., Stratton M.R., Rahman N., Sangrajrang S., Hughes D., Odefrey F., Brennan P., Spurdle A.B., Chenevix-Trench G., Beesley J., Mannermaa A., Hartikainen J., Kataja V., Kosma V.M., Couch F.J., Olson J.E., Goode E.L., Broeks A., Schmidt M.K., Hogervorst F.B.L., Van't Veer L.J., Kang D., Yoo K.-Y., Noh D.-Y., Ahn S.-H., Wedren S., Hall P., Low Y.-L., Liu J., Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Sigurdson A.J., Stredrick D.L., Alexander B.H., Struewing J.P., Pharoah P.D.P., Easton D.F. Nat. Genet. 39:352-358(2007) [PubMed: 17293864] [Abstract] Cited for: VARIANT HIS-285, PROTECTION AGAINST BREAST CANCER.
[27]	Erratum The Kathleen Cunningham foundation consortium for research into familial breast cancer, Breast cancer association consortium Cox A., Dunning A.M., Garcia-Closas M., Balasubramanian S., Reed M.W.R., Pooley K.A., Scollen S., Baynes C., Ponder B.A.J., Chanock S., Lissowska J., Brinton L., Peplonska B., Southey M.C., Hopper J.L., McCredie M.R.E., Giles G.G., Fletcher O. , Johnson N., dos Santos Silva I., Gibson L., Bojesen S.E., Nordestgaard B.G., Axelsson C.K., Torres D., Hamann U., Justenhoven C., Brauch H., Chang-Claude J., Kropp S., Risch A., Wang-Gohrke S., Schuermann P., Bogdanova N., Doerk T., Fagerholm R., Aaltonen K., Blomqvist C., Nevanlinna H., Seal S., Renwick A., Stratton M.R., Rahman N., Sangrajrang S., Hughes D., Odefrey F., Brennan P., Spurdle A.B., Chenevix-Trench G., Beesley J., Mannermaa A., Hartikainen J., Kataja V., Kosma V.M., Couch F.J., Olson J.E., Goode E.L., Broeks A., Schmidt M.K., Hogervorst F.B.L., Van't Veer L.J., Kang D., Yoo K.-Y., Noh D.-Y., Ahn S.-H., Wedren S., Hall P., Low Y.-L., Liu J., Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Sigurdson A.J., Stredrick D.L., Alexander B.H., Struewing J.P., Pharoah P.D.P., Easton D.F. Nat. Genet. 39:688-688(2007)
[28]	"A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers." Sun T., Gao Y., Tan W., Ma S., Shi Y., Yao J., Guo Y., Yang M., Zhang X., Zhang Q., Zeng C., Lin D. Nat. Genet. 39:605-613(2007) [PubMed: 17450141] [Abstract] Cited for: INVOLVEMENT IN PROTECTION AGAINST LUNG CANCER.
[29]	"Genetic variants and haplotypes of the caspase-8 and caspase-10 genes contribute to susceptibility to cutaneous melanoma." Li C., Zhao H., Hu Z., Liu Z., Wang L.-E., Gershenwald J.E., Prieto V.G., Lee J.E., Duvic M., Grimm E.A., Wei Q. Hum. Mutat. 29:1443-1451(2008) [PubMed: 18563783] [Abstract] Cited for: VARIANT HIS-285, RISK FACTOR FOR CUTANEOUS MELANOMA.
+	Additional computationally mapped references.

Web resources

CASP8base

CASP8 mutation db

GeneReviews

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X98172 mRNA. Translation: CAA66853.1.
X98173 mRNA. Translation: CAA66854.1.
X98174 mRNA. Translation: CAA66855.1.
X98175 mRNA. Translation: CAA66856.1.
X98176 mRNA. Translation: CAA66857.1.
X98177 mRNA. Translation: CAA66858.1. Sequence problems.
X98178 mRNA. Translation: CAA66859.1. Sequence problems.
U58143 mRNA. Translation: AAC50602.1.
U60520 mRNA. Translation: AAC50645.1.
AF009620 mRNA. Translation: AAB70913.1.
AF102146 , AF102139, AF102140, AF102141, AF102142, AF102143, AF102144, AF102145 Genomic DNA. Translation: AAD24962.1.
AB038985 Genomic DNA. Translation: BAB32555.1.
AF380342 mRNA. Translation: AAK57437.1.
AF422925 mRNA. Translation: AAL87628.1.
AF422926 mRNA. Translation: AAL87629.1.
AF422927 mRNA. Translation: AAL87630.1.
AF422928 mRNA. Translation: AAL87631.1.
AF422929 mRNA. Translation: AAL87632.1.
DQ355026 Genomic DNA. Translation: ABC67468.1.
AC007256 Genomic DNA. Translation: AAY24225.1.
BC028223 mRNA. No translation available.

IPI

IPI00000149.
IPI00073318.
IPI00220721.
IPI00220722.
IPI00220723.
IPI00220724.
IPI00220726.
IPI00305242.
IPI00793235.

RefSeq

NP_001073593.1.
NP_001073594.1.
NP_001219.2.
NP_203519.1.
NP_203520.1.
NP_203522.1.

UniGene

Hs.599762

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1F9E	X-ray	2.90	A/C/E/G/I/K	222-374	[»]
			B/D/F/H/J/L	390-478	[»]
1I4E	X-ray	3.00	B	222-479	[»]
1QDU	X-ray	2.80	A/C/E/G/I/K	222-374	[»]
			B/D/F/H/J/L	390-477	[»]
1QTN	X-ray	1.20	A	211-374	[»]
			B	385-479	[»]
2C2Z	X-ray	1.95	A	218-374	[»]
			B	376-479	[»]
2FUN	X-ray	3.00	B/D	222-479	[»]
2K7Z	NMR	-	A	217-479	[»]
3H11	X-ray	1.90	B	217-479	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

Q14790. 41 interactions.

STRING

Q14790.

Protein family/group databases

MEROPS

C14.009.

PTM databases

PhosphoSite

Q14790.

Proteomic databases

PRIDE

Q14790.

Genome annotation databases

Ensembl

ENST00000303385; ENSP00000307131; ENSG00000064012; Homo sapiens. [Genome view]
ENST00000358485; ENSP00000351273; ENSG00000064012; Homo sapiens. [Genome view]
ENST00000432109; ENSP00000412523; ENSG00000064012; Homo sapiens. [Genome view]

GeneID

841.

KEGG

hsa:841.

UCSC

uc002uxo.1. human.
uc002uxp.1. human.
uc002uxq.1. human.
uc002uxr.1. human.
uc002uxs.1. human.
uc002uxv.1. human.
uc002uxy.1. human.

Organism-specific databases

CTD

841.

GeneCards

GC02P201807.

H-InvDB

HIX0002736.

HGNC

HGNC:1509. CASP8.

HPA

CAB002047.
HPA001302.
HPA005688.
HPA008936.

MIM

211980. phenotype.
601763. gene.
607271. phenotype.

Orphanet

3261. Autoimmune lymphoproliferative syndrome.

PharmGKB

PA26092.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG05678.

HOVERGEN

Q14790.

InParanoid

Q14790.

Enzyme and pathway databases

BRENDA

3.4.22.61. 247.

Pathway_Interaction_DB

caspase_pathway. Caspase cascade in apoptosis.
ceramidepathway. Ceramide signaling pathway.
ar_pathway. Coregulation of Androgen receptor activity.
faspathway. FAS signaling pathway (CD95).
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
avb3_integrin_pathway. Integrins in angiogenesis.
tnfpathway. TNF receptor signaling pathway.
trail_pathway. TRAIL signaling pathway.

Reactome

REACT_578. Apoptosis.

Gene expression databases

ArrayExpress

Q14790.

Bgee

Q14790.

Genevestigator

Q14790.

GermOnline

ENSG00000064012. Homo sapiens.

Family and domain databases

InterPro

IPR011029. DEATH-like.
IPR001875. DED.
IPR011600. Pept_C14_cat.
IPR001309. Pept_C14_ICE_p20.
IPR016129. Pept_C14_ICE_p20_AS.
IPR002138. Pept_C14_p10.
IPR002398. Pept_C14_p45.
IPR015917. Pept_C14_p45_core.
[Graphical view]

Gene3D

G3DSA:1.10.533.10. DEATH_like. 2 hits.

PANTHER

PTHR10454. Pept_C14_p45. 1 hit.

Pfam

PF01335. DED. 2 hits.
PF00656. Peptidase_C14. 1 hit.
[Graphical view]

PRINTS

PR00376. IL1BCENZYME.

SMART

SM00115. CASc. 1 hit.
SM00031. DED. 2 hits.
[Graphical view]

PROSITE

PS01122. CASPASE_CYS. 1 hit.
PS01121. CASPASE_HIS. 1 hit.
PS50207. CASPASE_P10. 1 hit.
PS50208. CASPASE_P20. 1 hit.
PS50168. DED. 2 hits.
[Graphical view]

ProtoNet

Search...

Other Resources

BindingDB

Q14790.

NextBio

3510.

PMAP-CutDB

Q14790.

SOURCE

Search...

Entry information

Entry name

CASP8_HUMAN

Accession

Primary (citable) accession number: Q14790
Secondary accession number(s): O14676 , Q14791, Q14792, Q14793, Q14794, Q14795, Q14796, Q15780, Q15806, Q53TT5, Q8TDI1, Q8TDI2, Q8TDI3, Q8TDI4, Q8TDI5, Q96T22, Q9C0K4, Q9UQ81

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1996
Last modified:	January 19, 2010
This is version 131 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.