BIRC2 (Danio rerio)

Description [+]

Synonyms: BIRC2, BACULOVIRAL IAP REPEAT-CONTAINING 2, IAP1, BIRC3
Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Pisces; Danio rerio
Short gene description: baculoviral IAP repeat-containing 2 [Source:RefSeq_peptide;Acc:NP_919376]
Family: BIR-containing protein : IAP
Process: apoptosis,
Pathways: TNF/NF-kappaB signaling,
Criteria: manually curated
Curator comment: A loss of function mutation in the zebrafish Birc2 locus produces a hemorrhagic phenotype, vascular regression, and Caspase-8-dependent endothelial cell apoptosis [17934460]. Zebrafish Birc2 binds endogenous mammalian TRAF2 when transfected into HEK293 cells [17934460].
Human ortholog(s): cIAP1 BIRC2 BIRC3
WIKI: BIRC2-D_rerio

References [+]

Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasis.
Santoro MM, Samuel T, Mitchell T, Reed JC, Stainier DY
Integrity of the blood vessel wall is essential for vascular homeostasis and organ function. A dynamic balance between endothelial cell survival and apoptosis contributes to this integrity during vascular development and pathological angiogenesis. The genetic and molecular mechanisms regulating these processes in vivo are still largely unknown. Here, we show that Birc2 (also known as cIap1) is essential for maintaining endothelial cell survival and blood vessel homeostasis during vascular development. Using a forward-genetic approach, we identified a zebrafish null mutant for birc2, which shows severe hemorrhage and vascular regression due to endothelial cell integrity defects and apoptosis. Using genetic and molecular approaches, we show that Birc2 positively regulates the formation of the TNF receptor complex I in endothelial cells, thereby promoting NF-kappaB activation and maintaining vessel integrity and stabilization. In the absence of Birc2, a caspase-8-dependent apoptotic program takes place that leads to vessel regression. Our findings identify Birc2 and TNF signaling components as critical regulators of vascular integrity and endothelial cell survival, thereby providing an additional target pathway for the control of angiogenesis and blood vessel homeostasis during embryogenesis, regeneration and tumorigenesis. Nat Genet. 2007 Nov;39(11):1397-402. Epub 2007 Oct 14.

References from Human ortholog(s):

The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases.
Eckelman BP, Salvesen GS
cIAPs (cellular inhibitor of apoptosis proteins) 1 and 2 are able to regulate apoptosis when ectopically expressed in recipient cells and probably also in vivo. Previous work suggested that this is at least partially due to direct caspase inhibition, mediated by two of the three baculovirus IAP repeat (BIR) domains that are contained in these proteins. In support of this we show that the BIR domains 2 and 3 of the two cIAPs are able to bind caspases-7 and -9. However, we demonstrate that neither of these BIR domains is able to inhibit caspases because of critical substitutions in the regions that target caspase inhibition in the X-linked IAP, a tight binding caspase inhibitor. The cIAP BIR domains can be converted to tight binding caspase inhibitors by substituting these critical residues with XIAP residues. Thus, cIAPs maintain protein scaffolds suitable for direct caspase inhibition but have lost or never acquired specific caspase inhibitory interaction sites. Consequently, although the binding function of the cIAP BIRs may be important for their physiologic function, caspase inhibition is not. J Biol Chem. 2006 Feb 10;281(6):3254-60. Epub 2005 Dec 8.

The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases.
Eckelman BP, Salvesen GS
cIAPs (cellular inhibitor of apoptosis proteins) 1 and 2 are able to regulate apoptosis when ectopically expressed in recipient cells and probably also in vivo. Previous work suggested that this is at least partially due to direct caspase inhibition, mediated by two of the three baculovirus IAP repeat (BIR) domains that are contained in these proteins. In support of this we show that the BIR domains 2 and 3 of the two cIAPs are able to bind caspases-7 and -9. However, we demonstrate that neither of these BIR domains is able to inhibit caspases because of critical substitutions in the regions that target caspase inhibition in the X-linked IAP, a tight binding caspase inhibitor. The cIAP BIR domains can be converted to tight binding caspase inhibitors by substituting these critical residues with XIAP residues. Thus, cIAPs maintain protein scaffolds suitable for direct caspase inhibition but have lost or never acquired specific caspase inhibitory interaction sites. Consequently, although the binding function of the cIAP BIRs may be important for their physiologic function, caspase inhibition is not. J Biol Chem. 2006 Feb 10;281(6):3254-60. Epub 2005 Dec 8.

IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.
Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J
XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-kappaB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kappaB-stimulated production of TNFalpha that killed cells in an autocrine fashion. Inhibition of NF-kappaB reduced TNFalpha production, and blocking NF-kappaB activation or TNFalpha allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha, suggesting novel uses of these compounds in treating cancer. Cell. 2007 Nov 16;131(4):682-93.

IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.
Varfolomeev E,Blankenship JW,Wayson SM,Fedorova AV,Kayagaki N,Garg P,Zobel K,Dynek JN,Elliott LO,Wallweber HJ,Flygare JA,Fairbrother WJ,Deshayes K,Dixit VM,Vucic D
Inhibitor of apoptosis (IAP) proteins are antiapoptotic regulators that block cell death in response to diverse stimuli. They are expressed at elevated levels in human malignancies and are attractive targets for the development of novel cancer therapeutics. Herein, we demonstrate that small-molecule IAP antagonists bind to select baculovirus IAP repeat (BIR) domains resulting in dramatic induction of auto-ubiquitination activity and rapid proteasomal degradation of c-IAPs. The IAP antagonists also induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. Additionally, the c-IAP proteins were found to function as regulators of NF-kappaB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c-IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the noncanonical NF-kappaB pathway. Cell. 2007 Nov 16;131(4):669-81.

An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer.
Zender L,Xue W,Zuber J,Semighini CP,Krasnitz A,Ma B,Zender P,Kubicka S,Luk JM,Schirmacher P,McCombie WR,Wigler M,Hicks J,Hannon GJ,Powers S,Lowe SW
Cancers are highly heterogeneous and contain many passenger and driver mutations. To functionally identify tumor suppressor genes relevant to human cancer, we compiled pools of short hairpin RNAs (shRNAs) targeting the mouse orthologs of genes recurrently deleted in a series of human hepatocellular carcinomas and tested their ability to promote tumorigenesis in a mosaic mouse model. In contrast to randomly selected shRNA pools, many deletion-specific pools accelerated hepatocarcinogenesis in mice. Through further analysis, we identified and validated 13 tumor suppressor genes, 12 of which had not been linked to cancer before. One gene, XPO4, encodes a nuclear export protein whose substrate, EIF5A2, is amplified in human tumors, is required for proliferation of XPO4-deficient tumor cells, and promotes hepatocellular carcinoma in mice. Our results establish the feasibility of in vivo RNAi screens and illustrate how combining cancer genomics, RNA interference, and mosaic mouse models can facilitate the functional annotation of the cancer genome. Cell. 2008 Nov 28;135(5):852-64. Epub 2008 Nov 13.

Structure & Sequence [+]

Pfam domains: (Pfam is a large collection of protein families.)

Source	Domain Name	Start	End
PFAM A	BIR	60	125
PFAM A	BIR	218	282
PFAM A	BIR	310	376
PFAM A	CARD	497	581

Protein sequence [+]

Structure links:

Smartdomain prediction information: SM00238
Smartdomain prediction information: SM00114
Smartdomain prediction information: SM00184
Prosite motif and domain information: PS01282

Evolution [+]

Name	Relationship	Species
A_aegypti_AAEL006633-PA	orthology	Aedes
Q5MM83_AEDAE	orthology	Aedes
IAP4	orthology	Anopheles
IAP3	orthology	Anopheles
A_gambiae_AGAP007293-PA	orthology	Anopheles
IAP2	orthology	Anopheles
BIR_CHICK	orthology	Chicken
BIR_CHICK	orthology	Chicken
BIRC3	orthology	Chimpanzee
BIRC3	orthology	Chimpanzee
BIRC2	orthology	Chimpanzee
BIRC2	orthology	Chimpanzee
C_intestinalis_ENSCINP00000000045	orthology	Ciona
C_intestinalis_ENSCINP00000000466	orthology	Ciona
NA	orthology	Ciona
C_intestinalis_ENSCINP00000000487	orthology	Ciona
C_intestinalis_ENSCINP00000000510	orthology	Ciona
C_intestinalis_ENSCINP00000002256	orthology	Ciona
C_intestinalis_ENSCINP00000002312	orthology	Ciona
C_intestinalis_ENSCINP00000005161	orthology	Ciona
C_intestinalis_ENSCINP00000008701	orthology	Ciona
C_intestinalis_ENSCINP00000009820	orthology	Ciona
C_intestinalis_ENSCINP00000010449	orthology	Ciona
C_intestinalis_ENSCINP00000011648	orthology	Ciona
C_intestinalis_ENSCINP00000020067	orthology	Ciona
NA	orthology	Ciona
C_intestinalis_ENSCINP00000021651	orthology	Ciona
NP_001030370.1	orthology	Cow
NP_001030370.1	orthology	Cow
IPI00824732.2	orthology	Cow
Q38JA8_CANFA	orthology	Dog
BIRC3_CANFA	orthology	Dog
BIRC3_CANFA	orthology	Dog
Q38JA8_CANFA	orthology	Dog
th	orthology	Fly
Iap2	orthology	Fly
Iap2	orthology	Fly
BIRC3	orthology	Fugu
BIRC3	orthology	Fugu
BIRC3	orthology	Gasterosteus
BIRC3	orthology	Gasterosteus
BIRC3	orthology	Gorilla
BIRC2	orthology	Gorilla
BIRC2	orthology	Gorilla
BIRC3	orthology	Horse
BIRC2	orthology	Horse
BIRC2	orthology	Horse
BIRC3	orthology	Horse
BIRC3	orthology	Human
BIRC3	orthology	Human
cIAP1	orthology	Human
BIRC2	orthology	Human
A_carolinensis_ENSACAP00000012475	orthology	Lyzard
A_carolinensis_ENSACAP00000012475	orthology	Lyzard
BIRC3	orthology	Macaca
BIRC3	orthology	Macaca
BIRC2	orthology	Macaca
BIRC2	orthology	Macaca
BIRC3	orthology	Medaka
M_domestica_ENSMODP00000000705	orthology	Monodelphis
M_domestica_ENSMODP00000000705	orthology	Monodelphis
M_domestica_ENSMODP00000000728	orthology	Monodelphis
XM_001362587.1	orthology	Monodelphis
cIAP2	orthology	Mouse
Birc3	orthology	Mouse
cIAP1	orthology	Mouse
Birc2	orthology	Mouse
BIRC3	orthology	Orangutan
BIRC3	orthology	Orangutan
Q5R9T1_PONPY	orthology	Orangutan
Q5R9T1_PONPY	orthology	Orangutan
O_anatinus_ENSOANP00000016616	orthology	Ornithorhynchus
O_anatinus_ENSOANP00000016616	orthology	Ornithorhynchus
BIRC3	orthology	Rabbit
BIRC3	orthology	Rabbit
O_cuniculus_ENSOCUP00000011948	orthology	Rabbit
O_cuniculus_ENSOCUP00000011948	orthology	Rabbit
O_cuniculus_ENSOCUP00000014265	orthology	Rabbit
Birc3	orthology	Rat
NP_076477.2	orthology	Rat
Birc2	orthology	Rat
NP_068520.2	orthology	Rat
BIRC3	orthology	Tetraodon
X_tropicalis_ENSXETP00000030727	orthology	Xenopus
X_tropicalis_ENSXETP00000030727	orthology	Xenopus
birc3	orthology	Xenopus
birc3	orthology	Xenopus
T_guttata_ENSTGUP00000013125	orthology	Zebra finch
BIRC2	orthology	Zebra finch
BIRC7	paralogy	Chicken
IPI00603248.2	paralogy	Chicken
NP_989919.1	paralogy	Chicken
NP_989919.1	paralogy	Chicken
MUL1	paralogy	Chimpanzee
BIRC8_PANTR	paralogy	Chimpanzee
XR_021305.1	paralogy	Chimpanzee
XR_021305.1	paralogy	Chimpanzee
XIAP	paralogy	Chimpanzee
XIAP	paralogy	Chimpanzee
P_troglodytes_ENSPTRP00000048273	paralogy	Chimpanzee
XM_001156604.1	paralogy	Chimpanzee
IPI00689691.3	paralogy	Cow
IPI00689691.3	paralogy	Cow
Q8WMY4_BOVIN	paralogy	Cow
Q8WMY4_BOVIN	paralogy	Cow
Q38IV1_CANFA	paralogy	Dog
Q38IV1_CANFA	paralogy	Dog
BIRC7	paralogy	Dog
BIRC7	paralogy	Dog
BIRC8	paralogy	Fugu
XIAP	paralogy	Fugu
BIRC7	paralogy	Fugu
BIRC7	paralogy	Fugu
BIRC7	paralogy	Gasterosteus
BIRC7	paralogy	Gasterosteus
BIRC8	paralogy	Gasterosteus
XIAP	paralogy	Gasterosteus
BIRC8	paralogy	Gorilla
BIRC7	paralogy	Gorilla
BIRC7	paralogy	Gorilla
XIAP	paralogy	Gorilla
XIAP	paralogy	Gorilla
MUL1	paralogy	Horse
BIRC8	paralogy	Horse
XIAP	paralogy	Horse
BIRC7	paralogy	Horse
BIRC7	paralogy	Horse
E_caballus_ENSECAP00000002314	paralogy	Horse
XP_001504091.2	paralogy	Horse
MUL1	paralogy	Human
BIRC8	paralogy	Human
BIRC8	paralogy	Human
XIAP	paralogy	Human
XIAP	paralogy	Human
BIRC1	paralogy	Human
NAIP	paralogy	Human
BIRC7	paralogy	Human
BIRC7	paralogy	Human
BIRC7	paralogy	Lyzard
BIRC7	paralogy	Lyzard
A_carolinensis_ENSACAP00000011315	paralogy	Lyzard
A_carolinensis_ENSACAP00000011315	paralogy	Lyzard
MUL1	paralogy	Macaca
BIRC7	paralogy	Macaca
BIRC7	paralogy	Macaca
BIRC8	paralogy	Medaka
XIAP	paralogy	Medaka
BIRC7	paralogy	Medaka
BIRC7	paralogy	Medaka
M_domestica_ENSMODP00000018715	paralogy	Monodelphis
XM_001364568.1	paralogy	Monodelphis
BIRC7	paralogy	Monodelphis
BIRC7	paralogy	Monodelphis
Xiap	paralogy	Mouse
Xiap	paralogy	Mouse
Birc1-rs1	paralogy	Mouse
Naip6	paralogy	Mouse
Naip2	paralogy	Mouse
Naip2	paralogy	Mouse
Naip1	paralogy	Mouse
Naip4	paralogy	Mouse
Naip5	paralogy	Mouse
Naip5	paralogy	Mouse
Birc7	paralogy	Mouse
Birc7	paralogy	Mouse
P_pygmaeus_ENSPPYP00000017359	paralogy	Orangutan
XIAP	paralogy	Orangutan
XIAP	paralogy	Orangutan
MUL1	paralogy	Orangutan
BIRC7	paralogy	Orangutan
BIRC7	paralogy	Orangutan
P_pygmaeus_ENSPPYP00000017359	paralogy	Orangutan
O_anatinus_ENSOANP00000006435	paralogy	Ornithorhynchus
O_anatinus_ENSOANP00000006435	paralogy	Ornithorhynchus
MUL1	paralogy	Rabbit
BIRC7	paralogy	Rabbit
O_cuniculus_ENSOCUP00000008505	paralogy	Rabbit
XIAP	paralogy	Rabbit
Birc4	paralogy	Rat
XIAP_RAT	paralogy	Rat
RGD1559914_predicted	paralogy	Rat
Q8R4U8_RAT	paralogy	Rat
BIRC8	paralogy	Tetraodon
XIAP	paralogy	Tetraodon
BIRC7	paralogy	Tetraodon
BIRC7	paralogy	Tetraodon
X_tropicalis_ENSXETP00000016312	paralogy	Xenopus
X_tropicalis_ENSXETP00000016315	paralogy	Xenopus
BIRC7	paralogy	Xenopus
BIRC7	paralogy	Xenopus
X_tropicalis_ENSXETP00000034890	paralogy	Xenopus
birc4	paralogy	Xenopus
birc4	paralogy	Xenopus
X_tropicalis_ENSXETP00000057704	paralogy	Xenopus
T_guttata_ENSTGUP00000003825	paralogy	Zebra finch
XIAP	paralogy	Zebra finch
BIRC7	paralogy	Zebra finch
BIRC7	paralogy	Zebra finch
birc4	paralogy	Zebrafish
xiap	paralogy	Zebrafish
BIRC7	paralogy	Zebrafish
zgc:165605	paralogy	Zebrafish

Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0042981	regulation of apoptosis	biological_proccess	IEA
GO:0005515	protein binding	mollecular_function	IEA
GO:0008270	zinc ion binding	mollecular_function	IEA
GO:0046872	metal ion binding	mollecular_function	IEA
GO:0005622	intracellular	cell_component	IEA

KEGG Pathways [+]

Information from other databases [+]