Apoptosis Reference Genome Targets (Archived)
Project leaders
UniProtKB GOA team, Emily Dimmer
Justification (Impact and significance)
Apoptosis is a programmed form of cell death involving the degradation of cellular constituents by a group of cysteine proteases called caspases. The caspases can be activated through either the intrinsic (mitochondrial mediated) or extrinsic (death receptor mediated) apoptotic pathways.
The intrinsic apoptotic pathway is characterized by permeabilisation of the mitochondria and release of cytochrome c into the cytoplasm. Cytochrome c then forms a multi-protein complex known as the ‘apoptosome’ and initiates activation of the caspase cascade through caspase 9.
The intrinsic apoptotic pathway has been chosen for a Reference Genome project as the curation work will complement and inform a planned apoptosis content meeting scheduled for June the 1st, assisted by domain experts from the Apo-Sys Consortium. In addition, as the intrinsic apoptotic pathway seems to have evolved at the same time as multicellular organisms, whereas the extrinsic pathway is a more recent evolutionary development in veterbrates, it is felt the intrinsic mechanism was more suited to a multi-organism curation project.
In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in an extensive variety of diseases. Excessive apoptosis causes atrophy, such as in ischemic damage, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer. [1],[2]
While the importance of apoptosis in metazoans for development and maintenance has long been recognized, data from single-celled organisms have suggested that apoptotic pathways have ancient origins [10]
Notes for curators
Although the presence of active caspases and DNA fragmentation is helpful in identifying possible apoptosis, they should not be employed as an exclusive means to demonstrate this process as apototic cell death can occur without DNA fragmentation or caspase activity.[1]
Cell death is frequently considered to be ‘caspase-dependent’ when it is suppressed by broad-spectrum caspase inhibitors such as N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk). As a word of caution, however, it should be noted that Z-VAD-fmk does not act on all caspases with an equal efficiency, and it also inhibits calpains and cathepsins, especially at high concentrations (>10 μM). Moreover, Z-VAD-fmk has been associated with several off-target effects that would result from the binding to cysteines on proteins other than cysteine proteases[1]
from Apoptosis. 2010 Mar;15(3):331-49.The zebrafish as a model organism for the study of apoptosis. Eimon PM, Ashkenazi A.
What to do if your target has no Panther family
Paul T has suggested it may be possible to add in (manually) any homologous genes that may have diverged too much to be recognized by the existing PANTHER HMMs. Panther did this for a C. elegans ortholog of p53 (though this revised family has not been released yet). Therefore if curators find any literature about the family history of these genes, it would be helpful if they could be flagged to be sent to Panther as they then can store the evidence for homology.
Range of species in which the pathway is found
Intrinsic apoptosis is thought to be present in all eukaryotes
Homologs of some apoptotic enzymes are found among the Bacteria, but not the Archaea [11].
Apoptosis Experts
Reactome (Mark Gillespie and Lisa Matthews) would like to hear feedback from the vertebrate groups on their representation of apoptosis
Ontology status
see also: http://wiki.geneontology.org/index.php/Apoptosis
Time frame of the project
Background reading
[1] [Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G; Nomenclature Committee on Cell Death 2009.Cell Death Differ. 2009 Jan;16(1):3-11. Epub 2008 Oct 10. http://www.ncbi.nlm.nih.gov/pubmed/18846107]
Highly recommended to read before starting curation; contains definitions of different types of cell death (apoptosis/necrosis/autophagic cell death/cornification, as described by the Nomenclature Committee on Cell Death.
[2] http://en.wikipedia.org/wiki/Apoptosis
[3] Molecular mechanisms of caspase regulation during apoptosis, Nature Reviews Molecular Cell Biology 5, 897-907 (November 2004) | doi:10.1038/nrm1496
[4] APOPTOSIS PATHWAYS AND DRUG TARGETS POSTER: John C. Reed and Ziwei Huang: http://www.nature.com/reviews/poster/apoptosis/index.html
[5] Apoptotic cell death "Nixed" by an ER-mitochondrial necrotic pathway.Kitsis RN, Molkentin JD. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9031-2. Epub 2010 May 6.
[6] The zebrafish as a model organism for the study of apoptosis. Eimon PM, Ashkenazi A.Apoptosis. 2010 Mar;15(3):331-49. good species comparison paper
[7]Apoptosis in yeast - mechanisms and benefits to a unicellular organism. Gourlay, C.W, Du, W. and Ayscough, K.R. Molecular Microbiology 2006 62 p.1515-1521.
[8]
[9]
[10]
[11] Koonin EV, Aravaind L. (2002) Origin and evolution of eukaryotic apoptosis: the bacterial connection. Cell Death Differ. 2002 Apr;9(4):394-404. http://www.ncbi.nlm.nih.gov/pubmed/11965492
Families to annotate
Number of Gene Products assigned per RefGen species
Gallus gallus: 22 targets
H. sapiens: 28 targets
Mus Musculus: 37 targets
Rattus norvegicus: 40 targets
Danio rerio: 50 targets
C. elegans: 12 targets
Drosophila Melanogaster: 19 targets
Arabidopsis thaliana: 25 targets
Dictyostelium discoideum: 4 targets
Saccharomyces cerevisiae: 5 targets
Schizosaccharomyces pombe: 4 targets
BCL family Proteins
1. PTHR11256:SF8 BCL-2 HOMOLOGOUS ANTAGONIST/KILLER (BAK) (PRO-APOPTOTIC)
Gallus gallus:
Q5F404
Homo sapiens:
Q16611 (BHF Priority, low: annotation incomplete) Reactome Link
Mus musculus:
MGI=MGI=1097161|UniProtKB=O08734
Rattus norvegicus:
RGD=621635|UniProtKB=Q9JK59 - done
2. PTHR11256:SF4 APOPTOSIS REGULATOR (BOK) (PRO-APOPTOTIC)
Danio rerio:
ZFIN=ZDB-GENE-040426-1346|UniProtKB=Q7T381 - DONE 3/8/11
ZFIN=ZDB-GENE-040801-131|UniProtKB=Q6DC66 - DONE 3/8/11
Gallus gallus:
UniProtKB=Q9I8I2
Homo sapiens:
UniProtKB=Q9UMX3 (BHF Priority, low: annotation incomplete)
Mus musculus:
MGI=1858494|UniProtKB=O35425
Rattus norvegicus:
RGD=70984|UniProtKB=Q792S6 - done
3. PTHR16615 FAMILY NOT NAMED (BAD) anti-apoptotic
HUMAN FUNCTION FROM UNIPROT ENTRY:
Promotes cell death. Successfully competes for the binding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the level of heterodimerization of these proteins with BAX. Can reverse the death repressor activity of Bcl-X(L), but not that of Bcl-2 By similarity. Appears to act as a link between growth factor receptor signaling and the apoptotic pathways.
Danio rerio:
ZFIN=ZDB-GENE-000616-1|UniProtKB=Q4V925 - DONE 3/10/11
Homo sapiens:
Q92934 (BHF-UCL priority; low; KRUK Priority: Annotation not complete)
Mus musculus:
MGI=1096330|UniProtKB=Q61337
Rattus norvegicus:
RGD=620103|UniProtKB=O35147 - done
4. PTHR15165 FAMILY NOT NAMED (BID). BH-3-only protein
HUMAN FUNCTION FROM UNIPROT ENTRY:
The major proteolytic product p15 BID allows the release of cytochrome c By similarity. Isoform 1, isoform 2 and isoform 4 induce ICE-like proteases and apoptosis. Isoform 3 does not induce apoptosis. Counters the protective effect of Bcl-2. Forms heterodimers either with the pro-apoptotic protein BAX or the anti-apoptotic protein Bcl-2 By similarity. p15 BID interacts with ITCH. (enables cross-talk between intrinsic and extrinsic pathways)
Gallus gallus:
UniProtKB=Q8JGM8
Homo sapiens:
P55957 (BHF Priority, low: annotation incomplete) Reactome Link
Mus musculus:
MGI=108093|UniProtKB=P70444
Rattus norvegicus:
RGD=620160|UniProtKB=Q9JLT6 - done
5. PTHR14299 (FAMILY NOT NAMED) PMAIP1
FROM HUMAN UNIPROT ENTRY:
Promotes activation of caspases and apoptosis. Promotes mitochondrial membrane changes and efflux of apoptogenic proteins from the mitochondria. Contributes to TP53/p53-dependent apoptosis after radiation exposure. Promotes proteasomal degradation of MCL1. Competes with BAK1 for binding to MCL1 and can displace BAK1 from its binding site on MCL1 By similarity. Competes with BIM/BCL2L11 for binding to MCL1 and can displace BIM/BCL2L11 from its binding site on MCL1. Interacts with MCL1 and BAX.
Danio rerio:
ZFIN=ZDB-GENE-070119-3|UniProtKB=Q0GKC8 - DONE 3/8/11
Gallus gallus:
ENTREZ=770077|NCBI=XP_001233390
Homo sapiens:
ENSEMBL=ENSG00000141682|UniProtKB=Q13794 (KRUK Priority) Reactome Link
Mus musculus:
MGI=1930146|UniProtKB=Q9JM54
Rattus norvegicus:
RGD=1359266|UniProtKB=Q5U777
6. PTHR15186 FAMILY NOT NAMED (BNIP3)
HUMAN FUNCTION FROM UNIPROT ENTRY:
Apoptosis-inducing protein that, which can overcome BCL2 suppression. May play a role in repartitioning calcium between the two major intracellular calcium stores in association with BCL2.
Might provide distinguishing information on involvement in programmed necrosis, as Nix/Bnip3L seems to be capable of inducing apoptotic and necrotic death programs, depending on whether it is located at the OMM or ER membrane.[5]
Caenorhabditis elegans:
WB=WBGene00015776|UniProtKB=Q09969
Danio rerio:
ZFIN=ZDB-GENE-051113-212|UniProtKB=Q32PK3 - DONE 3/8/11
ZFIN=ZDB-GENE-040325-1|UniProtKB=Q801Y7 - DONE 3/8/11
ZFIN=ZDB-GENE-050703-8|UniProtKB=Q801Y5 - DONE 3/8/11
ZFIN=ZDB-GENE-030131-8060|UniProtKB=Q5VK50 - DONE 3/8/11
ZFIN=ZDB-GENE-030131-2283|UniProtKB=Q5VK49 - DONE 3/8/11
Gallus gallus:
ENTREZ=419522|UniProtKB=Q5ZLK0
ENTREZ=423971|NCBI=XP_421829
Homo sapiens:
Q12983 BNIP3/NIX (BHF Priority, low: annotation incomplete)
O60238 BNIP3L (BHF Priority, low: annotation incomplete)
Mus musculus:
MGI=MGI=3646742|NCBI=XP_894501
MGI=MGI=3647611|NCBI=XP_001478238
MGI=MGI=3642435|NCBI=XP_001480489
MGI=MGI=109326|UniProtKB=O55003
MGI=MGI=1332659|UniProtKB=Q9Z2F7
Rattus norvegicus:
RGD=1565371|NCBI=XP_001063205 - pseudogene
RAT|RGD=1562663|NCBI=XP_573895 - gene record withdrawn
RAT|RGD=1565720|NCBI=XP_576259 - gene record withdrawn
RAT|RGD=621354|UniProtKB=Q66HQ4
RGD=620800|UniProtKB=Q9ET45
7. PTHR11256:SF3 (Buffy, Debcl BCL-2 RELATED)
Drosophila melanogaster:
FB=FBgn0029131|UniProtKB=Q7KM33
FB=FBgn0040491|UniProtKB=Q9NGX3
8. PTHR11256:SF19 (APOPTOSIS REGULATOR CED-9. BCL-2 RELATED)
C.Elegans UniProt Function:
Plays a major role in programmed cell death (PCD, apoptosis). Egl-1 binds to and directly inhibits the activity of ced-9, releasing the cell death activator ced-4 from a ced-9/ced-4 containing protein complex and allowing ced-4 to activate the cell-killing caspase ced-3.
Caenorhabditis elegans:
WB=WBGene00000423|UniProtKB=P41958
9. Reaper; Q24475 Drosophila; matches no Panther family
10. HID; Q24106 Drosophila; matches no Panther family
11. GRIM; Q24570 Drosophila; matches no Panther family
12. Sickle; Q9VVP8 Drosophila; matches no Panther family
13. EGL-1; O61667 C.elegans; matches no Panther family
14. CED-13; Q9TY06 C.elegans; matches no Panther family
15. CEP-1; Q20646 C.elegans; matches no Panther family
Apoptogenic factors released from the mitochondrion
1. PTHR11961 (FAMILY NOT NAMED) (Cytochrome C)
Arabidopsis thaliana:
TAIR=locus=2017729|NCBI=NP_173697
TAIR=locus=2140573|NCBI=NP_192742
Caenorhabditis elegans:
WB=WBGene00013854|UniProtKB=Q23240
WB=WBGene00017121|UniProtKB=P19974
Danio rerio:
ZFIN=ZDB-GENE-040625-38|UniProtKB=Q6IQM2
ENSEMBL=ENSDARG00000070841|ENSEMBL=ENSDARP00000095131 - REMOVED FROM ENSEMBLE Zv9, not remapped.
ZFIN=ZDB-GENE-060503-627|UniProtKB=Q1LW96 - DONE 3/10/11 I added this one (cycs) as it is the ortholog of the Human gene ENSG00000172115 in this cluster. Paul confirmed that it was absent from our gp2protein file at the last build of panther families..but will be present in next round.
Dictyostelium discoideum:
dictyBase=DDB_G0275537|UniProtKB=Q869N1
Drosophila melanogaster:
FB=FBgn0086907|UniProtKB=P04657
FB=FBgn0000409|UniProtKB=P84029
Gallus gallus:
ENTREZ=420624|UniProtKB=P67881
ENTREZ=770919|NCBI=XP_001234233
Homo sapiens:
ENSEMBL=ENSG00000188512|UniProtKB=A8MY23
ENSEMBL=ENSG00000172115|UniProtKB=P99999 (BHF Priority, low: annotation incomplete)
Mus musculus:
MGI=88579|UniProtKB=P00015
MGI=88578|UniProtKB=P62897
MGI=3708587|NCBI=XP_001480451
MGI=3704493|NCBI=XP_001478445
MGI=3642431|NCBI=XP_001479464
Rattus norvegicus: 12
Saccharomyces cerevisiae:
SGD=S000000765|UniProtKB=P00045
SGD=S000003809|UniProtKB=P00044
Schizosaccharomyces pombe:
GeneDB_Spombe=SPCC191.07|UniProtKB=P00046
2. PTHR16491:SF0 (SMAC/DIABLO)
HUMAN FUNCTION FROM UNIPROT ENTRY:
Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway. Acts by opposing the inhibitory activity of inhibitor of apoptosis proteins (IAP). Interacts with NGFRAP1/BEX3. Interacts with BIRC2, BIRC3, XIAP and BIRC7.
Danio rerio:
ZFIN=ZDB-GENE-040426-1303|UniProtKB=Q7T3E1 - DONE 3/10/11
ZFIN=ZDB-GENE-070112-202|UniProtKB=A7E270 - DONE 3/10/11
Gallus gallus:
ENTREZ=416860|NCBI=XP_415152
Homo sapiens:
Q9NR28 (BHF Priority, low: annotation incomplete)
Mus musculus:
MGI=MGI=1913843|UniProtKB=Q9JIQ3
Rattus norvegicus:
RGD=1310885|UniProtKB=Q5RK17
3. PTHR10356 (ALLOGRAFT INFLAMMATORY FACTOR-1, AIF1 )
HUMAN FUNCTION FROM UNIPROT ENTRY:
Apoptotic suppressor. Has E3 ubiquitin-protein ligase activity. HtrA2 can antagonize antiapoptotic activity by directly degrading th. Overexpression suppresses rpr and W-dependent cell death in the eye. Interaction of th with Nc is required to suppress Nc-mediated cell death; th-mediated ubiquitination of Nc. Interacts (via BIR 2 domain) with Nc (via residues 114-125). Rpr, W and grim can out compete Nc for binding th therefore removing th-mediated ubiquitination. Interacts (via BIR 2 domain) with HtrA2; this displaces any bound Nc
Danio rerio:
ZFIN=ZDB-GENE-030131-9646|UniProtKB=Q6PBZ5
Dictyostelium discoideum:
dictyBase=DDB_G0283533|UniProtKB=Q54QX0
Gallus gallus:
ENTREZ=417179|NCBI=XP_415461
Homo sapiens:
P55008 (AIF1) (BHF Priority, low: annotation incomplete)
Q9BQI0 (IBA2)
Mus musculus:
MGI=1919598|UniProtKB=Q9EQX4
MGI=1343098|UniProtKB=O70200
Rattus norvegicus:
RGD=61924|UniProtKB=P55007
RGD=1305081|NCBI=XP_001077954
4. PTHR22915:SF5 (APOPTOSIS-INDUCING FACTOR (AIF)-LIKE MITCHONDRION-ASSOCIATED INDUCER OF DEATH (P53-RESPONSIVE GENE 3) (AMID PROTEIN))
FROM YEAST UNIPROT ENTRY:
Putative FAD-dependent oxidoreductase involved in the resistance to cercosporin and other singlet oxygen-generating photosensitizers. Translocates from mitochondria to the nucleus under apoptotic conditions, where it degrades DNA and induces apoptosis
Arabidopsis thaliana:
TAIR=locus=504956456|NCBI=NP_680200
TAIR=locus=2081373|NCBI=NP_190005
Gallus gallus:
ENTREZ=423720|NCBI=XP_421597
Homo sapiens:
UniProtKB=Q9BRQ8 (BHF Priority; low)
Mus musculus:
MGI=1918611|UniProtKB=Q8BUE4
Rattus norvegicus:
RGD=1304964|NCBI=NP_001102004
Saccharomyces cerevisiae:
SGD=S000005357|UniProtKB=P52923
(An AIF orthologue regulates apoptosis in yeast.Wissing S et al. J Cell Biol. 2004 PMID: 15381687)
5. Apaf1 FAMILY NOT NAMED (PTHR22845)
HUMAN FUNCTION FROM UNIPROT ENTRY:
Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis. Monomer. Oligomerizes upon binding of cytochrome c and dATP. Oligomeric Apaf-1 and pro-caspase-9 bind to each other via their respective NH2-terminal CARD domains and consecutively mature caspase-9 is released from the complex. Pro-caspase-3 is recruited into the Apaf-1-pro-caspase-9 complex via interaction with pro-caspase-9. Interacts with APIP.
Danio rerio:
ZFIN=ZDB-GENE-000616-4|UniProtKB=Q9I9H8
Gallus gallus:
ENTREZ=417926|NCBI=XP_416167
Homo sapiens:
O14727 (BHF Priority, low: annotation incomplete)
Mus musculus:
MGI=1306796|UniProtKB=O88879
Rattus norvegicus:
RGD=620575|UniProtKB=Q9EPV5
6. C. Elegans Ced-4 (P30429) possible functional ortholog of Apaf1, however no Panther family match.
C. elegans:
ced-4=WBGene00000418=C35D10.9
7. Drosophila Dark(Q7KLI1), similar to Apaf1, has no Panther family
Caspases
1. Metacaspases
from wikipedia: Metacaspases are related to caspases and paracaspase. The metacaspases are Arginine/Lysine-specific, in contrast to caspases, which are Aspartate-specific. Metacaspases are found in plants, fungi, and "protists," but not in slime mold or animals, In an analogous manner to caspases, metacaspases induce programmed cell death in both plants and fungi (yeast)
YEAST FUNCTION FROM UNIPROT ENTRY:
Mediates cell death (apoptosis) triggered by oxygen stress, salt stress or chronological aging. Regulated cell death can prevent a release of toxic cellular components, thus avoiding necrotic collapse of the colony, and can also provide nutrients for healthy cells. Therefore, regulated cell death in yeast colonies can be as important for their development as are apoptosis and related processes that occur within metazoa.
S.cerevisiae:
S000005723 (MCA1, YCA1)
S. pombe:
SPCC1840.04.
Arabidposis:
At1g02170 | UniProtKB:Q7XJE6 (metacaspase 1, AtMC1)
At4g25110 | UniProtKB:Q7XJE5 (metacaspase 2, AMC2)
At5g64240 | UniProtKB:Q9FMG1 (metacapase 3, AMC3)
At1g79340 | UniProtKB:O64517 (metacaspase 4, AMC4)
At1g79330 | UniProtKB:O64518 (metacaspase 5, AMC5)
At1g79320 | UniProtKB:O64519 (metacaspase 6, AMC6)
At1g79310 | UniProtKB:Q6XPT5 (metacaspase 7, AMC7)
At1g16420 | UniProtKB:Q9SA41 (metacaspase 9, AMC8)
(no Panther family available)
2. PTHR10454:SF30 (Caspase 3)
HUMAN FUNCTION FROM UNIPROT ENTRY:
Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin
Danio rerio:
ZFIN=ZDB-GENE-070607-1|UniProtKB=Q0PKX2
ZFIN=ZDB-GENE-011210-1|UniProtKB=Q98UI8
Gallus gallus:
UniProtKB=O93417
Homo sapiens:
P42574 (BHF Priority, low: KRUK Priority: annotation incomplete)
Mus musculus:
MGI=107739|UniProtKB=P70677
Rattus norvegicus: RGD=2275|UniProtKB=P55213
3. PTHR10454:SF31 (CASPASE-7)
Danio rerio: ZFIN=ZDB-GENE-050522-506|UniProtKB=Q503H4
Gallus gallus: ENTREZ=423901|NCBI=XP_421764
Homo sapiens:
P55210 (BHF Priority, low: annotation incomplete)
Reactome Link Reactome Link Reactome Link
=Mus musculus:
MGI=MGI=109383|UniProtKB=P97864
Rattus norvegicus:
RGD=620944|UniProtKB=O88550
4. PTHR10454:SF28 (DRICE)
DROSOPHILA FUNCTION FROM UNIPROT ENTRY:
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 21 kDa (p21) and a 12 kDa (p12) subunit. Inactive pro-form can homodimerize. Nc and Ice can form a stable complex.
Drosophila melanogaster:
FB=FBgn0028381|UniProtKB=Q9VET9
FB=FBgn0019972|UniProtKB=O01382
FB=FBgn0010501|UniProtKB=O02002
5. PTHR10454:SF26 (CASPASE-8)
HUMAN FUNCTION FROM UNIPROT ENTRY:
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.
Gallus gallus:
ENTREZ=395284|UniProtKB=Q90WU1
ENTREZ=693266|UniProtKB=Q4JQQ0
Homo sapiens:
Q14790 (BHF Priority, low: annotation incomplete)
Mus musculus:
MGI=1261423|UniProtKB=O89110
Rattus norvegicus:
RGD=620945|UniProtKB=Q9JHX4
6. PTHR10454:SF25( Caspase 8)
Danio rerio:
ZFIN=ZDB-GENE-070608-1|UniProtKB=Q0PKX1 ZFIN=ZDB-GENE-000713-1|UniProtKB=Q9I8J3
7. PTHR10454:SF19 (CASPASE-9)
HUMAN FUNCTION FROM UNIPROT ENTRY:
Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates caspase-3. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP).Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9.
Homo sapiens:
P55211 (BHF Priority, low: annotation incomplete)
Mus musculus:
MGI=1277950|NCBI=NP_056548
Rattus norvegicus:
RGD=61867|UniProtKB=Q9JHK1
RGD=69064|UniProtKB=Q9JHK1
8. PTHR10454:SF38(Caspase -9)
Danio rerio:
ZFIN=ZDB-GENE-030825-5|UniProtKB=Q5U3Q7
9.PTHR10454:SF69 (CASPASE NC (DRONC))
DROSOPHILA FUNCTION FROM UNIPROT ENTRY:
Involved in the activation cascade of caspases responsible for apoptosis execution. Effector of steroid-mediated apoptosis during insect metamorphosis. Overexpression promotes programmed cell death. Interaction with th is required to suppress Nc-mediated cell death; via th-mediated ubiquitination of Nc. Rate-limiting caspase in rpr and W death pathway Interacts with th; residues 114-125 interact with the second BIR domain of th. Can form a stable complex with Ice. Rpr can out-compete Nc for binding th, therefore removing th-mediated ubiquitination.
Drosophila melanogaster:
FB=FBgn0026404|UniProtKB=Q9XYF4
10. PTHR10454:SF22 (CASPASE-8 DREDD)
Drosophila melanogaster:
FB=FBgn0020381|UniProtKB=Q8IRY7
11. PTHR10454:SF53 (Ced3 may be functional ortholog of vertebrate caspase -9)
C.ELEGANS FUNCTION FROM UNIPROT ENTRY:
Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates caspase-3. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP). Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9.
Caenorhabditis elegans:
WB=WBGene00000417|UniProtKB=P42573
WB=WBGene00000819|UniProtKB=O18203
Inhibitors of Apoptosis (IAPs) and their regulators
1. PTHR10044
IAP family of proteins can potentially inhibit the enzymatic activity of live caspases and permanently remove capases through the ubiquitylation-mediated proteasome pathway.
Arabidopsis thaliana:
TAIR=locus=2131571|NCBI=NP_195233
TAIR=locus=2012453|NCBI=NP_564945
TAIR=locus=2062374|NCBI=NP_181076
TAIR=locus=2014089|NCBI=NP_564052
TAIR=locus=2139310|NCBI=NP_192209
TAIR=locus=2207385|NCBI=NP_565200
TAIR=locus=2153227|NCBI=NP_851134
TAIR=locus=2133990|NCBI=NP_193705
TAIR=locus=2019983|NCBI=NP_172535
TAIR=locus=2036596|NCBI=NP_176260
TAIR=locus=2031471|NCBI=NP_177535
TAIR=locus=2033765|NCBI=NP_174531
TAIR=locus=2171042|NCBI=NP_199516
TAIR=locus=2063917|NCBI=NP_181511
Caenorhabditis elegans: WB=WBGene00000250|UniProtKB=Q18727
WB=WBGene00000249|UniProtKB=Q22837
Danio rerio:
ZFIN=ZDB-GENE-030825-7|UniProtKB=Q7SXU1
ZFIN=ZDB-GENE-030826-2|UniProtKB=Q90WU8
ZFIN=ZDB-GENE-030825-6|UniProtKB=Q6ZM93
ZFIN=ZDB-GENE-030826-1|UniProtKB=Q90WU9
ENSEMBL=ENSDARG00000058082|ENSEMBL=ENSDARP00000075338
Dictyostelium discoideum: dictyBase=DDB_G0268864|UniProtKB=Q55EJ5
dictyBase=DDB_G0269184|UniProtKB=Q94491
Drosophila melanogaster:
FB=FBgn0003691|UniProtKB=Q24306
FB=FBgn0015247|UniProtKB=Q24307
FB=FBgn0037808|UniProtKB=Q9VH01
FB=FBgn0038489|UniProtKB=Q9VEM2
FB=FBgn0034738|UniProtKB=Q8SWW8
Gallus gallus:
ENTREZ=374012|UniProtKB=Q90660
ENTREZ=374078|UniProtKB=Q9DDK0
ENTREZ=395280|UniProtKB=Q8UVF8
ENTREZ=768589|NCBI=XP_001231345
ENTREZ=421463|NCBI=XP_419512
ENTREZ=419239|NCBI=XP_417413
Homo sapiens: O15392 (BIRC5) Reactome Link
Q9NR09
Q96CA5
Q96P09 (BHF Priority, low: annotation incomplete)
Q13075
Q13490 (BIRC2)(BHF Priority, low: annotation incomplete)Reactome Link
Q13489 (BHF Priority, low: KRUK Priority annotation incomplete)
Q9NPP4 (BHF Priority, low: annotation incomplete)
P98170 (XIAP)(BHF Priority, low: annotation incomplete) Reactome Link
Mus musculus:
MGI=1203517|UniProtKB=O70201
MGI=1197009|UniProtKB=Q62210
MGI=MGI=1197007|UniProtKB=O08863
MGI=MGI=1298226|UniProtKB=Q9QUK4
MGI=MGI=1298220|UniProtKB=Q9R016
MGI=MGI=1298222|UniProtKB=Q9JIB6
MGI=MGI=107572|UniProtKB=Q60989
MGI=MGI=2676458|UniProtKB=A2AWP0
MGI=MGI=1858256|NCBI=NP_067520
MGI=MGI=3036243|NCBI=NP_001028539
MGI=MGI=1298223|UniProtKB=Q9QWK5
MGI=MGI=1276108|NCBI=NP_031592
Rattus norvegicus:
RGD=70499|UniProtKB=Q9JHY7
RGD=620692|UniProtKB=Q9R0I6
RGD=620690|UniProtKB=Q6P6S1
RGD=1307247|NCBI=XP_233842
RGD=1559914|NCBI=XP_226743
RGD=1562883|NCBI=XP_238302
RGD=621281|UniProtKB=Q8R4U8
RGD=621282|UniProtKB=Q9ESE9
RGD=1309831|NCBI=XP_001065561
Schizosaccharomyces pombe:
GeneDB_Spombe=SPCC962.02c|UniProtKB=O14064
2. PTHR22939:SF12 (SERINE PROTEASE HTRA2)
HUMAN FUNCTION FROM UNIPROT ENTRY: Serine protease that shows proteolytic activity against a non-specific substrate beta-casein. Promotes or induces cell death either by direct binding to and inhibition of BIRC proteins (also called inhibitor of apoptosis proteins, IAPs), leading to an increase in caspase activity, or by a BIRC inhibition-independent, caspase-independent and serine protease activity-dependent mechanism. Cleaves THAP5 and promotes its degradation during apoptosis. Isoform 2 seems to be proteolytically inactive. Cleavage of non-polar aliphatic amino-acids at the P1 position, with a preference for Val, Ile and Met. At the P2 and P3 positions, Arg is selected most strongly with a secondary preference for other hydrophilic residues.
Danio rerio:
Gallus gallus:
ENTREZ=395990|NCBI=XP_423666
Homo sapiens:
O43464 (BHF Priority, low: annotation incomplete)
Mus musculus:
MGI=1928676|UniProtKB=Q9JIY5
Rattus norvegicus:
RGD=1308906|NCBI=XP_001066414
3. PTHR22939:SF15(SUBFAMILY NOT NAMED) Pro-apoptotic serine protease NMA111
Arabidopsis thaliana:
TAIR=locus=2099619|NCBI=NP_566204
Saccharomyces cerevisiae
SGD=S000005067|UniProtKB=P53920, A6ZRW1
Schizosaccharomyces pombe
GeneDB_Spombe=SPAC23G3.12c|UniProtKB=Q9P7S1
Other possible targets
BAG family molecular chaperone regulators (Bcl-2 family)
ER Stress Response/Unfolded Protein Response
Defender against death DAD protein DAD1 or OST2
Arabidopsis thaliana: At1g32210
At2g35520
Saccharomyces cerevisiae: S000005629
Schizosaccharomyces pombe SPAC6F6.05
"Caenorhabditis elegans:" WBGene00000896
Drosophila melanogaster: FBgn0032035
Dictyostelium discoideum: DDB_G0291049
Danio rerio: ZDB-GENE-060503-233 | UniProtKB=A7E2L0
Gallus gallus: UniProtKB=O13113
Homo sapiens: UniProtKB=P61803
Mus musculus: MGI:101912 | UniProtKB=P61804
Rattus norvegicus: RGD:621028
Suggested from Reactome:
Q96FJ2 DYNLL2
P48454 PPP3CC
P63167 DYNLL1
P31749 AKT1
O43521 BCL2L11
Q9BXH1 BBC3
Q07817 BCL2L1
Q96LC9 BMF
P10144 GZMB
P30419 NMT1
P45983 MAPK8
P63098 PPP3R1
P31946 YWHAB
PDS5 Pdx1 PERK TRAF2 Ire1 Caspase4 CHOP ATF4
GO ontology developments
- When making term requests please prefix the SF summary field with 'APO', so that the GO editors can identify terms that are generated as a result of the work from the RefGen annotation project and content meeting.
- new term: intrinsic apoptotic pathway?
- new term: extrinsic apoptotic pathway?
[Ruth] below, trying out some ideas, not convinced these work yet.
- [Ruth] PMID: 21041309 new term:signal transduction involved in apoptosis
- [Ruth] PMID: 21041309 new term: induction (regulation?) of mitochondrial outer membrane permeabilization (exact synonym: regulation/induction of MOMP)
- Definition to include this concept: the release of apoptogenic proteins from the mitochondrial intermembrane space commits the cell to death, either by a caspase-dependent or -independent mechanism
- is a child of GO:0046902 regulation of mitochondrial membrane permeability
- part of child of GO:0006915 apoptosis
- Bax and Bak would be annotated with this term
- Plus regulation terms for this new term.
- [Ruth] PMID: 21041309 new term: Bax/Bak activation (can't really put this as a signaling pathway as it looks like it is just a single step)
- Definition to include: Upregulation of the activity of Bax or Bak, pro-apoptotic BCL-2 family members involved in apoptosis, by BH3-only BCL-2 family members.
- is a child of new term: positive regulation of induction of mitochondrial outer membrane permeabilization
- again part of child of GO:0006915 apoptosis (not an apoptosis regulation term)
- Bim, Bid, Bad, Bik, Bmf, Hrk, Puma, Noxa etc. would be annotated with this term
Taxonomic Restrictions of GO terms
- limit intrinsic apoptotic pathway (GO:new) to eukaryota
- limit extrinsic apoptotic pathway (GO:new) to vertebrata