Apoptosis Reference Genome Targets (Archived)

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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)

Reactome Link

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)

Reactome Link


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)

Reactome Link Reactome Link

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)

Reactome Link

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)

Reactome Link

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)

Reactome Link

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:

25

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 initiation of apoptosis

  • part of child of GO:0006915 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
  • GO:0006915 apoptosis
  • > part of child GO:0046902 regulation of mitochondrial membrane permeability
  • >> is a pos reg child of GO:0090200 positive regulation of release of cytochrome c from mitochondria (this new relationship needs to be created)
  • >>> is a child new term: induction of mitochondrial outer membrane permeabilization
  • GO:0006915 apoptosis
  • > part of child new term: induction of mitochondrial outer membrane permeabilization
  • Bax and Bak would be annotated with this term
  • Plus regulation terms for this new term.

- [Ruth] PMID: 21041309 new term: Bax/Bak activator activity (can't really put this as a signaling pathway as it looks like it is just a single step)

  • Definition to include: Increases the rate of induction of mitochondrial outer membrane permeabilization catalyzed by a pro-apoptotic BCL-2 family member (Bax or Bak). Note this term is intended for annotation of BH3-only BCL-2 family members.
  • part of 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

Manual Annotation Concerns

Automatic Annotation Concerns