Regulation of Apoptosis (Homo sapiens)

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3, 710, 119, 116, 10, 12, 1328210, 1126S proteasome DCCDIP13alphaCaspase-9 Caspase-3 heterodimer DCCDIP13alpha PAK-2p34RHG10 complex Unc5B with death domainDAPK Cleaved Caspase-9 DCCDIP13alpha Active Caspase-3 heterotetramer active caspase-3 UNC5ANRAGE Cleaved Caspase-9 cytosolperinuclear PAK-2p34RHG10 complex endosome membraneCleaved Caspase-9PSMD13 PSMD12 PSMA3 PSMD11 ADPARHGAP10 Unc5B with death domainDAPKUNC5BUbiquitin ligasep-T402-PAK2PSMA5 p-T402-PAK2PSMB11 PSMA1 UbPSMD7DAPKs26S proteasomePSMC2 APPL1 UNC5APSMB7 CASP3PSMA2 UNC5ADCCDIP13alphaPSMD14 DCCPSMD4PSMF1active caspase-3p-T402-PAK2PSMC6PSMB2 CASP3PSMC4 MAGED1 PSMB10 UNC5BCASP9perinuclear PAK-2p34RHG10 complexPSMD5 PSMD2 ARHGAP10PSMC5 PSMB6 UNC5ACASP9 Active Caspase-3 heterotetramerUNC5AATPPSMB1 CASP3PSMB5 APPL1 PSMB9 DCCPSMD3 PSMC1PSMC3 APPL1PSME1 PSMB4 DCCPSMD6PSMA8 PSMD9 ARHGAP10 PAK-2p34RHG10 complexPSMB8 PSMA7DCCDIP13alphaCaspase-9PSMA6 UNC5ANRAGEPSMD1 CASP3PSMD10 DCCK48poluUb-phospho-PAK-2p34DCCPSME4 UNC5BPSMB3 PSMD8 PSMA4 PSME2 CASP3CASP9 MAGED1CASP9PSME3 UNC5B41155111


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Wikipathways-description 
A regulated balance between cell survival and apoptosis is essential for normal

development and homeostasis of multicellular organisms (see Matsuzawa, 2001). Defects in control of this balance may contribute to autoimmune disease, neurodegeneration and cancer. Protein ubiquitination and degradation is one of the major mechanisms that regulate apoptotic cell death (reviewed in Yang and Yu 2003).
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=169911

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Bibliography

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  1. Matsuzawa A, Ichijo H.; ''Molecular mechanisms of the decision between life and death: regulation of apoptosis by apoptosis signal-regulating kinase 1.''; PubMed Europe PMC Scholia
  2. Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMed Europe PMC Scholia
  3. Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMed Europe PMC Scholia
  4. Yang Y, Yu X.; ''Regulation of apoptosis: the ubiquitous way.''; PubMed Europe PMC Scholia
  5. Koeppel MA, McCarthy CC, Moertl E, Jakobi R.; ''Identification and characterization of PS-GAP as a novel regulator of caspase-activated PAK-2.''; PubMed Europe PMC Scholia
  6. Head B, Griparic L, Amiri M, Gandre-Babbe S, van der Bliek AM.; ''Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells.''; PubMed Europe PMC Scholia
  7. Jakobi R, McCarthy CC, Koeppel MA, Stringer DK.; ''Caspase-activated PAK-2 is regulated by subcellular targeting and proteasomal degradation.''; PubMed Europe PMC Scholia
  8. Yu-Wai-Man P, Griffiths PG, Hudson G, Chinnery PF.; ''Inherited mitochondrial optic neuropathies.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
101467view11:33, 1 November 2018ReactomeTeamreactome version 66
101005view21:12, 31 October 2018ReactomeTeamreactome version 65
100541view19:46, 31 October 2018ReactomeTeamreactome version 64
100089view16:31, 31 October 2018ReactomeTeamreactome version 63
99639view15:02, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99242view12:44, 31 October 2018ReactomeTeamreactome version 62
93753view13:34, 16 August 2017ReactomeTeamreactome version 61
93273view11:19, 9 August 2017ReactomeTeamreactome version 61
86350view09:15, 11 July 2016ReactomeTeamreactome version 56
83218view10:25, 18 November 2015ReactomeTeamVersion54
81608view13:09, 21 August 2015ReactomeTeamVersion53
77071view08:37, 17 July 2014ReactomeTeamFixed remaining interactions
76776view12:14, 16 July 2014ReactomeTeamFixed remaining interactions
76099view10:16, 11 June 2014ReactomeTeamRe-fixing comment source
75811view11:35, 10 June 2014ReactomeTeamReactome 48 Update
75161view14:10, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74808view08:54, 30 April 2014ReactomeTeamReactome46
69017view17:47, 8 July 2013MaintBotUpdated to 2013 gpml schema
45054view19:23, 6 October 2011ThomasOntology Term : 'apoptotic cell death pathway' added !
42112view21:57, 4 March 2011MaintBotAutomatic update
39922view05:56, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
26S proteasomeComplexREACT_2353 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
APPL1 ProteinQ9UKG1 (Uniprot-TrEMBL)
APPL1ProteinQ9UKG1 (Uniprot-TrEMBL)
ARHGAP10 ProteinA1A4S6 (Uniprot-TrEMBL)
ARHGAP10ProteinA1A4S6 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active Caspase-3 heterotetramerComplexREACT_14435 (Reactome)
CASP3ProteinP42574 (Uniprot-TrEMBL)
CASP9 ProteinP55211 (Uniprot-TrEMBL)
CASP9ProteinP55211 (Uniprot-TrEMBL)
Cleaved Caspase-9ComplexREACT_5782 (Reactome)
DAPKsProteinREACT_22954 (Reactome)
DCC

DIP13alpha

Caspase-9
ComplexREACT_22628 (Reactome)
DCC DIP13alphaComplexREACT_23064 (Reactome)
DCCProteinP43146 (Uniprot-TrEMBL)
K48poluUb-phospho-PAK-2p34ProteinQ13177 (Uniprot-TrEMBL)
MAGED1 ProteinQ9Y5V3 (Uniprot-TrEMBL)
MAGED1ProteinQ9Y5V3 (Uniprot-TrEMBL)
PAK-2p34 RHG10 complexComplexREACT_14362 (Reactome)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6ProteinQ15008 (Uniprot-TrEMBL)
PSMD7ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1ProteinQ92530 (Uniprot-TrEMBL)
UNC5A NRAGEComplexREACT_23063 (Reactome)
UNC5AProteinQ6ZN44 (Uniprot-TrEMBL)
UNC5BProteinQ8IZJ1 (Uniprot-TrEMBL)
UbProteinREACT_3316 (Reactome)
Ubiquitin ligaseREACT_4282 (Reactome)
Unc5B with death domain DAPKComplexREACT_23335 (Reactome)
active caspase-3ComplexREACT_2467 (Reactome)
p-T402-PAK2ProteinQ13177 (Uniprot-TrEMBL)
perinuclear PAK-2p34 RHG10 complexComplexREACT_14389 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
26S proteasomeREACT_13413 (Reactome)
ADPArrowREACT_22412 (Reactome)
APPL1REACT_22288 (Reactome)
ARHGAP10REACT_13630 (Reactome)
ATPREACT_22412 (Reactome)
Active Caspase-3 heterotetramerREACT_22440 (Reactome)
CASP3REACT_22412 (Reactome)
Cleaved Caspase-9REACT_22246 (Reactome)
DAPKsREACT_22314 (Reactome)
DCC

DIP13alpha

Caspase-9
REACT_22412 (Reactome)
DCC DIP13alphaREACT_22246 (Reactome)
DCCArrowREACT_22440 (Reactome)
DCCREACT_22288 (Reactome)
MAGED1REACT_22178 (Reactome)
REACT_13413 (Reactome) Proteolytically activated PAK-2p34, but not full-length PAK-2, is degraded rapidly by the proteasome (Jakobi et al., 2003). Here, degradation of PAK-2p34 is described as occurring in the cytosol. However, to date it is not known whether this occurs in the nucleus or in the cytoplasm.
REACT_13600 (Reactome) PAK-2p34 is ubiquitinated prior to degradation (Jakobi et al., 2003). Here, ubiquitination of PAK-2p34 is described as occurring in the cytosol. However, to date it is not known whether this occurs in the nucleus or in the cytoplasm. Evidence for this reaction comes from experiments using both human and rabbit proteins. The polyubiquitin synthesized in the reaction is inferred to contain lysine-48 (K48) linkages because the modified protein is targeted to the proteasome (Komander 2009).
REACT_13630 (Reactome) Murine PS-GAP interacts specifically with caspase-activated PAK-2p34, but not active or inactive full-length PAK-2, through a region between the GAP and SH3 domains (Koeppel et al.,2004). Evidence for this reaction comes from experiments using both mouse and rabbit proteins.
REACT_13712 (Reactome) Following caspase mediated cleavage, PAK-2p34 translocates to the nucleus (Jakobi et al., 2003). The interaction with PS-GAP changes the localization of PAK-2p34 from the nucleus to the perinuclear region (Koeppel et al.,2004).
REACT_22178 (Reactome) The neurotrophin receptor-interacting melanoma-associated antigen (MAGE) homologue, NRAGE, known to be a regulator of apoptosis, has been identified as a specific binding partner of UNC5H1. NRAGE utilizes two mechanisms to induce UNC5H1mediated apoptosis in cells: first, through the degradation of the caspase inhibitor X-chromosome-linked inhibitor of apoptosis protein (XIAP), and second, through the activation of the proapoptotic c-JUN N-terminal kinase (JNK) signaling pathway.
REACT_22184 (Reactome) The UNC5H netrin1 receptors also contain death domains in their intracellular regions and function as dependence receptors. The cleavage site sequence DITD(S) found in UNC5H2 appears to be a classic caspase DXXD site and is conserved in UNC5H1 and UNC5H3 (DVAD(S) and DIID(S), respectively).
REACT_22246 (Reactome) The ADD domain of DCC complexed with DIP13alpha interacts with the initiator caspase-9, leading to caspase activation and caspase-dependent cell death. DIP13alpha appears to function as a required adaptor to mediate DCC-caspase-9 interaction.
REACT_22288 (Reactome) The ADD domain of DCC binds DCC-interacting 13alpha (DIP13alpha), which serves as an adaptor mediating the DCC apoptotic signal. The DIP13alpha protein has a pleckstrin homology domain and a phosphotyrosine binding domain. It interacts with the ADD region on the DCC cytoplasmic domain that is available after the caspase cleavage. This interaction is required for the induction of apoptosis.
REACT_22314 (Reactome) The released fragment of Unc5B with death domain interacts with a death domain containing serine/threonine kinase protein, death associated protein kinase (DAPK). DAPK mediates UNC5H2 induced cell death through a wide spectrum of apoptotic signals via its serine threonine kinase activity.
REACT_22343 (Reactome) The UNC5H family of netrin-1 receptors also contain death domains in their intracellular regions and function as dependence receptors. The cleavage site sequence DITD(S) found in UNC5H2 appears to be a classic caspase DXXD site and is conserved in UNC5H1 and UNC5H3 (DVAD(S) and DIID(S), respectively). UNC5H2, like DCC, is cleaved at Asp412 by caspase-3 or an unknown protease, but in contrast to DCC this results in the release of the death domain from the C-terminal region (Llambi et al. 2001).
REACT_22412 (Reactome) The DCC-caspase activating complex activates caspase-3 through caspase-9.
REACT_22440 (Reactome) DCC exerts its pro-apoptotic effect when netrin ligand is absent. When unbound to its ligand, DCC is cleaved roughly in the middle of its intracellular domain (aspartic acid residue 1290) by caspase-3 (Mehlen et al. 1998). The cleavage releases DCC's inhibitory C-terminal domain and exposes the addiction/dependence domain (ADD), which is sufficient for cell death induction.
UNC5AArrowREACT_22184 (Reactome)
UNC5AREACT_22178 (Reactome)
UNC5BArrowREACT_22343 (Reactome)
UNC5BREACT_22314 (Reactome)
UbREACT_13600 (Reactome)
Ubiquitin ligaseREACT_13600 (Reactome)
active caspase-3ArrowREACT_22412 (Reactome)
active caspase-3REACT_22184 (Reactome)
active caspase-3REACT_22343 (Reactome)
p-T402-PAK2REACT_13600 (Reactome)
p-T402-PAK2REACT_13630 (Reactome)
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