Regulation of Apoptosis (Homo sapiens)

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5, 131, 474, 8, 9, 111, 471, 312UNC5A:NRAGE[cytosol]DCC:DIP13alpha[plasma membrane]26S proteasome[cytosol]Caspase-3heterodimer[cytosol]Active Caspase-3heterotetramer[cytosol]DCC:DIP13alpha:Caspase-9[plasma membrane]perinuclearPAK-2p34:RHG10complex [cytosol]PAK-2p34:RHG10complex [cytosol]endosome membranecytosolCleaved Caspase-9[cytosol]active caspase-3[cytosol]Unc5B with deathdomain:DAPK[cytosol]Cleaved Caspase-9[cytosol]DCC:DIP13alpha[plasma membrane]PSMD2 [cytosol]26S proteasomeUbiquitin ligaseCASP3(1-277)active caspase-3p-T402-PAK2(213-524)PSMA8 [cytosol]PSMC1(2-440)[cytosol]APPL1 [endosomemembrane]ARHGAP10 [cytosol]ARHGAP10PSMB9 [cytosol]PSMB6 [cytosol]PSMA5 [cytosol]MAGED1p-T402-PAK2(213-524)[cytosol]CASP3(29-175)[cytosol]PSMD12 [cytosol]UNC5A(341-842)[cytosol]DCCUNC5B(413-945)Cleaved Caspase-9Unc5B with deathdomain:DAPKARHGAP10 [cytosol]PSMD11 [cytosol]PSMD13 [cytosol]CASP9 [cytosol]PSMA2 [cytosol]PSMB3 [cytosol]PSME3 [cytosol]ATPPSMC3 [cytosol]CASP9(?-315)[cytosol]UbPSME4 [cytosol]UNC5A(341-842)APPL1K48poluUb-phospho-PAK-2p34(Thr402)PAK-2p34:RHG10complexPSMD8 [cytosol]PSMC2 [cytosol]PSMA3 [cytosol]PSMD14 [cytosol]PSMB7 [cytosol]p-T402-PAK2(213-524)[cytosol]PSMD4(2-377)[cytosol]DCC(26-1290) [plasmamembrane]DCC:DIP13alphaUNC5B(27-412)PSME2 [cytosol]CASP9(?-315)[cytosol]PSMD6(2-389)[cytosol]DAPKsPSMD1 [cytosol]PSMA1 [cytosol]Active Caspase-3heterotetramerPSMD10 [cytosol]PSMB1 [cytosol]PSMC6(2-389)[cytosol]PSMA4 [cytosol]ADPPSMB5 [cytosol]PSMA7(2-248)[cytosol]PSMC4 [cytosol]PSMB8 [cytosol]UNC5B(413-945)[cytosol]UNC5A:NRAGEPSMD5 [cytosol]CASP3(29-175)[cytosol]DCC(1291-1447)DCC(26-1290) [plasmamembrane]PSMF1(2-271)[cytosol]CASP3(176-277)[cytosol]PSMD7(2-324)[cytosol]APPL1 [endosomemembrane]UNC5APSMC5 [cytosol]PSMB4 [cytosol]CASP3(176-277)[cytosol]PSMB11 [cytosol]CASP9 [cytosol]MAGED1 [cytosol]PSMA6 [cytosol]PSMB10 [cytosol]PSME1 [cytosol]PSMD9 [cytosol]DCC(26-1290)UNC5BUNC5A(26-340)PSMD3 [cytosol]PSMB2 [cytosol]perinuclearPAK-2p34:RHG10complexDCC:DIP13alpha:Caspase-91010626101010


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:

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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


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External references


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NameTypeDatabase referenceComment
26S proteasomeComplexREACT_2353 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
APPL1 [endosome membrane]ProteinQ9UKG1 (Uniprot-TrEMBL)
APPL1ProteinQ9UKG1 (Uniprot-TrEMBL)
ARHGAP10 [cytosol]ProteinA1A4S6 (Uniprot-TrEMBL)
ARHGAP10ProteinA1A4S6 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active Caspase-3 heterotetramerComplexREACT_14435 (Reactome)
CASP3(1-277)ProteinP42574 (Uniprot-TrEMBL)
CASP3(176-277) [cytosol]ProteinP42574 (Uniprot-TrEMBL)
CASP3(29-175) [cytosol]ProteinP42574 (Uniprot-TrEMBL)
CASP9 [cytosol]ProteinP55211 (Uniprot-TrEMBL)
CASP9(?-315) [cytosol]ProteinP55211 (Uniprot-TrEMBL)
Cleaved Caspase-9ComplexREACT_5782 (Reactome)
DAPKsProteinREACT_22954 (Reactome)
DCC(1291-1447)ProteinP43146 (Uniprot-TrEMBL)
DCC(26-1290) [plasma membrane]ProteinP43146 (Uniprot-TrEMBL)
DCC(26-1290)ProteinP43146 (Uniprot-TrEMBL)
DCC:DIP13alpha:Caspase-9ComplexREACT_22628 (Reactome)
DCC:DIP13alphaComplexREACT_23064 (Reactome)
DCCProteinP43146 (Uniprot-TrEMBL)
K48poluUb-phospho-PAK-2p34(Thr402)ProteinQ13177 (Uniprot-TrEMBL)
MAGED1 [cytosol]ProteinQ9Y5V3 (Uniprot-TrEMBL)
MAGED1ProteinQ9Y5V3 (Uniprot-TrEMBL)
PAK-2p34:RHG10 complexComplexREACT_14362 (Reactome)
PSMA1 [cytosol]ProteinP25786 (Uniprot-TrEMBL)
PSMA2 [cytosol]ProteinP25787 (Uniprot-TrEMBL)
PSMA3 [cytosol]ProteinP25788 (Uniprot-TrEMBL)
PSMA4 [cytosol]ProteinP25789 (Uniprot-TrEMBL)
PSMA5 [cytosol]ProteinP28066 (Uniprot-TrEMBL)
PSMA6 [cytosol]ProteinP60900 (Uniprot-TrEMBL)
PSMA7(2-248) [cytosol]ProteinO14818 (Uniprot-TrEMBL)
PSMA8 [cytosol]ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 [cytosol]ProteinP20618 (Uniprot-TrEMBL)
PSMB10 [cytosol]ProteinP40306 (Uniprot-TrEMBL)
PSMB11 [cytosol]ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 [cytosol]ProteinP49721 (Uniprot-TrEMBL)
PSMB3 [cytosol]ProteinP49720 (Uniprot-TrEMBL)
PSMB4 [cytosol]ProteinP28070 (Uniprot-TrEMBL)
PSMB5 [cytosol]ProteinP28074 (Uniprot-TrEMBL)
PSMB6 [cytosol]ProteinP28072 (Uniprot-TrEMBL)
PSMB7 [cytosol]ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 [cytosol]ProteinP28062 (Uniprot-TrEMBL)
PSMB9 [cytosol]ProteinP28065 (Uniprot-TrEMBL)
PSMC1(2-440) [cytosol]ProteinP62191 (Uniprot-TrEMBL)
PSMC2 [cytosol]ProteinP35998 (Uniprot-TrEMBL)
PSMC3 [cytosol]ProteinP17980 (Uniprot-TrEMBL)
PSMC4 [cytosol]ProteinP43686 (Uniprot-TrEMBL)
PSMC5 [cytosol]ProteinP62195 (Uniprot-TrEMBL)
PSMC6(2-389) [cytosol]ProteinP62333 (Uniprot-TrEMBL)
PSMD1 [cytosol]ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 [cytosol]ProteinO75832 (Uniprot-TrEMBL)
PSMD11 [cytosol]ProteinO00231 (Uniprot-TrEMBL)
PSMD12 [cytosol]ProteinO00232 (Uniprot-TrEMBL)
PSMD13 [cytosol]ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 [cytosol]ProteinO00487 (Uniprot-TrEMBL)
PSMD2 [cytosol]ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 [cytosol]ProteinO43242 (Uniprot-TrEMBL)
PSMD4(2-377) [cytosol]ProteinP55036 (Uniprot-TrEMBL)
PSMD5 [cytosol]ProteinQ16401 (Uniprot-TrEMBL)
PSMD6(2-389) [cytosol]ProteinQ15008 (Uniprot-TrEMBL)
PSMD7(2-324) [cytosol]ProteinP51665 (Uniprot-TrEMBL)
PSMD8 [cytosol]ProteinP48556 (Uniprot-TrEMBL)
PSMD9 [cytosol]ProteinO00233 (Uniprot-TrEMBL)
PSME1 [cytosol]ProteinQ06323 (Uniprot-TrEMBL)
PSME2 [cytosol]ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 [cytosol]ProteinP61289 (Uniprot-TrEMBL)
PSME4 [cytosol]ProteinQ14997 (Uniprot-TrEMBL)
PSMF1(2-271) [cytosol]ProteinQ92530 (Uniprot-TrEMBL)
UNC5A(26-340)ProteinQ6ZN44 (Uniprot-TrEMBL)
UNC5A(341-842) [cytosol]ProteinQ6ZN44 (Uniprot-TrEMBL)
UNC5A(341-842)ProteinQ6ZN44 (Uniprot-TrEMBL)
UNC5A:NRAGEComplexREACT_23063 (Reactome)
UNC5AProteinQ6ZN44 (Uniprot-TrEMBL)
UNC5B(27-412)ProteinQ8IZJ1 (Uniprot-TrEMBL)
UNC5B(413-945) [cytosol]ProteinQ8IZJ1 (Uniprot-TrEMBL)
UNC5B(413-945)ProteinQ8IZJ1 (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-PAK2(213-524) [cytosol]ProteinQ13177 (Uniprot-TrEMBL)
p-T402-PAK2(213-524)ProteinQ13177 (Uniprot-TrEMBL)


ComplexREACT_14389 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisREACT_13413 (Reactome)
ADPArrowREACT_22412 (Reactome)
APPL1REACT_22288 (Reactome)
ARHGAP10REACT_13630 (Reactome)
ATPREACT_22412 (Reactome)
Active Caspase-3 heterotetramermim-catalysisREACT_22440 (Reactome)
CASP3(1-277)REACT_22412 (Reactome)
Cleaved Caspase-9REACT_22246 (Reactome)
DAPKsREACT_22314 (Reactome)
DCC(1291-1447)ArrowREACT_22440 (Reactome)
DCC(26-1290)ArrowREACT_22440 (Reactome)
DCC(26-1290)REACT_22288 (Reactome)
DCC:DIP13alpha:Caspase-9ArrowREACT_22246 (Reactome)
DCC:DIP13alpha:Caspase-9mim-catalysisREACT_22412 (Reactome)
DCC:DIP13alphaArrowREACT_22288 (Reactome)
DCC:DIP13alphaREACT_22246 (Reactome)
DCCREACT_22440 (Reactome)
K48poluUb-phospho-PAK-2p34(Thr402)ArrowREACT_13600 (Reactome)
K48poluUb-phospho-PAK-2p34(Thr402)REACT_13413 (Reactome)
MAGED1REACT_22178 (Reactome)
PAK-2p34:RHG10 complexArrowREACT_13630 (Reactome)
PAK-2p34:RHG10 complexREACT_13712 (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.
UNC5A(26-340)ArrowREACT_22184 (Reactome)
UNC5A(341-842)ArrowREACT_22184 (Reactome)
UNC5A(341-842)REACT_22178 (Reactome)
UNC5A:NRAGEArrowREACT_22178 (Reactome)
UNC5AREACT_22184 (Reactome)
UNC5B(27-412)ArrowREACT_22343 (Reactome)
UNC5B(413-945)ArrowREACT_22343 (Reactome)
UNC5B(413-945)REACT_22314 (Reactome)
UNC5BREACT_22343 (Reactome)
UbArrowREACT_13413 (Reactome)
UbREACT_13600 (Reactome)
Ubiquitin ligasemim-catalysisREACT_13600 (Reactome)
Unc5B with death domain:DAPKArrowREACT_22314 (Reactome)
active caspase-3ArrowREACT_22412 (Reactome)
active caspase-3mim-catalysisREACT_22184 (Reactome)
active caspase-3mim-catalysisREACT_22343 (Reactome)
p-T402-PAK2(213-524)REACT_13600 (Reactome)
p-T402-PAK2(213-524)REACT_13630 (Reactome)


ArrowREACT_13712 (Reactome)
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