Caspase activation via dependence receptors in the absence of ligand (Homo sapiens)

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4-6, 95, 105, 105, 111, 2, 4, 10cytosolendosomeDCCCASP9(331-416) APPL1 DCC(1291-1447)UNC5B(413-945)UNC5B(27-412)DAPK1 DCC:DIP13alpha:Caspase-9DAPK3 DAPK2 DAPK1 APPL1 CASP3(1-277) dimerDAPK2 UNC5AADPCASP3(29-175) UNC5A(341-842) APPL1DCC(26-1290)UNC5A:NRAGEDAPK3 DCC:DIP13alphaUnc5B with deathdomain:DAPKMAGED1 Caspase-3UNC5BDCC(26-1290) UNC5B(413-945) CASP3(176-277) MAGED1Cleaved Caspase-9UNC5A(341-842)CASP3(1-277) DCC(26-1290) ATPCASP9(?-315) DAPKsCASP9(331-416) CASP9(?-315) UNC5A(26-340)83837


Description

In the presence of Netrin1, DCC and UNC5 generate attractive and repulsive signals to growing axons. In the absence of Netrin-1, DCC induces cell death signaling initiated via caspase cleavage of DCC and the interaction of caspase-9. Recent reports have shown that UNC5 receptors similarly induce apoptosis in the absence of Netrin-1. These reactions proceed without a requirement for cytochrome c release from mitochondria or interaction with apoptotic protease activating factor 1 (APAF1). DCC thus regulates an apoptosome-independent pathway for caspase activation. DCC and UNC-5 are hence defined as dependence receptors. Dependence receptors exhibit dual functions depending on the availability of ligand. They create cellular states of dependence on their respective ligands by either inducing apoptosis when unoccupied by the ligand, or inhibiting apoptosis in the presence of the ligand. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 418889
Reactome-version 
Reactome version: 63
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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Bibliography

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  1. Liu J, Yao F, Wu R, Morgan M, Thorburn A, Finley RL, Chen YQ.; ''Mediation of the DCC apoptotic signal by DIP13 alpha.''; PubMed Europe PMC Scholia
  2. Shi Y.; ''Mechanisms of caspase activation and inhibition during apoptosis.''; PubMed Europe PMC Scholia
  3. Arakawa H.; ''Netrin-1 and its receptors in tumorigenesis.''; PubMed Europe PMC Scholia
  4. Mehlen P, Rabizadeh S, Snipas SJ, Assa-Munt N, Salvesen GS, Bredesen DE.; ''The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis.''; PubMed Europe PMC Scholia
  5. Bialik S, Kimchi A.; ''The death-associated protein kinases: structure, function, and beyond.''; PubMed Europe PMC Scholia
  6. Thomsen ND, Koerber JT, Wells JA.; ''Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation.''; PubMed Europe PMC Scholia
  7. Mehlen P, Furne C.; ''Netrin-1: when a neuronal guidance cue turns out to be a regulator of tumorigenesis.''; PubMed Europe PMC Scholia
  8. Chen YQ, Hsieh JT, Yao F, Fang B, Pong RC, Cipriano SC, Krepulat F.; ''Induction of apoptosis and G2/M cell cycle arrest by DCC.''; PubMed Europe PMC Scholia
  9. Tanikawa C, Matsuda K, Fukuda S, Nakamura Y, Arakawa H.; ''p53RDL1 regulates p53-dependent apoptosis.''; PubMed Europe PMC Scholia
  10. Forcet C, Ye X, Granger L, Corset V, Shin H, Bredesen DE, Mehlen P.; ''The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation.''; PubMed Europe PMC Scholia
  11. Mehlen P, Fearon ER.; ''Role of the dependence receptor DCC in colorectal cancer pathogenesis.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
117672view11:59, 22 May 2021EweitzModified title
114917view16:43, 25 January 2021ReactomeTeamReactome version 75
113362view11:43, 2 November 2020ReactomeTeamReactome version 74
112571view15:54, 9 October 2020ReactomeTeamReactome version 73
101485view11:34, 1 November 2018ReactomeTeamreactome version 66
101022view21:14, 31 October 2018ReactomeTeamreactome version 65
100557view19:48, 31 October 2018ReactomeTeamreactome version 64
100105view16:33, 31 October 2018ReactomeTeamreactome version 63
99655view15:04, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99257view12:45, 31 October 2018ReactomeTeamreactome version 62
93770view13:35, 16 August 2017ReactomeTeamreactome version 61
93295view11:19, 9 August 2017ReactomeTeamreactome version 61
87869view12:09, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86380view09:16, 11 July 2016ReactomeTeamreactome version 56
83268view10:36, 18 November 2015ReactomeTeamVersion54
81378view12:54, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
APPL1 ProteinQ9UKG1 (Uniprot-TrEMBL)
APPL1ProteinQ9UKG1 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CASP3(1-277) ProteinP42574 (Uniprot-TrEMBL)
CASP3(1-277) dimerComplexR-HSA-6804299 (Reactome)
CASP3(176-277) ProteinP42574 (Uniprot-TrEMBL)
CASP3(29-175) ProteinP42574 (Uniprot-TrEMBL)
CASP9(331-416) ProteinP55211 (Uniprot-TrEMBL)
CASP9(?-315) ProteinP55211 (Uniprot-TrEMBL)
Caspase-3ComplexR-HSA-350870 (Reactome)
Cleaved Caspase-9ComplexR-HSA-141640 (Reactome)
DAPK1 ProteinP53355 (Uniprot-TrEMBL)
DAPK2 ProteinQ9UIK4 (Uniprot-TrEMBL)
DAPK3 ProteinO43293 (Uniprot-TrEMBL)
DAPKsComplexR-HSA-418812 (Reactome)
DCC(1291-1447)ProteinP43146 (Uniprot-TrEMBL)
DCC(26-1290) ProteinP43146 (Uniprot-TrEMBL)
DCC(26-1290)ProteinP43146 (Uniprot-TrEMBL)
DCC:DIP13alpha:Caspase-9ComplexR-HSA-373664 (Reactome)
DCC:DIP13alphaComplexR-HSA-373668 (Reactome)
DCCProteinP43146 (Uniprot-TrEMBL)
MAGED1 ProteinQ9Y5V3 (Uniprot-TrEMBL)
MAGED1ProteinQ9Y5V3 (Uniprot-TrEMBL)
UNC5A(26-340)ProteinQ6ZN44 (Uniprot-TrEMBL)
UNC5A(341-842) ProteinQ6ZN44 (Uniprot-TrEMBL)
UNC5A(341-842)ProteinQ6ZN44 (Uniprot-TrEMBL)
UNC5A:NRAGEComplexR-HSA-374596 (Reactome)
UNC5AProteinQ6ZN44 (Uniprot-TrEMBL)
UNC5B(27-412)ProteinQ8IZJ1 (Uniprot-TrEMBL)
UNC5B(413-945) ProteinQ8IZJ1 (Uniprot-TrEMBL)
UNC5B(413-945)ProteinQ8IZJ1 (Uniprot-TrEMBL)
UNC5BProteinQ8IZJ1 (Uniprot-TrEMBL)
Unc5B with death domain:DAPKComplexR-HSA-418842 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-418845 (Reactome)
APPL1R-HSA-373717 (Reactome)
ATPR-HSA-418845 (Reactome)
CASP3(1-277) dimerR-HSA-418845 (Reactome)
Caspase-3ArrowR-HSA-418845 (Reactome)
Caspase-3mim-catalysisR-HSA-373705 (Reactome)
Caspase-3mim-catalysisR-HSA-418846 (Reactome)
Caspase-3mim-catalysisR-HSA-418852 (Reactome)
Cleaved Caspase-9R-HSA-373700 (Reactome)
DAPKsR-HSA-418849 (Reactome)
DCC(1291-1447)ArrowR-HSA-373705 (Reactome)
DCC(26-1290)ArrowR-HSA-373705 (Reactome)
DCC(26-1290)R-HSA-373717 (Reactome)
DCC:DIP13alpha:Caspase-9ArrowR-HSA-373700 (Reactome)
DCC:DIP13alpha:Caspase-9mim-catalysisR-HSA-418845 (Reactome)
DCC:DIP13alphaArrowR-HSA-373717 (Reactome)
DCC:DIP13alphaR-HSA-373700 (Reactome)
DCCR-HSA-373705 (Reactome)
MAGED1R-HSA-374699 (Reactome)
R-HSA-373700 (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.
R-HSA-373705 (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.
R-HSA-373717 (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.
R-HSA-374699 (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.
R-HSA-418845 (Reactome) The DCC-caspase activating complex activates caspase-3 through caspase-9.
R-HSA-418846 (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).
R-HSA-418849 (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.
R-HSA-418852 (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).
UNC5A(26-340)ArrowR-HSA-418846 (Reactome)
UNC5A(341-842)ArrowR-HSA-418846 (Reactome)
UNC5A(341-842)R-HSA-374699 (Reactome)
UNC5A:NRAGEArrowR-HSA-374699 (Reactome)
UNC5AR-HSA-418846 (Reactome)
UNC5B(27-412)ArrowR-HSA-418852 (Reactome)
UNC5B(413-945)ArrowR-HSA-418852 (Reactome)
UNC5B(413-945)R-HSA-418849 (Reactome)
UNC5BR-HSA-418852 (Reactome)
Unc5B with death domain:DAPKArrowR-HSA-418849 (Reactome)
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