CED-12 is the C. elegans orthologue of mammalian ELMO1 and ELMO2. It is a cytoplasmic scaffold of 731 residues with N-terminal armadillo (ARM) repeats, a central ELMO domain, a C-terminal pleckstrin homology (PH) domain and a proline-rich SH3-binding motif. CED-12 binds directly to CED-5, the DOCK180-family exchange factor, and together with the CrkII-like adaptor CED-2 forms a ternary complex that acts as a bipartite guanine nucleotide exchange factor for the Rac GTPase CED-10. Within this complex the ELMO PH domain binds the CED-5-Rac complex in trans and helps hold Rac in the nucleotide-free state, so CED-12 raises the exchange activity of CED-5 rather than catalysing exchange itself. The ARM repeats bind active MIG-2 (RhoG), which places CED-12 downstream of the UNC-73/TRIO-MIG-2 module, and the PH domain binds phosphoinositides, which may help recruit the complex to the plasma membrane. CED-12 acts in engulfing cells, where Rac activation drives the actin rearrangements that extend the engulfing membrane around apoptotic and necrotic cell corpses. The same CED-2/CED-5/CED-12 module drives the migration of the gonadal distal tip cells, so ced-12 mutants have both persistent cell corpses and misshapen gonad arms. Upstream inputs include the Frizzled receptor MOM-5 and the myotubularin MTM-1, which restrains the pathway. Like other engulfment genes, ced-12 is thought to help engulfing cells promote the death of cells that receive weak death signals.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000132 establishment of mitotic spindle orientation | IGI PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | REMOVE | Summary: Establishment of mitotic spindle orientation (IGI with ced-5, Cabello et al. 2010). Reason: The full text was read. In this paper ABar spindle orientation needs MOM-5/Frizzled, GSK-3, beta-catenins and CED-10, but the authors state that the other ced genes, which include the CED-2/5/12 branch, showed no strong spindle defect, and they conclude that the spindle signal probably does not pass through CED-2/5/12. The only engulfment-gene spindle defect reported is a small fraction of ced-1; ced-5 double mutants, which does not involve ced-12. The paper therefore argues against, rather than for, a ced-12 role in spindle orientation. Supporting Evidence: PMID:20126385 neither apr-1 nor any of the other ced genes showed a strong defect, suggesting that the link to CED-10 may not occur through CED-2/5/12 as is the case for engulfment and DTC migration PMID:20126385 we found that the Ξ²-catenin WRM-1 (and to a minor extent, BAR-1 and HMP-2) is required for spindle orientation, but not for cell corpse clearance or DTC migration |
| GO:0005515 protein binding | IPI PMID:11595183 CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway... | MODIFY | Summary: Binding to CED-5/DOCK180 (Gumienny et al. 2001). Reason: The partner is CED-5 (WBGene00000419), the DOCK180-family exchange factor. The paper shows that CED-12 binds CED-5 directly and that the complex stimulates Rac exchange, which is what the more informative term guanyl nucleotide exchange factor activator activity describes. Proposed replacements: guanyl nucleotide exchange factor activator activity Supporting Evidence: PMID:11595183 CED-12/ELMO-1 binds directly to CED-5/Dock180; this evolutionarily conserved complex stimulates a Rac-GEF, leading to Rac1 activation and cytoskeletal rearrangements |
| GO:0005515 protein binding | IPI PMID:11703940 C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pa... | MODIFY | Summary: Binding to CED-5/DOCK180 (Wu et al. 2001). Reason: The partner is CED-5 (G5EEN3). Wu et al. show the CED-12-CED-5 interaction and a ternary complex with CED-2 that they propose activates CED-10; the parallel Gumienny et al. and Lu et al. papers show that ELMO/CED-12 binding raises DOCK180 exchange activity on Rac. The informative term is guanyl nucleotide exchange factor activator activity. Proposed replacements: guanyl nucleotide exchange factor activator activity Supporting Evidence: PMID:11703940 CED-12 physically interacts with CED-5 and forms a ternary complex with CED-2 in vitro PMID:15247908 the Dock180-ELMO complex functions as a bipartite GEF for Rac |
| GO:0005547 phosphatidylinositol-3,4,5-trisphosphate binding | IDA PMID:21490059 The phosphoinositide phosphatase MTM-1 regulates apoptotic c... | KEEP AS NON CORE | Summary: CED-12 PH domain binds PtdIns(3,4,5)P3 in vitro (Neukomm et al. 2011). Reason: The cached record is abstract-only. The abstract names only PtdIns(3,5)P2 binding, but UniProt reports that this paper shows the PH domain binding PtdIns(3,5)P2, PtdIns4P and PtdIns(3,4,5)P3 in vitro, so the row is plausibly from the same lipid-binding assay, and we defer to the curator. Binding of a PH domain to several phosphoinositides in vitro is consistent with membrane recruitment, but its role in vivo has not been shown, so this is not a core activity. Supporting Evidence: PMID:21490059 we show that the CED-12 PH domain can bind to PtdIns(3,5)P(2) (one target of MTM-1 phosphatase activity), suggesting that MTM-1 might regulate CED-12 recruitment to the plasma membrane |
| GO:0005737 cytoplasm | IDA PMID:11703939 The C. elegans PH domain protein CED-12 regulates cytoskelet... | ACCEPT | Summary: CED-12 is cytoplasmic (Zhou et al. 2001). Reason: The cached record is abstract-only. UniProt cites this paper for punctate cytoplasmic localization of CED-12, which needs the PH domain. A cytoplasmic scaffold that is recruited to the membrane fits all other data. Supporting Evidence: PMID:11703939 through interactions with membranes and with a CED-2/CED-5 protein complex, CED-12 regulates Rho/Rac GTPase signaling |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm from the UniProt subcellular location mapping. Reason: Mapped from the UniProt cytoplasm location, which rests on Zhou et al. 2001 and agrees with the IDA row. Supporting Evidence: PMID:11703939 through interactions with membranes and with a CED-2/CED-5 protein complex, CED-12 regulates Rho/Rac GTPase signaling |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane, inferred from the ELMO family tree (sources include human ELMO1 and CED-12 itself). Reason: ELMO proteins act at the plasma membrane, where the ELMO-DOCK complex activates Rac at sites of engulfment and protrusion. CED-12 appearing among the sources is expected and reflects its own experimental support. Supporting Evidence: PMID:11703940 We propose that the formation and localization of a CED-2-CED-5-CED-12 ternary complex to the plasma membrane activates CED-10 |
| GO:0005886 plasma membrane | IDA PMID:11595183 CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway... | ACCEPT | Summary: Plasma membrane localization (Gumienny et al. 2001). Reason: The cached record is abstract-only, so the localization data are not visible. Membrane recruitment of ELMO/CED-12 with DOCK180/CED-5 is well established and fits the IBA row and the PH-domain lipid binding; we defer to the curator. Supporting Evidence: PMID:11703940 We propose that the formation and localization of a CED-2-CED-5-CED-12 ternary complex to the plasma membrane activates CED-10 |
| GO:0006911 phagocytosis, engulfment | IMP PMID:11146658 A common set of engulfment genes mediates removal of both ap... | ACCEPT | Summary: ced-12 is needed to remove necrotic cell corpses (Chung et al. 2000). Reason: This paper identified ced-12 as an engulfment gene and showed that it is needed to clear necrotic corpses, not only apoptotic ones. Phagocytosis, engulfment is the right general term for removal of non-apoptotic corpses; the apoptotic case is captured by GO:0043652. Supporting Evidence: PMID:11146658 all previously reported ced genes required for phagocytotic removal of apoptotic corpses, as well as ced-12, a new engulfment gene we have identified, are required for efficient elimination of corpses generated by distinct necrosis-inducing stimuli |
| GO:0007015 actin filament organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Actin filament organization, inferred from the ELMO family tree (sources include Drosophila Ced-12, Dictyostelium ElmoA and CED-12 itself). Reason: ELMO proteins control actin organization through DOCK-mediated Rac activation across animals and Dictyostelium, and CED-12 is needed for actin rearrangement in engulfing cells, so the inheritance fits. The term is kept as non-core because it is a general mechanistic outcome; the in vivo role is better captured by cytoskeletal rearrangement involved in phagocytosis, engulfment and by actin cytoskeleton organization. Supporting Evidence: PMID:11595183 CED-12/ELMO-1 binds directly to CED-5/Dock180; this evolutionarily conserved complex stimulates a Rac-GEF, leading to Rac1 activation and cytoskeletal rearrangements |
| GO:0007015 actin filament organization | IDA PMID:11703939 The C. elegans PH domain protein CED-12 regulates cytoskelet... | KEEP AS NON CORE | Summary: CED-12 expression in mouse fibroblasts induces actin filament bundles (Zhou et al. 2001). Reason: The direct evidence is overexpression of CED-12 in mouse Swiss 3T3 cells, a heterologous system. It fits CED-12 driving Rho-family GTPase-dependent actin changes, but the in vivo role is better captured by cytoskeletal rearrangement involved in phagocytosis, engulfment. Supporting Evidence: PMID:11703939 Expression of CED-12 and its counterparts in murine Swiss 3T3 fibroblasts induced Rho GTPase-dependent formation of actin filament bundles |
| GO:0016477 cell migration | IMP PMID:11595183 CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway... | ACCEPT | Summary: ced-12 is required for cell migrations (Gumienny et al. 2001). Reason: ced-12 mutants have defective distal tip cell migration. CED-12 is part of the CED-2/CED-5/CED-12 Rac activator that drives the migrating cell, so it takes part in migration rather than regulating it from outside. The more specific distal tip cell migration term is applied where the source names that cell (see the GO:1903356 row). Supporting Evidence: PMID:11595183 In C. elegans, CED-12 is required for engulfment of dying cells and for cell migrations |
| GO:0016477 cell migration | IMP PMID:11703939 The C. elegans PH domain protein CED-12 regulates cytoskelet... | ACCEPT | Summary: ced-12 functions in cell migration (Zhou et al. 2001). Reason: Independent isolation of ced-12 with the same engulfment and migration phenotypes, acting upstream of CED-10/Rac. Supporting Evidence: PMID:11703939 The C. elegans gene ced-12 functions in the engulfment of apoptotic cells and in cell migration |
| GO:0016477 cell migration | IMP PMID:11703940 C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pa... | ACCEPT | Summary: ced-12 controls cell migration with CED-2, CED-5 and CED-10 (Wu et al. 2001). Reason: Third independent paper showing that ced-12 is needed for cell migration as part of the CED-2/CED-5/CED-10 pathway. Supporting Evidence: PMID:11703940 functions in the conserved GTPase signaling pathway mediated by CED-2/Crkll, CED-5/DOCK180, and CED-10/Rac to control cell migration and phagocytosis of apoptotic cells |
| GO:0016477 cell migration | IMP PMID:15247908 PH domain of ELMO functions in trans to regulate Rac activat... | ACCEPT | Summary: Rescue of ced-12 migration defects needs the ELMO PH domain (Lu et al. 2004). Reason: The cached record is abstract-only. Genetic rescue of ced-12 mutants with ELMO and CED-12 PH-domain variants shows that PH-domain-dependent Rac activation is needed for cell migration in vivo; UniProt cites this paper for the PH domain being required for distal tip cell migration. Supporting Evidence: PMID:15247908 this ELMO PH domain-dependent regulation is essential for the Dock180-ELMO complex to function in phagocytosis and cell migration PMID:15247908 Genetic rescue studies in Caenorhabditis elegans using ELMO and its homolog CED-12 support the above observations in vivo |
| GO:0016477 cell migration | IMP PMID:15620647 Phagocytosis of apoptotic cells is regulated by a UNC-73/TRI... | ACCEPT | Summary: Cell migration (deBakker et al. 2004). Reason: The cached record is abstract-only, and the abstract reports only engulfment data for ced-12 in worms; the migration result is presumably in the full text (for example, ARM-repeat mutants tested for rescue of distal tip cell migration). The role of ced-12 in cell migration is well established by other papers, so we defer to the curator. Supporting Evidence: PMID:15620647 ELMO functions together with Dock180 (a guanine nucleotide exchange factor for Rac) to mediate Rac-dependent cytoskeletal reorganization during engulfment and cell migration |
| GO:0017124 SH3 domain binding | TAS PMID:11703940 C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pa... | ACCEPT | Summary: CED-12 binds the SH3 domain of CED-5 (Wu et al. 2001, traceable author statement). Reason: CED-12 carries a C-terminal proline-rich SH3-binding motif that is needed for its function, and its partner CED-5 has an SH3 domain. This term describes how CED-12 binds CED-5, which underlies its GEF-activator role. Supporting Evidence: PMID:11703939 ced-12 encodes a protein with a pleckstrin homology (PH) domain and an SH3 binding motif, both of which are important for ced-12 function PMID:11703939 interacts physically with CED-5, which contains an SH3 domain |
| GO:0019899 enzyme binding | IPI PMID:14645848 Cell corpse engulfment mediated by C. elegans phosphatidylse... | MARK AS OVER ANNOTATED | Summary: Interaction with PSR-1 (Wang et al. 2003). Reason: The partner is PSR-1, a JmjC-domain protein that this paper proposed as a phosphatidylserine receptor upstream of CED-5 and CED-12. The abstract itself hedges the interaction ("possibly through direct interaction"). Enzyme binding says nothing about what CED-12 does; no enzymatic activity of PSR-1 is involved in the proposed mechanism, and the interaction has not been tied to a CED-12 activity. This does not mean the interaction is false. Supporting Evidence: PMID:14645848 possibly through direct interaction with CED-5 and CED-12 |
| GO:0030036 actin cytoskeleton organization | IMP PMID:11703939 The C. elegans PH domain protein CED-12 regulates cytoskelet... | ACCEPT | Summary: ced-12 acts in cytoskeletal reorganization (Zhou et al. 2001). Reason: CED-12 promotes Rac-dependent actin reorganization in both engulfing and migrating cells. The general term covers both contexts; the engulfment-specific child term is also accepted. Supporting Evidence: PMID:11703939 CED-12 regulates Rho/Rac GTPase signaling and leads to cytoskeletal reorganization by an evolutionarily conserved mechanism |
| GO:0030036 actin cytoskeleton organization | IMP PMID:11703940 C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pa... | ACCEPT | Summary: ced-12 acts in cytoskeletal reorganization in engulfing and migrating cells (Wu et al. 2001). Reason: The paper proposes that the CED-2-CED-5-CED-12 complex activates CED-10 to reorganize the cytoskeleton in both engulfing and migrating cells. Supporting Evidence: PMID:11703940 activates CED-10, leading to the cytoskeletal reorganization that occurs in the polarized extension of cell surfaces in engulfing cells and migrating cells |
| GO:0030036 actin cytoskeleton organization | IMP PMID:15744306 Two pathways converge at CED-10 to mediate actin rearrangeme... | ACCEPT | Summary: ced-12 is needed for actin halos around corpses (Kinchen et al. 2005). Reason: The cached record is abstract-only, and the abstract describes the actin phenotype for ced-1, ced-6 and ced-7. UniProt cites this paper for absent actin halos around early corpses in ced-12 mutants, and the CED-2/5/12 module is described as activating CED-10. We defer to the curator. Supporting Evidence: PMID:15744306 the proteins CED-2, CED-5 and CED-12 (mammalian homologues CrkII, Dock180 and ELMO, respectively) function to activate CED-10 (Rac1) |
| GO:0030334 regulation of cell migration | IMP PMID:14688791 An NDPase links ADAM protease glycosylation with organ morph... | KEEP AS NON CORE | Summary: Regulation of cell migration (Nishiwaki et al. 2004, mig-23 paper). Reason: The cached record is abstract-only and the abstract does not mention ced-12; the ced-12 allele was presumably used in genetic interaction tests on distal tip cell migration in the full text. ced-12 clearly acts in distal tip cell migration, so the row is not wrong, but CED-12 is part of the migration machinery itself, which is better captured by the cell migration and distal tip cell migration terms. Supporting Evidence: PMID:14688791 the gonad acquires two U-shaped arms through the directed migration of its distal tip cells (DTCs) |
| GO:0031267 small GTPase binding | IPI PMID:15620647 Phagocytosis of apoptotic cells is regulated by a UNC-73/TRI... | ACCEPT | Summary: CED-12 ARM repeats bind active MIG-2/RhoG (deBakker et al. 2004). Reason: The ARM repeats of CED-12/ELMO bind activated MIG-2 (RhoG), linking the UNC-73/TRIO-MIG-2 module to CED-5-dependent Rac activation. This is a specific, conserved input into CED-12 function. Supporting Evidence: PMID:15620647 we identify a novel set of evolutionarily conserved Armadillo (ARM) repeats within CED-12/ELMO that mediate an interaction with activated MIG-2/RhoG |
| GO:0032045 guanyl-nucleotide exchange factor complex | IDA PMID:11703940 C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pa... | ACCEPT | Summary: CED-12 forms a ternary complex with CED-5 and CED-2 (Wu et al. 2001). Reason: CED-12 is a subunit of the CED-2/CED-5/CED-12 complex that acts as the exchange factor for CED-10/Rac. Supporting Evidence: PMID:11703940 CED-12 physically interacts with CED-5 and forms a ternary complex with CED-2 in vitro PMID:21490059 the ternary GEF complex, which consists of ced-2, ced-5 and ced-12 |
| GO:0035262 gonad morphogenesis | IMP PMID:11595183 CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway... | KEEP AS NON CORE | Summary: Gonad shape defects in ced-12 mutants (Gumienny et al. 2001). Reason: The misshapen gonad arms of ced-12 mutants follow from defective distal tip cell migration, which lays down the gonad shape. The gonad phenotype is a real consequence, but the direct role is in the migration. Supporting Evidence: PMID:11595183 In C. elegans, CED-12 is required for engulfment of dying cells and for cell migrations |
| GO:0035262 gonad morphogenesis | IMP PMID:14688791 An NDPase links ADAM protease glycosylation with organ morph... | KEEP AS NON CORE | Summary: Gonad morphogenesis (Nishiwaki et al. 2004, mig-23 paper). Reason: The cached record is abstract-only and does not name ced-12. Gonad shape depends on distal tip cell migration, in which ced-12 acts, so the row is plausible but describes a downstream outcome. Supporting Evidence: PMID:14688791 the gonad acquires two U-shaped arms through the directed migration of its distal tip cells (DTCs) |
| GO:0043652 engulfment of apoptotic cell | IMP PMID:11595183 CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway... | ACCEPT | Summary: ced-12 is required for engulfment of dying cells (Gumienny et al. 2001). Reason: Core process. ced-12 mutants accumulate unengulfed apoptotic corpses, and CED-12 works with CED-5 to activate Rac in the engulfing cell. Supporting Evidence: PMID:11595183 In C. elegans, CED-12 is required for engulfment of dying cells and for cell migrations |
| GO:0043652 engulfment of apoptotic cell | IMP PMID:11703939 The C. elegans PH domain protein CED-12 regulates cytoskelet... | ACCEPT | Summary: CED-12 acts in engulfing cells for corpse engulfment (Zhou et al. 2001). Reason: Core process; this paper also shows that CED-12 acts in the engulfing cell. Supporting Evidence: PMID:11703939 CED-12 acts in engulfing cells for cell corpse engulfment |
| GO:0043652 engulfment of apoptotic cell | IMP PMID:11703940 C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pa... | ACCEPT | Summary: ced-12 controls phagocytosis of apoptotic cells (Wu et al. 2001). Reason: Core process, shown independently by a third group. Supporting Evidence: PMID:11703940 functions in the conserved GTPase signaling pathway mediated by CED-2/Crkll, CED-5/DOCK180, and CED-10/Rac to control cell migration and phagocytosis of apoptotic cells |
| GO:0043652 engulfment of apoptotic cell | IMP PMID:14645848 Cell corpse engulfment mediated by C. elegans phosphatidylse... | ACCEPT | Summary: ced-12 in the PSR-1 engulfment pathway (Wang et al. 2003). Reason: The ced-12 engulfment defect is used here to place psr-1 in the CED-2/5/10/12 pathway. The ced-12 phenotype itself is well established. Supporting Evidence: PMID:14645848 PSR-1 acts in the same cell corpse engulfment pathway mediated by intracellular signaling molecules CED-2 (homologous to the human CrkII protein), CED-5 (DOCK180), CED-10 (Rac GTPase), and CED-12 (ELMO) |
| GO:0044877 protein-containing complex binding | IPI PMID:11703940 C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pa... | MARK AS OVER ANNOTATED | Summary: CED-12 binds the CED-5 complex (Wu et al. 2001). Reason: CED-12 is a subunit of the CED-2/CED-5/CED-12 complex reported in this paper, not a protein that binds a pre-formed complex. Complex membership and the informative activity are captured elsewhere in this review, so this term is an over-annotation. Same action as the matching rows in the ced-2 and ced-5 reviews; the interaction itself is not disputed. Supporting Evidence: PMID:11703940 CED-12 physically interacts with CED-5 and forms a ternary complex with CED-2 in vitro PMID:15247908 the Dock180-ELMO complex functions as a bipartite GEF for Rac |
| GO:0044877 protein-containing complex binding | IPI PMID:11703940 C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pa... | MARK AS OVER ANNOTATED | Summary: CED-12 joins a ternary complex with CED-2 and CED-5 (Wu et al. 2001). Reason: CED-12 is a subunit of the CED-2/CED-5/CED-12 complex reported in this paper, not a protein that binds a pre-formed complex. Complex membership and the informative activity are captured elsewhere in this review, so this term is an over-annotation. Same action as the matching rows in the ced-2 and ced-5 reviews; the interaction itself is not disputed. Supporting Evidence: PMID:11703940 CED-12 physically interacts with CED-5 and forms a ternary complex with CED-2 in vitro PMID:11595183 CED-12/ELMO-1 binds directly to CED-5/Dock180; this evolutionarily conserved complex stimulates a Rac-GEF, leading to Rac1 activation and cytoskeletal rearrangements |
| GO:0060097 cytoskeletal rearrangement involved in phagocytosis, engulfment | IMP PMID:11703939 The C. elegans PH domain protein CED-12 regulates cytoskelet... | ACCEPT | Summary: CED-12 drives cytoskeletal reorganization in engulfing cells (Zhou et al. 2001). Reason: This is the most precise process term for what CED-12 does in engulfing cells, where Rac activation reorganizes actin to extend the membrane around the corpse. Supporting Evidence: PMID:11703939 CED-12 acts in engulfing cells for cell corpse engulfment PMID:11703939 CED-12 regulates Rho/Rac GTPase signaling and leads to cytoskeletal reorganization by an evolutionarily conserved mechanism |
| GO:0060097 cytoskeletal rearrangement involved in phagocytosis, engulfment | IMP PMID:11703940 C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pa... | ACCEPT | Summary: CED-12 drives cytoskeletal reorganization in engulfing cells (Wu et al. 2001). Reason: Wu et al. link the CED-2-CED-5-CED-12 complex to CED-10 activation and cytoskeletal reorganization in engulfing cells. Supporting Evidence: PMID:11703940 activates CED-10, leading to the cytoskeletal reorganization that occurs in the polarized extension of cell surfaces in engulfing cells and migrating cells |
| GO:0060097 cytoskeletal rearrangement involved in phagocytosis, engulfment | IMP PMID:15744306 Two pathways converge at CED-10 to mediate actin rearrangeme... | ACCEPT | Summary: ced-12 is needed for actin halos around early corpses (Kinchen et al. 2005). Reason: The cached record is abstract-only. UniProt cites this paper for loss of actin halos around early apoptotic corpses in ced-12 mutants, which is exactly this process. We defer to the curator. Supporting Evidence: PMID:15744306 the proteins CED-2, CED-5 and CED-12 (mammalian homologues CrkII, Dock180 and ELMO, respectively) function to activate CED-10 (Rac1) |
| GO:0070064 proline-rich region binding | IPI PMID:11703939 The C. elegans PH domain protein CED-12 regulates cytoskelet... | MODIFY | Summary: Interaction with CED-5 recorded as proline-rich region binding (Zhou et al. 2001). Reason: The orientation is reversed. In this paper CED-12 is the protein with the proline-rich SH3-binding motif, and CED-5 is the partner with the SH3 domain. CED-12 therefore binds an SH3 domain, not a proline-rich region. The matching term is SH3 domain binding, which is also carried by the TAS row. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:11703939 ced-12 encodes a protein with a pleckstrin homology (PH) domain and an SH3 binding motif, both of which are important for ced-12 function PMID:11703939 interacts physically with CED-5, which contains an SH3 domain |
| GO:0070273 phosphatidylinositol-4-phosphate binding | IDA PMID:21490059 The phosphoinositide phosphatase MTM-1 regulates apoptotic c... | KEEP AS NON CORE | Summary: CED-12 PH domain binds PtdIns4P in vitro (Neukomm et al. 2011). Reason: The cached record is abstract-only and names only PtdIns(3,5)P2. UniProt reports PtdIns4P binding from the same paper, so we defer to the curator. In vitro binding to several phosphoinositides fits a PH domain that helps membrane recruitment, but no single lipid has been shown to matter in vivo. Supporting Evidence: PMID:21490059 we show that the CED-12 PH domain can bind to PtdIns(3,5)P(2) (one target of MTM-1 phosphatase activity), suggesting that MTM-1 might regulate CED-12 recruitment to the plasma membrane |
| GO:0070986 left/right axis specification | IGI PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | REMOVE | Summary: Left/right axis specification (IGI with ced-5, Cabello et al. 2010). Reason: The full text was read. In this paper the left/right defect follows from failed rotation of the ABar spindle, which needs MOM-5, GSK-3, beta-catenins and CED-10. The authors conclude that the CED-2/5/12 branch is probably not the link to CED-10 for spindle orientation, and they report no ced-12 spindle or left/right phenotype. The paper does not support a ced-12 role in left/right axis specification. Supporting Evidence: PMID:20126385 neither apr-1 nor any of the other ced genes showed a strong defect, suggesting that the link to CED-10 may not occur through CED-2/5/12 as is the case for engulfment and DTC migration |
| GO:0080025 phosphatidylinositol-3,5-bisphosphate binding | IDA PMID:21490059 The phosphoinositide phosphatase MTM-1 regulates apoptotic c... | KEEP AS NON CORE | Summary: CED-12 PH domain binds PtdIns(3,5)P2 (Neukomm et al. 2011). Reason: Stated in the abstract. The authors suggest that this binding could let MTM-1 control CED-12 recruitment to the plasma membrane, but this is not yet shown in vivo, and the PH domain also binds other phosphoinositides. The binding is real but not the core activity of CED-12. Supporting Evidence: PMID:21490059 we show that the CED-12 PH domain can bind to PtdIns(3,5)P(2) (one target of MTM-1 phosphatase activity), suggesting that MTM-1 might regulate CED-12 recruitment to the plasma membrane |
| GO:0160124 guanyl nucleotide exchange factor activator activity | ISS PMID:11595183 CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway... | ACCEPT | Summary: GEF activator activity, by similarity to human ELMO1. Reason: Core molecular function. ELMO/CED-12 binds DOCK180/CED-5 and raises its exchange activity on Rac; the ELMO PH domain binds the DOCK180-Rac complex in trans and stabilizes the nucleotide-free state. CED-12 does not catalyse exchange itself, so activator of a GEF is the right description. Supporting Evidence: PMID:11595183 CED-12/ELMO-1 binds directly to CED-5/Dock180; this evolutionarily conserved complex stimulates a Rac-GEF, leading to Rac1 activation and cytoskeletal rearrangements PMID:15247908 the PH domain of ELMO, by binding the Dock180-Rac complex in trans, stabilizes Rac in the nucleotide-free transition state |
| GO:1901076 positive regulation of engulfment of apoptotic cell | IGI PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | MODIFY | Summary: Positive regulation of engulfment of apoptotic cell (IGI with ced-5, Cabello et al. 2010). Reason: CED-12 does not regulate engulfment from outside; it is part of the CED-2/CED-5/CED-12 exchange-factor complex that carries out the Rac activation needed for engulfment. In this paper MOM-5/Frizzled is placed upstream of that complex, which is what the epistasis shows. The direct process term is the accurate one for ced-12. Proposed replacements: engulfment of apoptotic cell Supporting Evidence: PMID:20126385 The epistatic and bypass experiments indeed indicate that MOM-5/Fz activates CED-10/Rac through the GEF complex CED-2, CED-5, CED-12 PMID:20126385 Mutations in this second pathway not only result in defects in cell corpse engulfment but also result in aberrant distal tip cell (DTC) migration |
| GO:1901076 positive regulation of engulfment of apoptotic cell | IGI PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | MODIFY | Summary: Positive regulation of engulfment of apoptotic cell (IGI with ced-1, Cabello et al. 2010). Reason: As for the ced-5 row. ced-12 is engulfment machinery rather than an outside regulator. The ced-1 double mutant analysis in this paper bears on whether the two engulfment branches act in one pathway in early embryos; it does not make ced-12 a regulator of engulfment. Proposed replacements: engulfment of apoptotic cell Supporting Evidence: PMID:20126385 The epistatic and bypass experiments indeed indicate that MOM-5/Fz activates CED-10/Rac through the GEF complex CED-2, CED-5, CED-12 PMID:20126385 the CED-12/ELMO-CED-5/DOCK180 complex, which acts as a GEF to activate CED-10/Rac |
| GO:1902742 apoptotic process involved in development | IGI PMID:24225442 Caspase-mediated activation of Caenorhabditis elegans CED-8 ... | MODIFY | Summary: Apoptotic process involved in development (IGI with ced-8, Chen et al. 2013). Reason: In the full text, ced-12(n3261) is used only as an engulfment-defective background in which corpses persist and can be counted; the paper tests ced-8, so this is a clearance readout, not evidence that CED-12 takes part in the dying cell's apoptotic program. The positive regulation term is supported instead by Reddien et al. 2001, whose abstract defines the engulfment genes it studies as ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 and states that mutations in engulfment genes alone allow some cells that would normally die to survive, and by Hoeppner et al. 2001. ced-12 is in that enumerated set, and engulfment genes act from the engulfing cell to promote death, which is positive regulation rather than participation. The replacement is GO:0043065 positive regulation of apoptotic process, without the developmental context of its precomposed child GO:1904747. Proposed replacements: positive regulation of apoptotic process Context of precomposed term: context dropped The replacement is unfolded from GO:1904747 positive regulation of apoptotic process involved in development to GO:0043065 (projects/INVOLVED_IN_PRECOMPOSITION.md, round 6); the sign correction (regulation, not participation) is unchanged. The developmental context is not carried: it is where the engulfment genes' pro-death role was measured (Reddien 2001; Hoeppner 2001), not a mechanism, and the role is non-core for this gene. Supporting Evidence: PMID:24225442 ced-8(n1891) markedly enhanced the cell corpse engulfment defect of the ced-2, ced-5 or ced-12 mutants PMID:11449278 the engulfment of dying cells requires the genes ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 PMID:11449278 mutations in engulfment genes alone allow the survival and differentiation of some cells that would normally die PMID:11449278 mutations in engulfment genes enhance the frequency of this cell survival PMID:11449279 genes that mediate corpse removal can also function to actively kill cells |
| GO:1902742 apoptotic process involved in development | IMP PMID:24225442 Caspase-mediated activation of Caenorhabditis elegans CED-8 ... | MODIFY | Summary: Apoptotic process involved in development (Chen et al. 2013, CED-8 paper). Reason: In the full text, ced-12(n3261) is used only as an engulfment-defective background in which corpses persist and can be counted; the paper tests ced-8, so this is a clearance readout, not evidence that CED-12 takes part in the dying cell's apoptotic program. The positive regulation term is supported instead by Reddien et al. 2001, whose abstract defines the engulfment genes it studies as ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 and states that mutations in engulfment genes alone allow some cells that would normally die to survive, and by Hoeppner et al. 2001. ced-12 is in that enumerated set, and engulfment genes act from the engulfing cell to promote death, which is positive regulation rather than participation. The replacement is GO:0043065 positive regulation of apoptotic process, without the developmental context of its precomposed child GO:1904747. Proposed replacements: positive regulation of apoptotic process Context of precomposed term: context dropped The replacement is unfolded from GO:1904747 positive regulation of apoptotic process involved in development to GO:0043065 (projects/INVOLVED_IN_PRECOMPOSITION.md, round 6); the sign correction (regulation, not participation) is unchanged. The developmental context is not carried: it is where the engulfment genes' pro-death role was measured (Reddien 2001; Hoeppner 2001), not a mechanism, and the role is non-core for this gene. Supporting Evidence: PMID:24225442 ced-8(n1891) markedly enhanced the cell corpse engulfment defect of the ced-2, ced-5 or ced-12 mutants PMID:11449278 the engulfment of dying cells requires the genes ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 PMID:11449278 mutations in engulfment genes alone allow the survival and differentiation of some cells that would normally die PMID:11449278 mutations in engulfment genes enhance the frequency of this cell survival PMID:11449279 genes that mediate corpse removal can also function to actively kill cells |
| GO:1903356 positive regulation of distal tip cell migration | IGI PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie... | MODIFY | Summary: Positive regulation of distal tip cell migration (IGI with ced-5, Cabello et al. 2010). Reason: Unlike the CED-1/6/7 branch, the CED-2/5/12 branch is what MOM-5 acts through for distal tip cell migration in this paper, and mutations in this branch cause distal tip cell migration defects. CED-12 is part of the Rac activator that drives the migrating cell, so the direct process term distal tip cell migration fits better than a regulation term. Proposed replacements: distal tip cell migration Supporting Evidence: PMID:20126385 Apoptotic cell clearance and migration of the distal tip cell require the MOM-5/Fz receptor, GSK-3 kinase, and APC/APR-1, which activate the CED-2/5/12 branch of the engulfment machinery PMID:20126385 Mutations in this second pathway not only result in defects in cell corpse engulfment but also result in aberrant distal tip cell (DTC) migration |
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Download this section (compressed HTML)Q: Which phosphoinositide does the CED-12 PH domain bind in vivo, and does MTM-1 control CED-12 recruitment to the engulfing membrane through PtdIns(3,5)P2 or another lipid?
Q: How are the inputs to CED-12 (MOM-5/Frizzled via CED-2, MIG-2/RhoG via the ARM repeats, and phosphoinositides via the PH domain) combined in a single engulfing cell?
Q: How does CED-12 act on the UNC-5 netrin receptor to steer distal tip cells, and is this the same Rac-activating activity used in engulfment?
Experiment: Express PH-domain lipid-binding mutants of CED-12 in ced-12 null animals, image CED-12::GFP at phagocytic cups in wild-type and mtm-1 backgrounds, and score embryonic and germ-cell corpse numbers.
Hypothesis: The CED-12 PH domain binds PtdIns(3,5)P2 in vivo and this binding is needed for membrane recruitment and engulfment.
Type: genetic
Experiment: Score extra surviving cells (for example, in the anterior pharynx) in ced-3 partial loss-of-function animals with and without a ced-12 null allele, and test whether ced-12 expression in engulfing cells reverses the effect.
Hypothesis: ced-12 loss enhances the survival of cells receiving weak death signals.
Type: genetic
ced-12 encodes the C. elegans ELMO ortholog; ced-12 is required both for phagocytotic engulfment of apoptotic cells, and for normal migrations of healthy cells during development; CED-12 binds directly to CED-5, the C. elegans DOCK180 ortholog.
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