ced-2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005515 protein binding	IPI PMID:10707082 CED-2/CrkII and CED-10/Rac control phagocytosis and cell mig...	MODIFY	Summary: CED-2 physically interacts with CED-5/DOCK180 (Reddien and Horvitz 2000). Reason: 'Protein binding' is uninformative. CED-2 binds CED-5 as part of its role as the adaptor that relays engulfment signals to the CED-5/CED-12 Rac exchange factor. The informative activity is signaling adaptor activity. The cached record is abstract-only, but the abstract states the interaction and the proposed adaptor role directly. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:10707082 CED-2 and CED-5 physically interact PMID:10707082 We propose that CED-2/CrkII and CED-5/DOCK180 function to activate CED-10/Rac in a GTPase signalling pathway
GO:0005515 protein binding	IPI PMID:10707082 CED-2/CrkII and CED-10/Rac control phagocytosis and cell mig...	MODIFY	Summary: CED-2 physically interacts with CED-5/DOCK180 (Reddien and Horvitz 2000; WormBase gene identifier for ced-5). Reason: Same interaction as the UniProt-sourced row for this paper. 'Protein binding' is uninformative; the interaction is how CED-2 acts as an adaptor for the CED-5/CED-12 exchange factor. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:10707082 CED-2 and CED-5 physically interact PMID:10707082 We propose that CED-2/CrkII and CED-5/DOCK180 function to activate CED-10/Rac in a GTPase signalling pathway
GO:0005515 protein binding	IPI PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie...	MODIFY	Summary: The CED-2 SH2 domain binds APR-1/APC in a phosphotyrosine-dependent yeast two-hybrid assay (Cabello et al. 2010). Reason: In the full text, a yeast two-hybrid screen with constitutively active Src identified APR-1 as one of the strongest phosphorylation-dependent partners of the CED-2 SH2 domain. That is phosphotyrosine binding by the SH2 domain, which is more informative than protein binding. Caveat: the authors could not detect the interaction in vivo, so APR-1 as a physiological partner remains unconfirmed. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:20126385 one of the two strongest phosphorylation-dependent interactors identified in this screen was APR-1 PMID:20126385 Despite extensive proteomics efforts, we were unable to identify any interaction between CED-2 and APR-1 in vivo
GO:0005515 protein binding	IPI PMID:21616056 Crystal structure of the cell corpse engulfment protein CED-...	MODIFY	Summary: CED-2 binds the N-terminal region of CED-5 (Kang et al. 2011, crystal structure paper). Reason: 'Protein binding' is uninformative. The cached abstract shows that a CED-2 mutation that breaks binding to the CED-5 PXXP motif still rescues, and that CED-2 instead binds the CED-5 N-terminal region. Proline-rich region binding would therefore be misleading. The interaction is part of CED-2's adaptor role toward the CED-5/CED-12 exchange factor. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:21616056 CED-2 was found to interact with the N-terminal region of CED-5 PMID:21616056 CED-2 may regulate cell corpse engulfment by interacting with CED-5 through the N-terminal region rather than the PXXP motif
GO:0005515 protein binding	IPI PMID:25564762 A lysine-rich motif in the phosphatidylserine receptor PSR-1...	MODIFY	Summary: Endogenous CED-2 co-immunoprecipitates with Flag-tagged PSR-1 in worms (Yang et al. 2015). Reason: Full text. CED-2 co-precipitates specifically with the phosphatidylserine receptor PSR-1 and not with a control transmembrane receptor, supporting the model that PSR-1 recruits the CED-2/CED-5/CED-12 complex. This is the adaptor linking a corpse receptor to the Rac exchange factor: signaling adaptor activity. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:25564762 co-precipitated the endogenous CED-2 protein PMID:25564762 This result provides further support that PSR-1 acts through the CED-2, CED-5 and CED-12 pathway to promote clearance of dead cells
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Cytoplasm (IBA, SH2-SH3 adaptor family node). Reason: CED-2 has no transmembrane segment or signal peptide and is a soluble SH2/SH3 adaptor, like the CRK and NCK family members on this node. It acts on the cytoplasmic side, where the CED-2/CED-5/CED-12 complex is recruited to the membrane of the engulfing cell. 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	NAS PMID:10707082 CED-2/CrkII and CED-10/Rac control phagocytosis and cell mig...	KEEP AS NON CORE	Summary: Plasma membrane (NAS, Reddien and Horvitz 2000). Reason: This is an author statement, not a localization experiment. The cached abstracts only propose that the CED-2/CED-5/CED-12 complex is recruited to the plasma membrane to drive polarized surface extension, and CED-2 co-precipitates with the membrane receptor PSR-1. Plausible for a soluble adaptor recruited to receptors, but it is a recruited, not a resident, location. Supporting Evidence: PMID:10707082 GTPase signalling pathway that controls the polarized extension of cell surfaces 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:0006915 apoptotic process	IMP PMID:6857247 Mutations affecting programmed cell deaths in the nematode C...	MARK AS OVER ANNOTATED	Summary: Apoptotic process (IMP, Hedgecock et al. 1983). Reason: The two genes in this paper are ced-1 and ced-2, and the phenotype is persistent, unengulfed corpses. The paper itself concludes that cells programmed to die still die in these mutants. Engulfment genes do promote death of weakly signalled cells (Reddien 2001; Hoeppner 2001), but that is a regulatory contribution from the engulfing cell, not part of the dying cell's apoptotic program. Supporting Evidence: PMID:6857247 Mutations in two nonessential genes specifically block the phagocytosis of cells programmed to die during development PMID:6857247 With few exceptions, these cells still die, suggesting that, in nematodes, engulfment is not necessary for most programmed deaths
GO:0007165 signal transduction	IMP PMID:10707082 CED-2/CrkII and CED-10/Rac control phagocytosis and cell mig...	MODIFY	Summary: Signal transduction (IMP, Reddien and Horvitz 2000). Reason: Correct but very general. The paper places CED-2 upstream of CED-10/Rac with CED-5/DOCK180 in a GTPase signalling pathway, so the specific process is Rac protein signal transduction. Proposed replacements: Rac protein signal transduction Supporting Evidence: PMID:10707082 We propose that CED-2/CrkII and CED-5/DOCK180 function to activate CED-10/Rac in a GTPase signalling pathway PMID:10707082 ced-10 probably functions downstream of ced-2 and ced-5
GO:0007167 enzyme-linked receptor protein signaling pathway	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Enzyme-linked receptor protein signaling pathway (IBA, SH2-SH3 adaptor node with CRK, CRKL, NCK and Drosophila Crk donors). Reason: SH2-SH3 adaptors on this node act downstream of receptor tyrosine kinases, and CED-2 keeps the SH2 domain and its phosphotyrosine-dependent binding. The node placement is not in dispute. However, no study ties CED-2 to an enzyme-linked receptor in C. elegans; its known inputs are PSR-1, MOM-5/Frizzled with APR-1, and the non-receptor kinase SRC-1. Kept as an inherited, non-core capacity. Supporting Evidence: PMID:20126385 By analogy with its mammalian homologue, CED-2 has been proposed to bind to upstream activating signalling molecules via its SH2 domain, and relay this information to CED-5 via its first SH3 domain
GO:0012501 programmed cell death	IMP PMID:10707082 CED-2/CrkII and CED-10/Rac control phagocytosis and cell mig...	MARK AS OVER ANNOTATED	Summary: Programmed cell death (IMP, Reddien and Horvitz 2000). Reason: The ced-2 mutant phenotype in this paper is failed engulfment of dying cells and abnormal distal tip cell migration, with CED-2 acting in the engulfing cell. That is corpse clearance, not the death program. The modest pro-death role of engulfment genes is a regulatory effect, better described by positive regulation of apoptotic process (GO:0043065). Supporting Evidence: PMID:10707082 CED-2 and CED-10 function in engulfing rather than dying cells to control the phagocytosis of cell corpses PMID:6857247 With few exceptions, these cells still die, suggesting that, in nematodes, engulfment is not necessary for most programmed deaths
GO:0016477 cell migration	IBA GO_REF:0000033	ACCEPT	Summary: Cell migration (IBA). ced-2 itself (WBGene00000416) is among the descendant evidences. Reason: ced-2 has its own experimental evidence for a cell migration role (distal tip cell migration), and its appearance among the sources shows the node was grounded partly on that evidence. The IBA adds that the role is shared across the CRK/NCK adaptor clade. The specific migration is distal tip cell migration. Supporting Evidence: PMID:10707082 result in defects both in the engulfment of dying cells and in the migrations of the two distal tip cells of the developing gonad
GO:0016477 cell migration	IMP PMID:10707082 CED-2/CrkII and CED-10/Rac control phagocytosis and cell mig...	ACCEPT	Summary: Cell migration (IMP, Reddien and Horvitz 2000). Reason: ced-2 mutants are defective in the migration of the two gonadal distal tip cells, and the paper proposes that CED-2 acts with CED-5 to activate CED-10/Rac for polarized extension of the cell surface. Distal tip cell migration is the more specific process. Supporting Evidence: PMID:10707082 result in defects both in the engulfment of dying cells and in the migrations of the two distal tip cells of the developing gonad PMID:19402756 As with ced-2, ced-5, and ced-12 null mutants, the DTC defect of these ced-10 null mutants was suppressed
GO:0030036 actin cytoskeleton organization	IMP PMID:15744306 Two pathways converge at CED-10 to mediate actin rearrangeme...	KEEP AS NON CORE	Summary: Actin cytoskeleton organization (IMP, Kinchen et al. 2005). Reason: The cached record is abstract-only; UniProt records that actin halos around corpses are absent in ced-2 mutants from this paper. The abstract places CED-2 with CED-5 and CED-12 upstream of CED-10/Rac, which drives actin rearrangement. Actin reorganization is a step within engulfment downstream of CED-2, so it is kept as non-core, as for CED-1. Supporting Evidence: PMID:15744306 In the first pathway, the proteins CED-2, CED-5 and CED-12 (mammalian homologues CrkII, Dock180 and ELMO, respectively) function to activate CED-10 (Rac1) PMID:21616056 act in the same pathway to regulate the activation of the Rac small GTPase, CED-10, leading to the rearrangement of the actin cytoskeleton for engulfing apoptotic cells
GO:0030971 receptor tyrosine kinase binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Receptor tyrosine kinase binding (IBA, with NCK1 and Drosophila Crk as donors). Reason: CED-2 keeps a functional SH2 domain that binds phosphotyrosine-containing partners, which is how CRK and NCK adaptors bind activated receptor tyrosine kinases. The inheritance is plausible and the node placement is not disputed. No receptor tyrosine kinase partner of CED-2 has been shown in C. elegans, so this is kept as non-core. Supporting Evidence: PMID:20126385 one of the two strongest phosphorylation-dependent interactors identified in this screen was APR-1
GO:0035591 signaling adaptor activity	IBA GO_REF:0000033	ACCEPT	Summary: Signaling adaptor activity (IBA, CRK/NCK adaptor node). Reason: Core molecular function. CED-2 is a non-catalytic SH2/SH3 adaptor that binds upstream signals and relays them to the CED-5/CED-12 exchange factor for CED-10/Rac. Supporting Evidence: PMID:10707082 ced-2 and ced-10 encode proteins similar to the human adaptor protein CrkII and the human GTPase Rac PMID:11703940 CED-12 physically interacts with CED-5 and forms a ternary complex with CED-2 in vitro PMID:25564762 co-precipitated the endogenous CED-2 protein
GO:0035591 signaling adaptor activity	ISS PMID:10707082 CED-2/CrkII and CED-10/Rac control phagocytosis and cell mig...	ACCEPT	Summary: Signaling adaptor activity by similarity to mouse Crk (ISS, Reddien and Horvitz 2000). Reason: Core molecular function. CED-2 is the CrkII orthologue and genetically acts as the adaptor upstream of CED-5/DOCK180 and CED-10/Rac. Supporting Evidence: PMID:10707082 ced-2 and ced-10 encode proteins similar to the human adaptor protein CrkII and the human GTPase Rac PMID:10707082 We propose that CED-2/CrkII and CED-5/DOCK180 function to activate CED-10/Rac in a GTPase signalling pathway
GO:0043652 engulfment of apoptotic cell	IMP PMID:10707082 CED-2/CrkII and CED-10/Rac control phagocytosis and cell mig...	ACCEPT	Summary: Engulfment of apoptotic cell (IMP, Reddien and Horvitz 2000). Reason: Core process. ced-2 mutants fail to engulf dying cells, and CED-2 acts in the engulfing cell. Supporting Evidence: PMID:10707082 CED-2 and CED-10 function in engulfing rather than dying cells to control the phagocytosis of cell corpses
GO:0043652 engulfment of apoptotic cell	IMP PMID:11449278 Phagocytosis promotes programmed cell death in C. elegans.	ACCEPT	Summary: Engulfment of apoptotic cell (IMP, Reddien et al. 2001). Reason: The abstract lists ced-2 among the genes required for engulfment of dying cells. Core process. Supporting Evidence: 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
GO:0043652 engulfment of apoptotic cell	IMP PMID:1936965 Genes required for the engulfment of cell corpses during pro...	ACCEPT	Summary: Engulfment of apoptotic cell (IMP, Ellis et al. 1991). Reason: ced-2 was one of the three genes already known to eliminate cell corpses, and this paper defined the two partially redundant engulfment gene sets. Core process. Supporting Evidence: PMID:1936965 Previously, three genes were known to be involved in eliminating cell corpses in the nematode Caenorhabditis elegans: ced-1, ced-2 and nuc-1 PMID:1936965 these two sets of genes are involved in distinct and partially redundant processes that act in the engulfment of cell corpses
GO:0043652 engulfment of apoptotic cell	IMP PMID:19402756 Abl kinase inhibits the engulfment of apoptotic [corrected] ...	ACCEPT	Summary: Engulfment of apoptotic cell (IMP, Hurwitz et al. 2009, Abl paper). Reason: Full text. ced-2 null and partial loss-of-function alleles both cause engulfment defects (persistent corpses), which abl-1 loss partially suppresses. Core process. Supporting Evidence: PMID:19402756 abl-1 mutation did partially suppress the engulfment defect caused by ced-2(n1994) alone
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-2 forms a ternary complex with CED-5 and CED-12 in vitro (Wu et al. 2001). Reason: CED-2 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-5 and ced-12 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
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-2 forms a ternary complex with CED-5 and CED-12 in vitro (Wu et al. 2001). Reason: CED-2 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-5 and ced-12 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
GO:1901076 positive regulation of engulfment of apoptotic cell	IMP PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie...	MODIFY	Summary: Positive regulation of engulfment of apoptotic cell (Cabello et al. 2010). Reason: In this full-text paper the CED-2/5/12 branch is the route through which MOM-5/Frizzled acts for engulfment, so the paper supports CED-2's role. But CED-2 does not regulate engulfment from outside: it is a core part of the machinery that activates CED-10/Rac in the engulfing cell. The direct process term is the accurate one. The paper mostly cites ced-2 mutants as a comparison (no ced-2 allele is in its strain list), so the ced-2 evidence here is largely by pathway placement. 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 loss of apr-1 function results in a persistent cell corpse phenotype similar in strength to that of ced-2 mutants PMID:10707082 CED-2 and CED-10 function in engulfing rather than dying cells to control the phagocytosis of cell corpses
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-2(n1994) 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-2 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-2 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 (IMP, Chen et al. 2013). Reason: In the full text, ced-2(n1994) 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-2 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-2 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	IMP PMID:20126385 The Wnt pathway controls cell death engulfment, spindle orie...	MODIFY	Summary: Positive regulation of distal tip cell migration (Cabello et al. 2010). Reason: Unlike the CED-1/6/7 branch, the CED-2/5/12 branch is what MOM-5/Frizzled acts through for distal tip cell migration, so a role for CED-2 is well supported (also by Reddien 2000 and Hurwitz 2009). But CED-2 is part of the Rac-activating machinery that moves the distal tip cell, not an outside regulator of it. The direct process term, distal tip cell migration, is more accurate. 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:10707082 result in defects both in the engulfment of dying cells and in the migrations of the two distal tip cells of the developing gonad PMID:19402756 As with ced-2, ced-5, and ced-12 null mutants, the DTC defect of these ced-10 null mutants was suppressed

Gene Description

Existing Annotations Review

Core Functions

SH2/SH3 adaptor in engulfing cells that links corpse-recognition signals (PSR-1, MOM-5/Frizzled) to the CED-5/CED-12 exchange factor, leading to CED-10/Rac activation, actin rearrangement and engulfment of apoptotic cells.

The same CED-2/CED-5/CED-12/CED-10 adaptor-GEF-Rac module drives migration of the gonadal distal tip cells, downstream of MOM-5/Frizzled.

References

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WormBase

WormBase gene description for ced-2 (worm)

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