gcA encodes GCA (DdGCA), a large membrane-bound guanylyl cyclase of Dictyostelium discoideum that catalyzes the synthesis of the second messenger cGMP from GTP. Unusually for a membrane guanylyl cyclase, GCA has the topology of a metazoan membrane adenylyl cyclase, with 12 transmembrane-spanning regions and two intramolecular cyclase domains (arranged in transposed order relative to adenylyl cyclases) that fold into a single catalytic center. It requires Mg2+, is inhibited by calcium, and is activated in vitro by GTPgammaS, apparently through a monomeric G protein. In vivo the enzyme is activated by extracellular cAMP acting through a G-protein-coupled cAMP receptor. GCA is one of two guanylyl cyclases in Dictyostelium (the other being the soluble sGC/sgcA); the two are partially redundant, and only the double null loses all detectable guanylyl cyclase activity. GCA is expressed mainly during growth and later multicellular development, whereas sGC predominates during aggregation. The cGMP produced by these cyclases acts as a diffusible second messenger that promotes cortical myosin II filament assembly in the rear and sides of chemotaxing cells, suppressing lateral pseudopodia and thereby refining directional movement during cAMP-mediated chemotaxis, cell streaming, and electrotaxis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004383 guanylate cyclase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of guanylate cyclase activity is correct and is strongly corroborated by direct biochemical evidence for GCA. This is the core molecular function of the gene product. Reason: GCA is a bona fide guanylyl cyclase demonstrated experimentally to synthesize cGMP from GTP. The IBA inference agrees with the direct assays. Supporting Evidence: PMID:11237875 DdGCA expressed in Dictyostelium exhibits high guanylate cyclase activity and no detectable adenylate cyclase activity |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: GCA is an integral, multi-pass membrane protein that is exclusively membrane-bound. Plasma membrane localization is consistent with its activation downstream of the plasma-membrane cAMP receptor and with its localization to the leading-edge membrane. Reason: The enzyme is membrane-bound with 12 transmembrane spans; activation by the plasma-membrane cAMP GPCR and leading-edge localization support a plasma membrane site of action. Supporting Evidence: PMID:11777934 GCA is exclusively membrane-bound and is active mainly with Mg(2+) PMID:11237875 We have cloned a Dictyostelium gene, DdGCA, encoding a protein with 12 transmembrane spanning regions and two cyclase domains |
| GO:0006182 cGMP biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: cGMP biosynthesis is the core biological process carried out by GCA and is well supported by direct enzymology. Reason: GCA synthesizes cGMP from GTP; the double gca/sgc null loses all detectable guanylyl cyclase activity, confirming these enzymes are the source of cGMP. Supporting Evidence: PMID:11777934 all detectable GC activity is lost in a cell line in which both genes have been inactivated |
| GO:0007168 receptor guanylyl cyclase signaling pathway | IBA GO_REF:0000033 | REMOVE | Summary: This IBA transfers the metazoan receptor-guanylyl-cyclase signaling role (as in natriuretic peptide receptors NPR-A/B) to GCA. GCA is not a receptor guanylyl cyclase. Metazoan receptor GCs have a single transmembrane span and one cyclase domain and are directly activated by extracellular peptide ligand binding, whereas GCA has 12 transmembrane spans and two cyclase domains (adenylyl-cyclase topology) and is activated indirectly, downstream of a G-protein-coupled cAMP receptor. The inference does not transfer to this divergent enzyme. Reason: GCA does not act in a receptor guanylyl cyclase signaling pathway. It is a G-protein-activated 12-transmembrane cyclase, not a ligand-binding receptor cyclase; the phylogenetic inference from metazoan peptide-receptor guanylyl cyclases is a mis-propagation to a structurally and mechanistically distinct enzyme. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000229249 · PANTHER node for the guanylyl cyclase family SUPPORTS SOURCE BUT NOT TARGET The receptor-guanylyl-cyclase signaling role reflects metazoan single-pass receptor GCs in the family; GCA is a 12-transmembrane, G-protein-activated cyclase and does not use this receptor mechanism UniProtKB:P16066 · human guanylyl cyclase GUCY2C (heat-stable enterotoxin/guanylin receptor) SUPPORTS SOURCE BUT NOT TARGET GUCY2C is a genuine peptide-activated receptor guanylyl cyclase; this signaling-pathway role does not transfer to the topologically distinct GCA Supporting Evidence: PMID:11237875 membrane-bound guanylate cyclase activity is induced after cAMP stimulation; a G-protein-coupled cAMP receptor and G-proteins are essential for this activation PMID:11522784 DdGCA is a Dictyostelium guanylyl cyclase with a topology typical for mammalian adenylyl cyclases containing 12 transmembrane-spanning regions and two cyclase domain |
| GO:0001653 peptide receptor activity | IBA GO_REF:0000033 | REMOVE | Summary: This IBA transfers peptide receptor activity from metazoan receptor guanylyl cyclases (natriuretic peptide receptors) to GCA. GCA has no ligand- binding ectodomain of a peptide receptor; it is a 12-transmembrane, adenylyl-cyclase-topology enzyme activated indirectly via a G-protein, not by direct peptide binding. Reason: GCA is not a peptide receptor. The inference derives from mammalian single-pass receptor guanylyl cyclases that bind natriuretic peptides; this function does not transfer to a G-protein-activated 12-transmembrane cyclase. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000229249 · PANTHER node for the guanylyl cyclase family SUPPORTS SOURCE BUT NOT TARGET Peptide receptor activity reflects metazoan single-pass receptor guanylyl cyclases (natriuretic/guanylin receptors) in the family; GCA has no peptide-receptor ectodomain UniProtKB:P20594 · human natriuretic peptide receptor NPR2 (guanylyl cyclase) SUPPORTS SOURCE BUT NOT TARGET NPR2 is a bona fide peptide-binding receptor guanylyl cyclase; this ligand-receptor activity does not transfer to the G-protein-activated 12-transmembrane GCA Supporting Evidence: PMID:11522784 DdGCA is a Dictyostelium guanylyl cyclase with a topology typical for mammalian adenylyl cyclases containing 12 transmembrane-spanning regions and two cyclase domain PMID:11522784 GTPgammaS activation is not mediated by a heterotrimeric G-protein but possibly by a monomeric G-protein |
| GO:0004383 guanylate cyclase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated EC-to-GO mapping (EC 4.6.1.2) for guanylate cyclase activity. Correct and consistent with the direct biochemical evidence. Reason: GCA catalyzes GTP to 3',5'-cyclic GMP (EC 4.6.1.2), matching this annotation. Supporting Evidence: PMID:11237875 DdGCA expressed in Dictyostelium exhibits high guanylate cyclase activity and no detectable adenylate cyclase activity |
| GO:0009190 cyclic nucleotide biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO inference from the adenylyl/guanylyl cyclase domain. It is correct but general; the more specific cGMP biosynthetic process is captured by another annotation. Reason: GCA produces the cyclic nucleotide cGMP, so cyclic nucleotide biosynthetic process is a correct (if general) parent term. Supporting Evidence: PMID:11237875 DdGCA expressed in Dictyostelium exhibits high guanylate cyclase activity and no detectable adenylate cyclase activity |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to membrane. Correct; GCA is a multi-pass integral membrane protein and is exclusively membrane-bound. Reason: GCA is an integral membrane protein (12 transmembrane spans) that is exclusively membrane-bound, so the membrane annotation is accurate. Supporting Evidence: PMID:11777934 GCA is exclusively membrane-bound and is active mainly with Mg(2+) |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO inference. GCA produces the intracellular second messenger cGMP downstream of receptor activation, so participation in intracellular signal transduction is correct, though general. Reason: cGMP synthesis by GCA is an intracellular signal transduction event downstream of the cAMP receptor; the term is correct at a general level. Supporting Evidence: PMID:11237875 membrane-bound guanylate cyclase activity is induced after cAMP stimulation; a G-protein-coupled cAMP receptor and G-proteins are essential for this activation |
| GO:0007168 receptor guanylyl cyclase signaling pathway | TAS PMID:15473840 Chemoattractant signaling in dictyostelium discoideum. | MARK AS OVER ANNOTATED | Summary: This term implies GCA is a ligand-binding receptor guanylyl cyclase, which it is not. GCA participates in cGMP signaling downstream of the cAMP GPCR, but the specific receptor-guanylyl-cyclase term is a misnomer for this 12-transmembrane, G-protein-activated enzyme. Reason: GCA functions in cGMP-mediated signaling downstream of a G-protein- coupled cAMP receptor, not as a receptor guanylyl cyclase. The term over- specifies a receptor-cyclase mechanism that does not apply; the genuine signaling role is better captured by cGMP biosynthetic process and the chemotaxis/myosin annotations. Supporting Evidence: PMID:11522784 DdGCA is a Dictyostelium guanylyl cyclase with a topology typical for mammalian adenylyl cyclases containing 12 transmembrane-spanning regions and two cyclase domain |
| GO:0019722 calcium-mediated signaling | IGI NOT PMID:40295210 Intracellular Calcium Responses to External Calcium Stimuli ... | ACCEPT | Summary: NOT annotation. In gca/sgc double-null cells, the intracellular calcium response to external calcium is only slightly delayed rather than abolished, indicating that GCA (and cGMP synthesis) is not required for calcium-mediated signaling. The negation is supported. Reason: The genetic evidence shows the calcium response persists (merely delayed) without GCA/sGC, so GCA does not act within calcium-mediated signaling. The negated annotation correctly records this non-requirement. Supporting Evidence: PMID:40295210 gca/sgc-null cells showed a slightly delayed response PMID:40295210 Although calcium signaling is not strictly necessary for chemotaxis |
| GO:0016020 membrane | TAS PMID:15473840 Chemoattractant signaling in dictyostelium discoideum. | ACCEPT | Summary: Membrane localization of GCA. Correct; the enzyme is an integral multi-pass membrane protein. Reason: GCA is exclusively membrane-bound, consistent with a membrane localization annotation. Supporting Evidence: PMID:11777934 GCA is exclusively membrane-bound and is active mainly with Mg(2+) |
| GO:0004383 guanylate cyclase activity | IDA PMID:11522784 GTPgammaS regulation of a 12-transmembrane guanylyl cyclase ... | ACCEPT | Summary: Direct assay of GCA guanylyl cyclase activity, including GTPgammaS stimulation and mutagenesis of catalytic residues. This is core, well- supported experimental evidence. Reason: Roelofs et al. directly measured GCA guanylyl cyclase activity and its regulation, firmly establishing the catalytic function. Supporting Evidence: PMID:11522784 guanylyl cyclase activity is strongly stimulated by guanosine 5'-3-O-(thio) triphosphate (GTPgammaS) |
| GO:0031252 cell leading edge | IDA PMID:19346484 Switching direction in electric-signal-induced cell migratio... | KEEP AS NON CORE | Summary: Components of the guanylyl-cyclase-dependent signaling pathway localize to the leading edge of migrating cells in an actin-dependent manner. As a membrane cyclase in this pathway, GCA at the leading edge is consistent with the data, though leading-edge enrichment is best characterized for the soluble sGC. Reason: Leading-edge localization is a context-dependent property tied to directed migration rather than the core catalytic function; it is supported for the GCase-dependent signaling components in migrating cells. Supporting Evidence: PMID:19346484 Molecular components of the GCase- and PI3K-dependent signaling pathways localized at the leading edge of migrating cells during electrotaxis in an actin-dependent manner |
| GO:0051602 response to electrical stimulus | IGI PMID:19346484 Switching direction in electric-signal-induced cell migratio... | KEEP AS NON CORE | Summary: Genetic modulation of the guanylyl cyclases (with cGMP-binding GbpC and PI3K) reverses the preferred direction of electrotaxis, implicating the GCase pathway in the response to a direct-current electric field. This is a valid accessory role, not the core molecular function. Reason: GCA contributes, via cGMP, to directional bias during electrotaxis, an accessory physiological process downstream of its catalytic activity. Supporting Evidence: PMID:19346484 the preferential direction of migration during electrotaxis in Dictyostelium cells can be reversed by genetically modulating both guanylyl cyclases (GCases) |
| GO:0004383 guanylate cyclase activity | IDA PMID:11237875 Guanylate cyclase in Dictyostelium discoideum with the topol... | ACCEPT | Summary: Direct demonstration that expressed DdGCA has high guanylyl cyclase activity and no detectable adenylyl cyclase activity. Core experimental evidence for the molecular function. Reason: This is the original biochemical characterization establishing GCA as a guanylyl cyclase. Supporting Evidence: PMID:11237875 DdGCA expressed in Dictyostelium exhibits high guanylate cyclase activity and no detectable adenylate cyclase activity |
| GO:0004383 guanylate cyclase activity | IMP PMID:11777934 Characterization of two unusual guanylyl cyclases from dicty... | ACCEPT | Summary: Gene-inactivation evidence from characterizing GCA in sgc-null cells and the loss of all guanylyl cyclase activity in the gca/sgc double null confirms GCA guanylyl cyclase activity in vivo. Core function. Reason: The double-null result (all detectable GC activity lost) and single- null characterization firmly attribute guanylyl cyclase activity to GCA. Supporting Evidence: PMID:11777934 all detectable GC activity is lost in a cell line in which both genes have been inactivated |
| GO:0050920 regulation of chemotaxis | IGI PMID:22081140 Dictyostelium chemotaxis: essential Ras activation and acces... | KEEP AS NON CORE | Summary: The guanylyl cyclase pathway (sGC/GCA-derived cGMP) is one of several accessory signaling enzymes that are not required for the basal Ras module but improve orientation and sensitivity of chemotaxis in shallow gradients. This is a modulatory, non-core role. Reason: cGMP signaling amplifies and refines chemotaxis rather than being essential; GCA's contribution here is downstream of its catalytic function and is redundant with sGC. Supporting Evidence: PMID:22081140 The signalling enzymes PI3K, TorC2, PLA2 and sGC are not required for Ras activation and chemotaxis to folate or to steep gradients of cAMP, but they provide a memory of direction and improved orientation of the cell |
| GO:0006935 chemotaxis | IGI PMID:18073238 The role of cGMP and the rear of the cell in Dictyostelium c... | KEEP AS NON CORE | Summary: cGMP signaling controls the quiescent rear of the cell during cAMP- wave chemotaxis and cell streaming. GCA-derived cGMP contributes to this process, an accessory role downstream of catalysis. Reason: Chemotaxis is a downstream physiological process supported by cGMP; it is a valid but non-core role for GCA, which is redundant with sGC. Supporting Evidence: PMID:18073238 Wild-type cells efficiently retract pseudopodia in the rear of the cell during the rising flank of the cAMP wave and have a quiescent cell posterior |
| GO:0120320 lateral pseudopodium retraction | IGI PMID:18073238 The role of cGMP and the rear of the cell in Dictyostelium c... | KEEP AS NON CORE | Summary: cGMP suppresses pseudopod formation in the rear and sides of the cell by promoting cortical myosin, so lateral pseudopodia are retracted. GCA- derived cGMP contributes to this rear/side response. Reason: Suppression/retraction of lateral pseudopodia is a downstream effect of cGMP signaling; a valid non-core role for GCA. Supporting Evidence: PMID:18073238 a quiescent rear of the cell increases the efficiency of directional movement and is essential to maintain stable cell-cell contacts PMID:16790492 cGMP suppresses pseudopod formation in the back of the cell, whereas the sGC protein refines pseudopod formation at the leading edge |
| GO:0031033 myosin filament organization | IGI PMID:16790492 Guanylyl cyclase protein and cGMP product independently cont... | KEEP AS NON CORE | Summary: cGMP mediates the formation of cortical myosin II filaments in response to a cAMP stimulus, organizing myosin in the back of the cell. GCA- derived cGMP contributes to this, downstream of its catalytic activity. Reason: Regulation of myosin filament organization is a key downstream effect of the cGMP produced by GCA, but is not GCA's core molecular function. Supporting Evidence: PMID:16790492 One of the second messengers used during Dictyostelium chemotaxis is cGMP, which mediates the formation of myosin filaments in response to a cAMP stimulus PMID:16790492 In a cAMP gradient, myosin is mostly found in the back of the cell, where it increases the cortical tension and suppress pseudopod extension |
| GO:0031037 myosin II filament disassembly | TAS PMID:14710184 Chemotaxis: signalling modules join hands at front and tail. | KEEP AS NON CORE | Summary: The cGMP-signaling cascade regulates cortical myosin II filament dynamics in the posterior of the cell. The cited review emphasizes cGMP- driven myosin filament formation in the rear; the specific disassembly framing is one side of the assembly/disassembly regulation attributed to this pathway. Reason: Regulation of cortical myosin II filament dynamics is a downstream role of GCA-derived cGMP. The annotation captures a real regulatory role, though the primary reported effect of the cGMP cascade is promotion of myosin filament formation in the posterior. Supporting Evidence: PMID:14710184 a cyclic-GMP-signalling cascade has been identified that regulates myosin filament formation in the posterior of the cell, thereby inhibiting the formation of lateral pseudopodia that could misdirect the cell |
| GO:0120320 lateral pseudopodium retraction | TAS PMID:14710184 Chemotaxis: signalling modules join hands at front and tail. | KEEP AS NON CORE | Summary: The cGMP cascade inhibits formation of lateral pseudopodia (favoring their retraction) by promoting posterior myosin. GCA-derived cGMP contributes to this rear/side function. Reason: Suppression/retraction of lateral pseudopodia is a downstream effect of cGMP signaling; a valid non-core role for GCA. Supporting Evidence: PMID:14710184 a cyclic-GMP-signalling cascade has been identified that regulates myosin filament formation in the posterior of the cell, thereby inhibiting the formation of lateral pseudopodia that could misdirect the cell |
| GO:0006935 chemotaxis | TAS PMID:15473840 Chemoattractant signaling in dictyostelium discoideum. | KEEP AS NON CORE | Summary: cGMP signaling contributes to the cortical-myosin module that underlies cAMP chemotaxis in Dictyostelium. GCA-derived cGMP participates in chemotaxis as an accessory role. Reason: Chemotaxis is a downstream physiological process to which GCA contributes via cGMP; it is valid but non-core and redundant with sGC. Supporting Evidence: PMID:16790492 One of the second messengers used during Dictyostelium chemotaxis is cGMP, which mediates the formation of myosin filaments in response to a cAMP stimulus |
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