ANTXR2 (CMG2) is a single-pass cell-surface receptor that couples extracellular ligation to cytoplasmic signaling, cytoskeletal interactions and receptor internalization. Its extracellular von Willebrand factor A domain contains a metal-dependent ligand-binding site. Full-length surface forms contribute to extracellular-matrix handling, including receptor-dependent collagen uptake and lysosomal delivery in tested human cells, although direct collagen-VI recognition remains experimentally contested. ANTXR2 also binds anthrax protective antigen and enables toxin entry. Alternative products have distinct trafficking properties, including a reported endoplasmic-reticulum form and a predicted secreted form whose endogenous production is uncertain. Biallelic loss of ANTXR2 causes hyaline fibromatosis syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004888 transmembrane signaling receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Human ligand-dependent signal coupling supports the inherited receptor activity. Reason: Ligand binding to full-length ANTXR2 couples the extracellular VWA domain to cytoplasmic Src-dependent phosphorylation and recruitment of beta-arrestin and cytoskeletal regulators. Human receptor experiments support this signaling-receptor function, including the ligand-induced talin-to-RhoA switch and its dependence on receptor S-acylation. Supporting Evidence: PMID:28604699 This binding event leads to intracellular signals such as the src-dependent phosphorylation of CMG2 cytoplasmic tail and the recruitment of Ξ²-arrestin. PMID:28604699 Human CMG2 (isoform 4, Uniprot identifier P58335-4) was cloned in a pcDNA3.5/V5-HIS-TOPO expression vector. file:human/ANTXR2/ANTXR2-notes.md PMID:32428455 CMG2 binds talin, and thereby the actin cytoskeleton, only in its ligand-free state. Extracellular ligand binding leads to src-dependent talin release and recruitment of the actin cytoskeleton regulator RhoA and its effectors. PMID:42409807 These findings show that CMG2 must be S-acylated for it to transduce ligand binding information into cytosolic signalling PMID:42409807 Human CMG2 (isoform 4, UniProt P58335-4) WT was cloned in a pcDNA3.5/V5-HIS-TOPO expression vector or in pHS003-EGFP. |
| GO:0005515 protein binding | IPI PMID:15044490 Binding stoichiometry and kinetics of the interaction of a h... | MODIFY | Summary: ANTXR2 recognizes anthrax toxin through its protective-antigen component. Reason: Purified human CMG2 VWA binds monomeric and heptameric protective antigen with defined affinity and stoichiometry. Protective antigen is the receptor-binding moiety of anthrax toxin, and human CMG2-mediated binding supports toxin entry. Toxic substance binding is therefore a specific description of this pathogen-recognition interaction. The term does not require each bound component of a multipart toxin to be independently poisonous. This does not assert binding to isolated lethal or edema factors, or intrinsic toxin or antitoxin activity of ANTXR2. Proposed replacements: toxic substance binding Supporting Evidence: PMID:15044490 We expressed and purified the von Willebrand A (VWA) domain of CMG2 and examined its interactions with monomeric and heptameric forms of PA. PMID:15326297 The structure of the PA heptamer:CMG2 VWA domain complex was determined at 4.3 Γ
and reveals the CMG2 MIDAS occupied by PA D683 PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. |
| GO:0005515 protein binding | IPI PMID:15243628 Crystal structure of a complex between anthrax toxin and its... | MODIFY | Summary: ANTXR2 recognizes anthrax toxin through its protective-antigen component. Reason: The PA-CMG2 crystal structure directly resolves the receptor interface with protective antigen, the receptor-binding moiety of anthrax toxin. Together with receptor-dependent toxin entry, this supports the specific toxic substance binding term. PA remains the exact assayed partner; no independent toxicity of isolated PA, binding to isolated lethal or edema factors, or pore-forming activity of ANTXR2 is implied. Proposed replacements: toxic substance binding Supporting Evidence: PMID:15243628 we report the crystal structure of the PA-CMG2 complex at 2.5 A resolution. PMID:15326297 The structure of the PA heptamer:CMG2 VWA domain complex was determined at 4.3 Γ
and reveals the CMG2 MIDAS occupied by PA D683 PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. |
| GO:0005515 protein binding | IPI PMID:15326297 Structure of heptameric protective antigen bound to an anthr... | MODIFY | Summary: ANTXR2 recognizes anthrax toxin through its protective-antigen component. Reason: The human CMG2 VWA domain binds the heptameric PA prepore and contacts PA domains involved in receptor recognition and pore conversion. This is recognition of anthrax toxin through its PA moiety, supporting toxic substance binding. The receptor influences the pH threshold for PA conversion but does not itself form the toxin pore or carry out lethal-factor or edema-factor chemistry. Proposed replacements: toxic substance binding Supporting Evidence: PMID:15326297 The structure of the PA heptamer:CMG2 VWA domain complex was determined at 4.3 Γ
and reveals the CMG2 MIDAS occupied by PA D683 PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | UNDECIDED | Summary: Production and secretion of the predicted soluble alternative product remain unresolved. Reason: Isoform3 lacks the membrane-spanning region and is predicted to be soluble, but its transcript may undergo nonsense-mediated decay. Production and secretion of the endogenous protein remain unresolved. The available evidence establishes neither a secreted pool nor a contradiction of the prediction. Supporting Evidence: file:human/ANTXR2/ANTXR2-notes.md |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:11683410 Differential gene expression during capillary morphogenesis ... | KEEP AS NON CORE | Summary: The historical CMG2 construct localizes to the endoplasmic reticulum. Reason: The historical human CMG2-GFP experiment reports endoplasmic-reticulum targeting of the 386-amino-acid product now assigned to isoform2. This product-specific location is valid but does not describe the predominant surface-receptor role of the longer products. Supporting Evidence: PMID:11683410 a CMG-2-GFP chimera was observed to target to the endoplasmic reticulum. file:human/ANTXR2/ANTXR2-notes.md |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The ER mapping represents a non-core alternative-product context. Reason: The UniProt ER membrane mapping is coherent with the directly reported historical isoform 2 localization. Keep as a non-core alternative-product context without asserting that every isoform is retained in the ER. Supporting Evidence: PMID:11683410 a CMG-2-GFP chimera was observed to target to the endoplasmic reticulum. file:human/ANTXR2/ANTXR2-notes.md |
| GO:0005886 plasma membrane | EXP PMID:12700348 Human capillary morphogenesis protein 2 functions as an anth... | ACCEPT | Summary: The human receptor is accessible at the cell surface. Reason: The original primary human receptor study establishes surface accessibility and receptor-dependent toxin uptake. Plasma membrane is central to full-length receptor activity; later human P58335-4 surface biotinylation/localization corroborates it. Supporting Evidence: PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. file:human/ANTXR2/ANTXR2-notes.md PMID:42409807 In control cells, CMG2 was predominantly detected at the plasma membrane, whereas ZDHHC3 knockdown caused a marked accumulation of CMG2 in the Golgi |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Human evidence corroborates the inherited plasma-membrane location. Reason: Human receptor-mediated toxin entry, surface biotinylation and imaging establish a plasma-membrane pool. The later human-cell studies independently support the location inferred by this ancestral annotation. Supporting Evidence: PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. file:human/ANTXR2/ANTXR2-notes.md PMID:42409807 In control cells, CMG2 was predominantly detected at the plasma membrane, whereas ZDHHC3 knockdown caused a marked accumulation of CMG2 in the Golgi |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic plasma-membrane mapping agrees with direct receptor evidence. Reason: The electronic plasma-membrane assignment agrees with direct human receptor expression, surface labeling and trafficking experiments. Supporting Evidence: PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. file:human/ANTXR2/ANTXR2-notes.md PMID:42409807 In control cells, CMG2 was predominantly detected at the plasma membrane, whereas ZDHHC3 knockdown caused a marked accumulation of CMG2 in the Golgi |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5210892 | ACCEPT | Summary: The receptor-bound toxin assembly is at the cell surface. Reason: The complete Reactome summary places EF/LF recruitment to receptor-bound PA at the cell surface. This supports receptor location, not direct binding of every toxin enzyme to ANTXR2. Supporting Evidence: Reactome:R-HSA-5210892 The enzyme components of anthrax toxins cya (also known as EF, Edema Factor - Robertson et al. 1988) and lef (also known as LF, Lethal Factor - Bragg & Robertson 1989; Klimpel et al. 1994) bind to pagA(197-794):ANTXR2 (protective antigen, large fragment: Anthrax receptor 2) oligomers on the target cell surface. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5210912 | ACCEPT | Summary: Furin processes receptor-bound protective antigen at the cell surface. Reason: The complete Reactome summary places host furin cleavage of bound PA at the plasma membrane, with receptor retaining the large PA fragment. Furin performs cleavage; ANTXR2 location is supported without assigning it protease activity. Supporting Evidence: Reactome:R-HSA-5210912 Furin or a related protease at the cell surface cleaves ANTXR2-bound pagA (Anthrax Protective Antigen, full-length). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5210918 | ACCEPT | Summary: The curated reaction explicitly places human ANTXR2 at the plasma membrane. Reason: The complete Reactome entry identifies human CMG2 toxin receptor at the surface and distinguishes surface isoforms. Its statement about uncertain LRP6 cofactor scope does not undermine receptor localization. Supporting Evidence: Reactome:R-HSA-5210918 Extracellular pagA (PA83, full length Protective Antigen - Petosa et al. 1997) produced by Bacillus anthracis binds to either of two isoforms of ANTXR2 (Anthrax Toxin Receptor 2, also known as CMG2 - Scobie et al. 2003) in the plasma membrane of a target human cell. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5210932 | ACCEPT | Summary: Receptor-bound protective antigen oligomerizes at the plasma membrane. Reason: The complete Reactome entry places receptor-bound PA oligomer assembly at the plasma membrane. PA oligomerization/pore chemistry belongs to PA, while ANTXR2 supplies surface receptor binding. Supporting Evidence: Reactome:R-HSA-5210932 ANTXR2 (Anthrax Receptor 2)-bound pagA(197-794) (protective antigen, large fragment) forms oligomers in the target cell plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5210959 | ACCEPT | Summary: The curated uptake reaction starts at the plasma membrane. Reason: The complete entry traces PA:ANTXR2 uptake from plasma membrane to endosome and supports both locations. A parenthetical receptor 1 naming inconsistency does not erase the stable ANTXR2 event or independent human surface evidence; canonical cache remains unchanged. Supporting Evidence: Reactome:R-HSA-5210959 cya (Anthrax EF, edema factor) and lef (LF, lethal factor) toxins bound to pagA(197-794):ANTXR2 (protective antigen, large fragment:Anthrax receptor 1) oligomer on the plasma membrane of the target cell, are localized into clathrin coated vesicles and transported to endosomes. PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: The extracellular receptor domain supports the external-face location. Reason: The extracellular VWA domain of full-length ANTXR2 is exposed on the outer face of the plasma membrane, where it recognizes extracellular ligand. This describes domain topology of a transmembrane receptor, rather than peripheral attachment of the entire protein. Supporting Evidence: PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. file:human/ANTXR2/ANTXR2-notes.md |
| GO:0009986 cell surface | IBA GO_REF:0000033 | ACCEPT | Summary: Human receptor evidence corroborates the inherited cell-surface location. Reason: Surface receptor function and surface labeling are established in human cells and corroborate the inherited cell-surface location. Supporting Evidence: PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. file:human/ANTXR2/ANTXR2-notes.md PMID:42409807 In control cells, CMG2 was predominantly detected at the plasma membrane, whereas ZDHHC3 knockdown caused a marked accumulation of CMG2 in the Golgi |
| GO:0009986 cell surface | IEA GO_REF:0000107 | ACCEPT | Summary: The orthology-based surface mapping agrees with human experiments. Reason: Direct human surface-receptor experiments corroborate the cell-surface location transferred from the mouse ortholog. Supporting Evidence: PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. file:human/ANTXR2/ANTXR2-notes.md PMID:42409807 In control cells, CMG2 was predominantly detected at the plasma membrane, whereas ZDHHC3 knockdown caused a marked accumulation of CMG2 in the Golgi |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-5210943 | ACCEPT | Summary: The endosomal receptor pool is distinct from the protective-antigen pore. Reason: The complete Reactome summary locates receptor-associated toxin in the endosomal membrane before low-pH receptor release and PA pore conversion. This is a genuine receptor trafficking compartment, not evidence that ANTXR2 forms the pore. Supporting Evidence: Reactome:R-HSA-5210943 Through the action of vacuolar ATPase the pH of the target cell early endosome is lowered. In this environment, paga (PA63, Anthrax protective antigen, large fragment) dissociates from its receptor and forms an oligomeric channel in the endosome membrane through which the anthrax cya (EF, edema factor) and lef (LF, lethal factor) pass (Milne et al. 1994). |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-5210959 | ACCEPT | Summary: The receptorβtoxin complex is transported into endosomes. Reason: The complete Reactome uptake entry carries receptor-bound PA from the cell surface into endosomes. Retain this experimentally coherent trafficking location; do not infer an intrinsic transporter or protease function. Supporting Evidence: Reactome:R-HSA-5210959 cya (Anthrax EF, edema factor) and lef (LF, lethal factor) toxins bound to pagA(197-794):ANTXR2 (protective antigen, large fragment:Anthrax receptor 1) oligomer on the plasma membrane of the target cell, are localized into clathrin coated vesicles and transported to endosomes. |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Broad membrane association encompasses the supported membrane products. Reason: Full-length ANTXR2 contains a membrane-spanning segment and is observed in plasma and endosomal membranes; the shorter historical product is associated with the endoplasmic reticulum. The broad membrane term is supported. Supporting Evidence: PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. file:human/ANTXR2/ANTXR2-notes.md |
| GO:0038023 signaling receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Domain-based receptor activity agrees with direct human signal coupling. Reason: Human ANTXR2 couples extracellular ligand engagement to Src-dependent phosphorylation and recruitment of beta-arrestin, RhoA and cytoskeletal partners. This is receptor signaling, without assigning intrinsic kinase or GTPase activity to ANTXR2. Supporting Evidence: PMID:28604699 This binding event leads to intracellular signals such as the src-dependent phosphorylation of CMG2 cytoplasmic tail and the recruitment of Ξ²-arrestin. PMID:28604699 Human CMG2 (isoform 4, Uniprot identifier P58335-4) was cloned in a pcDNA3.5/V5-HIS-TOPO expression vector. file:human/ANTXR2/ANTXR2-notes.md PMID:32428455 CMG2 binds talin, and thereby the actin cytoskeleton, only in its ligand-free state. Extracellular ligand binding leads to src-dependent talin release and recruitment of the actin cytoskeleton regulator RhoA and its effectors. PMID:42409807 These findings show that CMG2 must be S-acylated for it to transduce ligand binding information into cytosolic signalling |
| GO:0006898 receptor-mediated endocytosis | IMP PMID:28604699 CMG2/ANTXR2 regulates extracellular collagen VI which accumu... | NEW | Summary: ANTXR2 supplies ligand recognition and cytoplasmic recruitment during receptor-mediated uptake. Reason: ANTXR2 contributes the surface-recognition and cytoplasmic recruitment steps of endocytosis. In human cells, ligand exposure induces receptor phosphorylation and endogenous beta-arrestin association. ANTXR2 loss impairs collagen-VI lysosomal clearance while IgG internalization and degradation remain intact. These recruitment experiments establish receptor participation beyond a loss-of-function phenotype alone. Independent human CMG2 expression supports anthrax-toxin internalization, and receptor-tail switching studies corroborate its active role. The collagen assay measures clearance rather than initial uptake directly, and direct collagen-VI specificity remains disputed. ANTXR2 is not assigned clathrin assembly or lysosomal protease activity. Supporting Evidence: PMID:28604699 This binding event leads to intracellular signals such as the src-dependent phosphorylation of CMG2 cytoplasmic tail and the recruitment of Ξ²-arrestin. PMID:28604699 Thus, HFS patient fibroblasts essentially devoid of CMG2 protein are unable to degrade collagen VI. PMID:28604699 Loss of CMG2 does not have a pleiotropic effect on the endocytic pathway since internalization and lysosomal degradation of mouse IgGs was unaffected by CMG2 knockdown (Supplementary Fig. 6c). PMID:12700348 A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. PMID:32428455 CMG2 binds talin, and thereby the actin cytoskeleton, only in its ligand-free state. Extracellular ligand binding leads to src-dependent talin release and recruitment of the actin cytoskeleton regulator RhoA and its effectors. file:human/ANTXR2/ANTXR2-notes.md |
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Download this section (compressed HTML)Q: Which receptor species, constructs, modifications and collagen preparations account for the conflicting collagen-VI binding results, and which interactions occur at endogenous human receptor abundance?
Q: Is the predicted soluble isoform 3 translated and secreted in vivo despite its possible nonsense-mediated decay, and in which tissues?
Q: Does the preprint-reported direct F-actin interaction generalize across full-length human products, and how does it relate to the talin/vinculin-mediated interactions in published studies?
Q: Which receptor-bound adaptor directly connects ligand-engaged ANTXR2 to the vesicle coat, and can the cargo-receptor bridge be demonstrated separately from receptor signaling and downstream ligand degradation?
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