EPHB4

Summary: EPHB4 participates in angiogenesis through ephrin-dependent endothelial signaling.

Reason: The mammalian PTN000700012 IBD explicitly places angiogenesis in the clade containing human EPHB4 and mouse Ephb4. Actual tree descent and matching IBD provenance are verified; target appearance among descendant evidence is legitimate. The accessible PMID:10518221 abstract independently reports an endothelial EphB4 mutation phenotype and an angiogenic role, while its full original remains unavailable. This supports the conserved receptor-mediated vascular role without claiming to have read the original developmental assays.

Summary: EphB4-dependent endothelial signaling contributes to angiogenesis.

Reason: The original PMID:12734395 Methods/Results remain unavailable; its verified abstract is not used to infer assay details. The verified mammalian EPHB4 PAINT assertion is supported by the actual receptor biology and independent vascular experiments. PMID:16424904 Results Figures 2–5 and 7–8 manipulate EphB4 in proliferating mouse endothelium and examine tumor/retinal vascular remodeling, branching and sprouting. Both full-length and kinase-truncated reagents affect vascular architecture, implicating bidirectional EphB4/ephrin-B2 signaling rather than proving that every vascular effect is caused by forward kinase signaling. These artificial reagents do not establish the functions of natural short human products.

Summary: The combined electronic angiogenesis assertion agrees with the independently supported endothelial receptor role.

Reason: Current ARBA00090097 explicitly emits GO:0001525, and the combined source also names mouse Ephb4. Its full FunFam eligibility was not independently reconstructed from the target UniProt record, which does not expose those assignments. Biological acceptance rests on the verified EPHB4 ancestral assertion and inspected vascular experiments, not an assumed rule match. The verified mammalian EPHB4 PAINT assertion is supported by the actual receptor biology and independent vascular experiments. PMID:16424904 Results Figures 2–5 and 7–8 manipulate EphB4 in proliferating mouse endothelium and examine tumor/retinal vascular remodeling, branching and sprouting. Both full-length and kinase-truncated reagents affect vascular architecture, implicating bidirectional EphB4/ephrin-B2 signaling rather than proving that every vascular effect is caused by forward kinase signaling. These artificial reagents do not establish the functions of natural short human products.

Summary: Angiogenesis is a supported EphB4 function, with the cited human disease study providing contextual receptor evidence.

Reason: PMID:28687708 reports CM-AVM2 and altered abundance/localization/activation of EPHB4 constructs; its operative main text and supplementary Methods were recovered as author-uploaded original text. Those disease/construct results alone do not identify every step of new-vessel formation. The general angiogenesis role is retained using the independently inspected vascular experiments and valid PAINT assertion. The verified mammalian EPHB4 PAINT assertion is supported by the actual receptor biology and independent vascular experiments. PMID:16424904 Results Figures 2–5 and 7–8 manipulate EphB4 in proliferating mouse endothelium and examine tumor/retinal vascular remodeling, branching and sprouting. Both full-length and kinase-truncated reagents affect vascular architecture, implicating bidirectional EphB4/ephrin-B2 signaling rather than proving that every vascular effect is caused by forward kinase signaling. These artificial reagents do not establish the functions of natural short human products.

Summary: Angiogenesis is supported independently of the specific vein-of-Galen disease phenotype.

Reason: PMID:30578106 STAR Methods and Figure 4 use HA-tagged mouse Ephb4 in human HEK293T cells to examine phosphorylation and Ras-GAP association. That construct evidence must not be relabeled a direct human-protein assay or equated with all angiogenic steps. The broad process is retained because it is independently supported by the conserved receptor role and inspected vascular experiments. The verified mammalian EPHB4 PAINT assertion is supported by the actual receptor biology and independent vascular experiments. PMID:16424904 Results Figures 2–5 and 7–8 manipulate EphB4 in proliferating mouse endothelium and examine tumor/retinal vascular remodeling, branching and sprouting. Both full-length and kinase-truncated reagents affect vascular architecture, implicating bidirectional EphB4/ephrin-B2 signaling rather than proving that every vascular effect is caused by forward kinase signaling. These artificial reagents do not establish the functions of natural short human products.

Summary: The specific cell-migration component of sprouting angiogenesis remains source-limited.

Reason: The current term concerns cell movement associated with sprouting new vessels. PMID:12734395 is available here as verified abstract/preview, but its full operative migration and sprouting experiments could not be inspected. PMID:16424904 supports vascular remodeling and altered sprouting; PMID:22555806 supports human receptor signaling and growth responses. Neither inspected evidence set independently resolves the exact migration assertion and its experimental conditions. Preserve uncertainty rather than infer absence of migration from incomplete access.

Summary: The mouse heart-morphogenesis donor is real, but its specific experimental support remains unresolved.

Reason: The donor is verified mouse Ephb4 (UniProtKB:P54761), not another Eph receptor. Current QuickGO and UniProt retain a genuine IMP heart-morphogenesis annotation to PMID:10518221. The accessible abstract supports vascular endothelial EphB4 and angiogenesis but does not specify the heart-generation or organization experiments required to assess GO:0003007. The full original was unavailable in the documented access attempt. Orthology is supported by the actual PANTHER tree and matching MSA sequences; the unresolved point is the heart-specific experimental scope, not absence of a donor or a demonstrated transfer error.

Summary: The mouse heart-morphogenesis donor is real, but its specific experimental support remains unresolved.

Reason: The donor is verified mouse Ephb4 (UniProtKB:P54761), not another Eph receptor. Current QuickGO and UniProt retain a genuine IMP heart-morphogenesis annotation to PMID:10518221. The accessible abstract supports vascular endothelial EphB4 and angiogenesis but does not specify the heart-generation or organization experiments required to assess GO:0003007. The full original was unavailable in the documented access attempt. Orthology is supported by the actual PANTHER tree and matching MSA sequences; the unresolved point is the heart-specific experimental scope, not absence of a donor or a demonstrated transfer error.

Summary: EPHB4 is an active receptor for transmembrane ephrin-B ligands.

Reason: The actual IPR001245/IPR008266 mappings correctly identify protein kinase activity but are less specific than the experimentally established receptor role. The current GO:0005005 term specifies activation by a transmembrane ephrin and is a descendant of ephrin receptor and receptor tyrosine kinase activities. Human EPHB4 responds to ephrin-B2 in cell-based activation assays (PMID:27400125, receptor-phosphorylation experiments; PMID:22555806, Figures 1–3), while purified human EPHB4 residues 588–987 catalyze phosphorylation in PMID:34431498 Methods and Figure 4. Those domain reagents are not full-length receptor preparations. This specificity concerns the canonical membrane receptor; it is not assigned indiscriminately to the three short splice products.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: EPHB4 is an active receptor for transmembrane ephrin-B ligands.

Reason: The actual IPR020635 mapping and current RHEA:10596 record specify ATP-dependent phosphorylation of protein tyrosine. The chemistry is supported, but the generic tyrosine-kinase term is less informative than the established ligand-gated receptor activity. The current GO:0005005 term specifies activation by a transmembrane ephrin and is a descendant of ephrin receptor and receptor tyrosine kinase activities. Human EPHB4 responds to ephrin-B2 in cell-based activation assays (PMID:27400125, receptor-phosphorylation experiments; PMID:22555806, Figures 1–3), while purified human EPHB4 residues 588–987 catalyze phosphorylation in PMID:34431498 Methods and Figure 4. Those domain reagents are not full-length receptor preparations. This specificity concerns the canonical membrane receptor; it is not assigned indiscriminately to the three short splice products.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: EPHB4 is an active receptor for transmembrane ephrin-B ligands.

Reason: The PTN001230349 IBD and target descent are valid and support the inherited receptor-kinase mechanism. Refine the broad inherited term to the experimentally established ephrin-B receptor specificity without alleging a phylogenetic failure. The current GO:0005005 term specifies activation by a transmembrane ephrin and is a descendant of ephrin receptor and receptor tyrosine kinase activities. Human EPHB4 responds to ephrin-B2 in cell-based activation assays (PMID:27400125, receptor-phosphorylation experiments; PMID:22555806, Figures 1–3), while purified human EPHB4 residues 588–987 catalyze phosphorylation in PMID:34431498 Methods and Figure 4. Those domain reagents are not full-length receptor preparations. This specificity concerns the canonical membrane receptor; it is not assigned indiscriminately to the three short splice products.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: EPHB4 is an active receptor for transmembrane ephrin-B ligands.

Reason: The operative paper directly tests purified human EPHB4 kinase-domain-containing residues 588–987, despite its title foregrounding Eph pseudokinases. Its WT and juxtamembrane-mutant proteins phosphorylate EPHB6 (Figure 4); it does not alone test ligand activation of full-length EPHB4. Independent intact-receptor experiments supply that context. The current GO:0005005 term specifies activation by a transmembrane ephrin and is a descendant of ephrin receptor and receptor tyrosine kinase activities. Human EPHB4 responds to ephrin-B2 in cell-based activation assays (PMID:27400125, receptor-phosphorylation experiments; PMID:22555806, Figures 1–3), while purified human EPHB4 residues 588–987 catalyze phosphorylation in PMID:34431498 Methods and Figure 4. Those domain reagents are not full-length receptor preparations. This specificity concerns the canonical membrane receptor; it is not assigned indiscriminately to the three short splice products.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: EPHB4 is an active receptor for transmembrane ephrin-B ligands.

Reason: EC 2.7.10.1 correctly represents receptor tyrosine kinase chemistry. Refine the broad enzyme class to the established ephrin-B-triggered receptor activity. The current GO:0005005 term specifies activation by a transmembrane ephrin and is a descendant of ephrin receptor and receptor tyrosine kinase activities. Human EPHB4 responds to ephrin-B2 in cell-based activation assays (PMID:27400125, receptor-phosphorylation experiments; PMID:22555806, Figures 1–3), while purified human EPHB4 residues 588–987 catalyze phosphorylation in PMID:34431498 Methods and Figure 4. Those domain reagents are not full-length receptor preparations. This specificity concerns the canonical membrane receptor; it is not assigned indiscriminately to the three short splice products.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: EPHB4 is an active receptor for transmembrane ephrin-B ligands.

Reason: The cited PMID:12734395 main original is unavailable here. Independent human receptor experiments establish the same function and its transmembrane ephrin-B ligand specificity; no claim is made to have inspected the original cell-segregation assays. The current GO:0005005 term specifies activation by a transmembrane ephrin and is a descendant of ephrin receptor and receptor tyrosine kinase activities. Human EPHB4 responds to ephrin-B2 in cell-based activation assays (PMID:27400125, receptor-phosphorylation experiments; PMID:22555806, Figures 1–3), while purified human EPHB4 residues 588–987 catalyze phosphorylation in PMID:34431498 Methods and Figure 4. Those domain reagents are not full-length receptor preparations. This specificity concerns the canonical membrane receptor; it is not assigned indiscriminately to the three short splice products.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: EPHB4 is an active receptor for transmembrane ephrin-B ligands.

Reason: PMID:15930280 remains abstract-only after bounded publisher attempts. Independent human receptor assays establish ephrin-B2 recognition and activation, so the general receptor function is not left undecided solely because this source is inaccessible. The current GO:0005005 term specifies activation by a transmembrane ephrin and is a descendant of ephrin receptor and receptor tyrosine kinase activities. Human EPHB4 responds to ephrin-B2 in cell-based activation assays (PMID:27400125, receptor-phosphorylation experiments; PMID:22555806, Figures 1–3), while purified human EPHB4 residues 588–987 catalyze phosphorylation in PMID:34431498 Methods and Figure 4. Those domain reagents are not full-length receptor preparations. This specificity concerns the canonical membrane receptor; it is not assigned indiscriminately to the three short splice products.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: EPHB4 is an active receptor for transmembrane ephrin-B ligands.

Reason: The verified original and linked human EphB4–ephrin-B2 structural entry support ligand specificity, but the complete PMID:16867992 Methods/Results were not recovered. Independent binding/activation assays establish the more specific receptor function; structural partner binding is not by itself a full signaling assay. The current GO:0005005 term specifies activation by a transmembrane ephrin and is a descendant of ephrin receptor and receptor tyrosine kinase activities. Human EPHB4 responds to ephrin-B2 in cell-based activation assays (PMID:27400125, receptor-phosphorylation experiments; PMID:22555806, Figures 1–3), while purified human EPHB4 residues 588–987 catalyze phosphorylation in PMID:34431498 Methods and Figure 4. Those domain reagents are not full-length receptor preparations. This specificity concerns the canonical membrane receptor; it is not assigned indiscriminately to the three short splice products.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: EPHB4 is an active receptor for transmembrane ephrin-B ligands.

Reason: The original publisher-indexed Results/Figure 1–3 captions report human HUVEC/MCF-7 receptor activation, EPHB4-versus-EPHB2 knockdown controls and a selective agonist antibody. Publisher-indexed cell-line/reagent, proliferation and siRNA Methods were also recovered; a complete downloadable main text and complete Methods remained inaccessible. Opposite ERK responses in the two cell types do not invalidate the receptor activity and are not generalized to one signed pathway effect. The current GO:0005005 term specifies activation by a transmembrane ephrin and is a descendant of ephrin receptor and receptor tyrosine kinase activities. Human EPHB4 responds to ephrin-B2 in cell-based activation assays (PMID:27400125, receptor-phosphorylation experiments; PMID:22555806, Figures 1–3), while purified human EPHB4 residues 588–987 catalyze phosphorylation in PMID:34431498 Methods and Figure 4. Those domain reagents are not full-length receptor preparations. This specificity concerns the canonical membrane receptor; it is not assigned indiscriminately to the three short splice products.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: EPHB4 is an active receptor for transmembrane ephrin-B ligands.

Reason: PMID:8188704 remains limited to verified abstract and partial original text; its title is not treated as evidence of a different target. Independent human receptor and kinase experiments establish the specific function. The current GO:0005005 term specifies activation by a transmembrane ephrin and is a descendant of ephrin receptor and receptor tyrosine kinase activities. Human EPHB4 responds to ephrin-B2 in cell-based activation assays (PMID:27400125, receptor-phosphorylation experiments; PMID:22555806, Figures 1–3), while purified human EPHB4 residues 588–987 catalyze phosphorylation in PMID:34431498 Methods and Figure 4. Those domain reagents are not full-length receptor preparations. This specificity concerns the canonical membrane receptor; it is not assigned indiscriminately to the three short splice products.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: EPHB4 is an active receptor for transmembrane ephrin-B ligands.

Reason: The actual IPR001426/IPR016257 maps and ARBA00086040 output identify the Eph receptor family. The ARBA target FunFam-condition match was not fully reconstructed. Independent EPHB4 binding and activation evidence supports refinement from the family-wide term to transmembrane-ephrin receptor activity. The current GO:0005005 term specifies activation by a transmembrane ephrin and is a descendant of ephrin receptor and receptor tyrosine kinase activities. Human EPHB4 responds to ephrin-B2 in cell-based activation assays (PMID:27400125, receptor-phosphorylation experiments; PMID:22555806, Figures 1–3), while purified human EPHB4 residues 588–987 catalyze phosphorylation in PMID:34431498 Methods and Figure 4. Those domain reagents are not full-length receptor preparations. This specificity concerns the canonical membrane receptor; it is not assigned indiscriminately to the three short splice products.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: Selected human tumor-cell models show erythropoietin-dependent EphB4 binding and receptor signaling.

Reason: PMID:26481148 establishes both EPO binding and an EPHB4-dependent cellular response in the tested models. Figure 1 measures binding of purified recombinant EPO to EphB4 by microscale thermophoresis and competition with ephrin-B2 by surface plasmon resonance. Figure 2 shows radiolabeled EPO binding in human A2780 cells after EPOR knockdown, whereas combined EPOR/EPHB4 knockdown eliminates detectable binding; expression in receptor-negative COS-1 cells provides a separate receptor-addition control. Figure 3 shows EPO-induced EphB4 phosphorylation and distinguishes EphB4-dependent SRC/STAT3 activation from the EPOR-dependent JAK2/STAT5 response using the receptor-knockdown cells. Binding coupled to receptor-dependent signal transmission satisfies the current GO:0004900 definition, justifying this specific replacement rather than generic binding. This is a contextual molecular function from the 2015 study, not a second core or a claim about normal erythropoiesis. Apparent affinity is lower than the EPOR comparison, and the inspected main Methods do not fully specify the commercial recombinant boundaries; neither observation erases the positive binding and signaling controls or establishes equal activity of the shorter natural products.

Proposed replacements: erythropoietin receptor activity

Summary: The ephrin-B2 interaction is part of the specific EphB4 receptor activity.

Reason: PMID:26481148 Methods and Figure 1 directly measure recombinant EphB4–ephrin-B2 binding; the cellular ligand response is reported separately. Independent recombinant binding and human cell-activation experiments establish the ligand/receptor role (PMID:26481148 Figure 1; PMID:27400125 activation assays; PMID:22555806 Figures 1–3). Refine generic binding to transmembrane-ephrin receptor activity, without treating AP-MS or proximity alone as proof of a native binary geometry.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: The ephrin-B2 interaction is part of the specific EphB4 receptor activity.

Reason: The actual BioPlex 2 network contains EFNB2 bait/P52799 and EPHB4 prey/P54760. Methods use human tagged-bait AP-MS in cultured cells; co-recovery alone is not binary reconstitution. Independent recombinant binding and human cell-activation experiments establish the ligand/receptor role (PMID:26481148 Figure 1; PMID:27400125 activation assays; PMID:22555806 Figures 1–3). Refine generic binding to transmembrane-ephrin receptor activity, without treating AP-MS or proximity alone as proof of a native binary geometry.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: EPHB4 associates with the RAS GTPase-activating protein RASA1/p120-RasGAP.

Reason: PMID:30578106 Figure 4E and STAR Methods show Ras-GAP co-immunoprecipitation with HA-tagged mouse Ephb4 expressed in human HEK293T cells, with reduced/absent association for kinase-domain disease-model mutants. The construct is mouse, not human simply because of its host. This conserved receptor–GAP association supports a partner-specific refinement to GTPase activating protein binding; PMID:22555806 Figure 5 additionally supports functional RasGAP coupling in human HUVECs but is not a direct binary binding assay. No GAP catalytic activity, exact human binary affinity, or equivalence of all splice products is assigned.

Proposed replacements: GTPase activating protein binding

Summary: The ephrin-B2 interaction is part of the specific EphB4 receptor activity.

Reason: The official BioPlex 3 HEK293T network contains the EFNB2–EPHB4 pair. The normal article cache does not contain the complete Methods, so dataset access is distinguished from a complete original-paper read. Independent recombinant binding and human cell-activation experiments establish the ligand/receptor role (PMID:26481148 Figure 1; PMID:27400125 activation assays; PMID:22555806 Figures 1–3). Refine generic binding to transmembrane-ephrin receptor activity, without treating AP-MS or proximity alone as proof of a native binary geometry.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: The ephrin-B2 interaction is part of the specific EphB4 receptor activity.

Reason: The actual Dataset EV1A contains EPHB4 WT AP-MS with EFNB2 (Excel row 5493), and other proximity/kinase-dead contexts. The screen uses tagged human receptors in HEK293 cells and pervanadate, not a normal tissue response. Independent recombinant binding and human cell-activation experiments establish the ligand/receptor role (PMID:26481148 Figure 1; PMID:27400125 activation assays; PMID:22555806 Figures 1–3). Refine generic binding to transmembrane-ephrin receptor activity, without treating AP-MS or proximity alone as proof of a native binary geometry.

Proposed replacements: transmembrane-ephrin receptor activity

Summary: The human RTK interactome detects EPHB4 association with EPHA5.

Reason: PMID:35384245 actual Dataset EV1A, Excel row 1792, records WT EPHA5 AP-MS recovery of the partner. The experiment uses tagged human receptors in HEK293 cells with pervanadate treatment. The current GO:0046875 term captures binding to an Eph receptor more specifically than generic protein binding. This complex-association evidence does not establish a binary ectodomain interface, ligand agonism, native trans orientation, or a newly measured receptor stoichiometry; target-specific co-IP validation was not found in EV1C. GO:0046875 names the Eph receptor partner class; it does not require ephrin identity or ligand agonism. Here the refinement records physical association in the specified affinity-purified complex, without asserting an isolated binary interface.

Proposed replacements: ephrin receptor binding

Summary: The human RTK interactome detects EPHB4 association with EPHA7.

Reason: PMID:35384245 actual Dataset EV1A, Excel row 1751, records WT EPHA7 AP-MS recovery of the partner. The experiment uses tagged human receptors in HEK293 cells with pervanadate treatment. The current GO:0046875 term captures binding to an Eph receptor more specifically than generic protein binding. This complex-association evidence does not establish a binary ectodomain interface, ligand agonism, native trans orientation, or a newly measured receptor stoichiometry; target-specific co-IP validation was not found in EV1C. GO:0046875 names the Eph receptor partner class; it does not require ephrin identity or ligand agonism. Here the refinement records physical association in the specified affinity-purified complex, without asserting an isolated binary interface.

Proposed replacements: ephrin receptor binding

Summary: The human RTK interactome detects EPHB4 association with EPHA6.

Reason: PMID:35384245 actual Dataset EV1A, Excel row 5498, records WT EPHB4 AP-MS recovery of the partner. The experiment uses tagged human receptors in HEK293 cells with pervanadate treatment. The current GO:0046875 term captures binding to an Eph receptor more specifically than generic protein binding. This complex-association evidence does not establish a binary ectodomain interface, ligand agonism, native trans orientation, or a newly measured receptor stoichiometry; target-specific co-IP validation was not found in EV1C. GO:0046875 names the Eph receptor partner class; it does not require ephrin identity or ligand agonism. Here the refinement records physical association in the specified affinity-purified complex, without asserting an isolated binary interface.

Proposed replacements: ephrin receptor binding

Summary: The specific EPHB4–EFNB2 interaction in the 2025 AP-MS dataset remains unadjudicated.

Reason: The actual PMID:40205054 U2OS AP-MS Methods were read, but the EPHB4–EFNB2 target pair was not independently located in the recovered Supplementary Tables 1–10. A negative targeted search is not proof that the interaction is absent or false. Retain this source-specific assertion as unresolved pending the exact dataset record. Independent recombinant binding and receptor-activation experiments establish the general EphB4–ephrin-B2 function elsewhere in the review, but do not verify this particular AP-MS observation.

Summary: ATP binding supports the catalytic activity of the displayed EphB4 kinase.

Reason: The actual InterPro mappings identify the kinase ATP-binding machinery. PMID:34431498 Methods and Figure 4 use purified human EPHB4 588–987 with ATP/Mg2+ and detect autophosphorylation and EPHB6 phosphorylation. Current RHEA:10596 explicitly uses ATP for protein-tyrosine phosphorylation. This is a catalytic co-substrate-binding property of the kinase-containing product, not evidence that the three natural short products retain an ATP-binding kinase domain.

Summary: Reactome explicitly models an extracellular EPHB4 cleavage fragment; direct EPHB4 support for that processing remains unresolved.

Reason: R-HSA-3928657 outputs set R-HSA-3928488, whose member R-HSA-3928420 is a human P54760 N-terminal fragment in GO:0005576. Thus the annotation has an exact participant-level source even though the event itself is assigned plasma membrane. Actual PMID:18713744 Methods and Figures 1-3 assay endogenous or recombinant mouse EphB2 and chicken EphB2; the EphB2-4/5 name denotes cleavage-site mutants, not EPHB4. Its Discussion proposes broader Eph-family cleavage from site conservation, but that is not a direct EPHB4 assay. PMID:17428795 Methods and Figures 1-2 likewise assay murine EphB2, including its released extracellular fragment. Retain uncertainty about the family-level cleavage extension without declaring the source target absent, inferring an impossible location from full-length topology, or assigning experimental EphB2 cut sites to EPHB4.

Summary: Reactome explicitly models a cytosolic EPHB4 cleavage fragment; direct EPHB4 release by gamma-secretase remains unresolved.

Reason: R-HSA-3928656 outputs set R-HSA-3928494, whose member R-HSA-3928406 is a human P54760 C-terminal fragment in GO:0005829. This is a traceable fragment assertion, not a claim that intact EPHB4 is freely cytosolic. PMID:17428795 Experimental Procedures and Figure 1C-D establish presenilin-dependent processing of murine EphB2 in mouse fibroblast membranes and transfected HEK293T cells; Figure 2 and processing-site Results identify mouse EphB2 products. The human host cell does not make the tested construct human EPHB4. PMID:18713744 also tests mouse/chicken EphB2 cleavage, and the additional event citation PMID:16511561 was not independently read in this bounded lane. The exact Reactome entity is verified, but the inspected evidence does not resolve the transfer of this processing mechanism to human EPHB4; neither REMOVE nor a claim of absent EPHB4 processing is justified.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: The author-uploaded original PMID:28687708 Figure 2 legend/Results shows membranous WT EGFP-EPHB4 staining in COS-7 and altered mutant abundance/localization; the exact construct species/isoform is not stated in the inspected Methods. Independent human receptor evidence supports the same compartment. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: The actual PTN001230349 IBD lies above the human leaf and supports plasma-membrane activity; there is no demonstrated target-specific loss. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: The cited older original is not fully accessible here, but independent human cell-surface binding, activation and imaging establish the same compartment. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: The cited older original is not fully accessible here, but independent human cell-surface binding, activation and imaging establish the same compartment. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: The actual IPR016257 mapping and UniProt SL-0039 correctly identify plasma membrane. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928578, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928591, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928592, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928595, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928597, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928598, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928601, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928604, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928607, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928612, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928614, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928615, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928617, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928624, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928625, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928627, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928628, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928631, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928633, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928639, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928640, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928641, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928645, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928654, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928656, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-3928657, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-4093329, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-4093331, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-4093332, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-4093336, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The intact EphB4 receptor is active at the plasma membrane.

Reason: This row asserts the plasma-membrane location in Reactome:R-HSA-4093339, not that EPHB4 catalyzes every named downstream reaction. The intact receptor location is independently established by its topology and human cell-surface ligand binding/activation and receptor imaging. The separately modeled extracellular/cytosolic fragment claims remain independently undecided. PMID:27400125 uses human receptor activation constructs; PMID:26481148 Figures 2–3 uses surface radioligand/receptor-dependent signaling; PMID:35384245 Figure EV2 includes the tagged human EPHB4 localization. A cytoplasmic kinase domain does not make the intact receptor a freely cytosolic protein, and truncated source products are not automatically assigned this location.

Summary: The exact cell-adhesion assertion remains limited by access to its operative source.

Reason: PMID:12734395 reports endothelial repulsion/segregation in its verified abstract, but the complete adhesion assay, substrate and signaling conditions were not recovered. Independently established ephrin binding and vascular remodeling do not alone distinguish adhesive attachment from repulsion or prove this source-specific GO:0007155 claim. Preserve uncertainty without asserting that the original experimental annotation is wrong.

Summary: The specific receptor pathway is ephrin receptor signaling.

Reason: The actual IPR001426/IPR016257 mappings assign the broad receptor-tyrosine-kinase pathway. EPHB4 is the ligand-binding and kinase-signaling participant in the more specific ephrin receptor pathway, already supported by its valid mammalian IBD and human ligand-activation experiments. This is refinement of an existing process, not a new downstream process inferred merely from perturbation.

Proposed replacements: ephrin receptor signaling pathway

Summary: The displayed receptor is specifically a plasma-membrane protein.

Reason: The IPR001426 mapping is a valid but broad membrane annotation. Existing plasma-membrane rows and independent cell-surface receptor assays identify the specific compartment. Refine to plasma membrane for the intact receptor without asserting that all natural short products are membrane anchored.

Proposed replacements: plasma membrane

Summary: EPHB4 participates in a signaling receptor complex.

Reason: The positive GO:0043235 IBD is assigned to PTN001230349 and reaches the verified EPHB4 leaf. The current term covers protein complexes that bind a signal and initiate a cellular change, fitting ephrin-bound receptor assemblies. The target UniProt record supports ligand-dependent receptor association, with oligomeric detail explicitly qualified as similarity-based. Acceptance of the broad complex membership does not assert that an exact human tetramer stoichiometry was independently demonstrated in this lane.

Summary: Ephrin receptor signaling is a conserved direct role of EPHB4.

Reason: The GO:0048013 IBD is present at the verified mammalian PTN000700012 ancestor of human EPHB4 and mouse Ephb4. EPHB4 supplies the signal-binding receptor and catalytic transduction machinery rather than merely undergoing a downstream phenotype. The current donor IMP and the accessible PMID:10518221 abstract independently support EphB4-ephrin-B2 signaling; the original developmental experiments were not recovered. This agrees with the phylogenetic judgment without treating the target as a circular source.

Summary: EPHB4 directly transduces ephrin-dependent signals.

Reason: The complete original PMID:12734395 remains unavailable, but independent human receptor experiments establish the same pathway: ephrin-B2-dependent receptor phosphorylation in PMID:27400125 and receptor-selective knockdown/agonist controls in PMID:22555806 Figures 1–3. EPHB4 is the receptor/kinase performing signal transduction, not just a downstream phenotype-associated gene. Cell-context-dependent ERK direction does not negate the general ephrin receptor pathway.

Summary: Transfer of the mouse ephrin receptor signaling function to human EPHB4 is supported.

Reason: The current mouse P54761 record contains a genuine IMP GO:0048013 assertion from PMID:10518221 in addition to inferred records. Therefore the inspected donor chain is not solely a reciprocal electronic transfer. The original remains unavailable, but its accessible abstract explicitly identifies EphB4-ephrin-B2 interaction and signaling in endothelial angiogenesis. The human receptor identity, actual shared Ephb4 tree placement and conserved receptor mechanism support this broad pathway assertion; they do not by themselves resolve the more specific heart-morphogenesis rows.

Summary: The target-specific exosome proteomics detection was not independently recovered.

Reason: The inspected PMID:23533145 Methods describe expressed-prostatic-secretion urine pools, differential ultracentrifugation and LC-MS/MS; Results refer to the protein inventory in Supplemental Table 2. That target-level table could not be recovered from the tested original supplement routes, so the precise EPHB4 identification and peptide evidence remain unchecked. The plasma-membrane topology neither verifies nor disproves vesicle occurrence. Preserve this high-throughput annotation as uncertain without converting occurrence into an exosome-biogenesis function.