CCM2

Summary: Retain vasculogenesis as a non-core developmental context.

Reason: Retain the PAINT inference in light of vertebrate vascular phenotypes and direct human endothelial tube-formation evidence in PMID:19151727. The WITH/FROM occurrence of Q9BSQ5 is expected when a target experimental annotation contributed to the ancestral assertion; it is not circular. No target-specific loss or divergence is established. This broad developmental outcome is retained as non-core; the synthesis selects the specific endothelial tube-morphogenesis context of the signaling-adaptor mechanism.

Summary: Retain vasculogenesis as a non-core developmental context.

Reason: CCM2 coordinates signaling needed for vascular endothelial organization. Existing experimental and phylogenetic annotations converge on this role, so the electronic assertion is retained without treating it as an independent experiment. This broad developmental outcome is retained as non-core; the synthesis selects the specific endothelial tube-morphogenesis context of the signaling-adaptor mechanism.

Summary: Retain vasculogenesis as a non-core developmental context.

Reason: The available PMID:14740320 abstract establishes human CCM2 genetics, not a directly observed vasculogenesis assay. Its full text was not available for checking the assigned IMP experiment. The function is independently supported by human endothelial experiments in PMID:19151727 and vertebrate studies, so retain the existing curator assertion rather than infer a citation error from an abstract alone. This broad developmental outcome is retained as non-core; the synthesis selects the specific endothelial tube-morphogenesis context of the signaling-adaptor mechanism.

Summary: Retain endothelium development as a non-core developmental context.

Reason: The ARBA assertion agrees with the CCM signaling complex and the endothelial morphogenesis phenotype. This broad developmental annotation is retained; the core synthesis uses the existing, more specific endothelial tube-morphogenesis term. This broad developmental outcome is retained as non-core; the synthesis selects the specific endothelial tube-morphogenesis context of the signaling-adaptor mechanism.

Summary: Retain endothelium development as a non-core developmental context.

Reason: PMID:17657516 describes CCM2-containing signaling complexes relevant to vascular development. Its accessible abstract does not report a new CCM2 endothelial differentiation assay, and the NAS code is preserved. Independent human endothelial evidence supports the biological role without promoting this row to experimental evidence. This broad developmental outcome is retained as non-core; the synthesis selects the specific endothelial tube-morphogenesis context of the signaling-adaptor mechanism.

Summary: Refine generic binding to signaling adaptor activity.

Reason: PMID:16037064 reports PTB-dependent KRIT1 association, altered KRIT1 localization and a KRIT1-CCM2-MEKK3 ternary complex, supporting signaling adaptor activity beyond one binding event. The original OSM study (PMID:14634666) also includes MKK3: the literature is not limited to a single kinase partner. Its mouse OSM scaffold experiments provide conserved osmotic-stress context; they are not relabelled as direct human endothelial assays. Retain GO:0035591 for this human interaction source and the broader CCM mechanism, without manufacturing a second function from the ortholog study.

Proposed replacements: signaling adaptor activity

Summary: Retain the reported CCM2-KRIT1 association as supporting interaction evidence.

Reason: The exact O00522/KRIT1 interaction is consistent with targeted CCM-complex studies, including PMID:16037064 and PMID:25525273. PMID:17657516 is available here as an abstract focused on CCM3, so its title and emphasis do not establish that the KRIT1 assay was absent. Generic protein binding does not specify the coordinated adaptor function and is retained as non-core interaction evidence.

Summary: Retain the reported CCM2-PDCD10/CCM3 association.

Reason: The PMID:17657516 abstract explicitly reports CCM3 coprecipitation and colocalization with CCM2. Those results support the curated association, while direct STK25 binding, phosphorylation and FAP-1 dephosphorylation in the abstract concern CCM3. None of those enzymatic activities is assigned to CCM2. The generic binding term is supporting non-core evidence for its adaptor role.

Summary: The CCM3 structural study also directly tests its interaction with CCM2.

Reason: The selected primary Results and Methods of PMID:20489202 include binding of CCM3 to a CCM2 construct spanning residues 51-251. This establishes target relevance despite the CCM3-focused title. That construct includes the region after the narrower PTB fold; it must not be read as proving that the isolated PTB domain or the CCM2 C-terminal HHD binds CCM3. Retain the pairwise binding evidence outside the core molecular-function label.

Summary: Retain the KRIT1 interaction associated with junctional assembly of the CCM complex.

Reason: The PMID:23007647 abstract and the independent CCM2-KRIT1 structural study support the association with O00522. HEG1 recruits the complex through KRIT1, so membership in that assembly does not itself establish direct CCM2-HEG1 binding. The generic binding assertion is retained as non-core support; the canonical abstract-only cache is unchanged.

Summary: CCM2 binds CCM3 through a region distinct from its isolated HHD.

Reason: Selected Results in PMID:23266514 show CCM3 association with full-length CCM2 but not the isolated C-terminal HHD, and place the relevant segment after the PTB domain. The weak crystallographic HHD dimer does not establish a stable physiological CCM2 homodimer; solution analysis supports a monomer. Preserve the Q9BUL8/PDCD10 interaction without inventing a catalytic activity or relocating its binding site.

Summary: Structural evidence supports CCM2 PTB-domain binding to KRIT1.

Reason: PMID:25525273 describes the CCM2-KRIT1 interface and disruption by disease-associated mutations. This is strong pairwise interaction evidence. A PTB-domain name alone does not establish that this interaction requires phosphotyrosine. Retain the generic binding assertion as non-core support for the independently specified adaptor function.

Summary: Retain the reported KRIT1 interaction from the phosphotyrosine interaction survey.

Reason: Preserve the exact O00522 partner and IPI provenance in PMID:25814554. KRIT1 association is independently established, but the survey title does not prove a phosphotyrosine requirement for this particular edge. Its target-specific supplemental assay details were not inspected. Generic binding remains supporting interaction evidence rather than the core functional description.

Summary: Retain the reported Q8TEW6 interaction with its screen-specific scope.

Reason: The positive curated IPI edge in PMID:25814554 is preserved. The accessible study describes a phosphotyrosine interaction survey, but the target-specific assay table was not inspected; neither a phosphorylation requirement for this edge nor a new endothelial mechanism is inferred. Retain generic binding as non-core experimental interaction evidence.

Summary: Retain the reported Q8WVJ9 interaction with its screen-specific scope.

Reason: Preserve the exact partner and experimental IPI provenance from PMID:25814554. The survey-level description cannot establish the phosphorylation state or physiological role of this individual CCM2 interaction. With no contradictory target evidence, retain the association as non-core rather than turn the missing supplemental detail into a negative claim.

Summary: Retain the reported Q96N03 interaction with its screen-specific scope.

Reason: The curated PMID:25814554 IPI assertion records an interaction with this exact accession. Target-specific table details were unavailable to this review, so no dependency on phosphorylation or additional pathway is assigned. Generic binding is retained as non-core positive interaction evidence.

Summary: Retain the KRIT1 interaction studied in a disease-variant interaction framework.

Reason: PMID:25910212 investigates interaction perturbations caused by human disease variants. Preserve its exact O00522 edge without assuming that every variant or assay context has the same effect. Independent targeted CCM2-KRIT1 evidence supports the association; the generic binding term is non-core and does not describe the whole adaptor mechanism.

Summary: Retain the reported P31273 binary interaction.

Reason: PMID:32296183 is a human binary interactome resource. The exact curated IPI pair is retained as positive interaction evidence, while no target-specific physiological pathway or endothelial role is inferred without the individual assay and contextual validation. Generic binding is non-core.

Summary: Retain the reported Q13671 binary interaction.

Reason: Preserve the PMID:32296183 binary-interaction assertion and exact partner. The study-wide methodology supports the type of evidence but does not by itself identify the cellular function of this CCM2 interaction. Retain it as non-core support without converting it into a defined adaptor mechanism.

Summary: Retain the reported Q9H1K6 binary interaction.

Reason: The exact PMID:32296183 IPI edge is retained. A proteome-scale binary interaction is not evidence for intrinsic enzymatic activity or an additional CCM2 core function. Target-specific in-cell requirements were not established from the accessible study overview, so the broad binding assertion remains non-core.

Summary: Retain the KRIT1 association in the cell-specific interaction network.

Reason: PMID:33961781 maps proteome-scale cellular interaction networks. Preserve the O00522 association and its source; network association alone does not establish direct physical contact, although targeted studies independently support direct CCM2-KRIT1 binding. Generic binding is non-core supporting evidence.

Summary: Retain the Q13671 association with the network study context.

Reason: The exact IPI assertion from PMID:33961781 is preserved. Cell-specific network association does not by itself specify a direct binding interface or a vascular signaling function for this partner. In the absence of contradictory evidence, retain generic binding as non-core experimental support.

Summary: Retain the Q9H1K6 association with its cellular-network provenance.

Reason: Preserve the positive CCM2 interaction reported through PMID:33961781 without promoting a network association to a direct biochemical mechanism. Its particular cellular context and interface were not independently resolved here. Generic binding is non-core.

Summary: Retain the KRIT1 association in the multimodal cell-map resource.

Reason: The exact O00522 IPI edge from PMID:40205054 is consistent with established CCM2-KRIT1 biology. The resource integrates several types of cellular evidence, so an individual edge is not assigned a more specific assay mechanism from the paper title alone. Retain the binding row as non-core support.

Summary: Retain the Q9H1K6 association in the multimodal cell-map resource.

Reason: The PMID:40205054 curated IPI edge is preserved as positive association evidence. Its source-specific target table and interface were not examined, so no intrinsic catalysis or additional core pathway is inferred from the network. Generic binding remains non-core.

Summary: Cytoplasmic localization is consistent with CCM2 intracellular signaling.

Reason: PMID:16037064 explicitly uses subcellular localization measurements in its analysis of CCM1/CCM2 coordination. The available abstract does not provide all target-specific images, but cytoplasmic CCM2 is coherent with its established intracellular adaptor role. Retain the curator IDA annotation without replacing it with a more specific location that was not directly verified.

Summary: Retain the broad cytoplasmic localization from the UniProt mapping.

Reason: The electronic location agrees with the experimental cytoplasm assertion and the intracellular signaling complex. It does not imply exclusive cytoplasmic residence or establish a particular subcellular junction by itself.

Summary: Retain the Human Protein Atlas mitochondrial localization in its measured cell context.

Reason: The official HPA record (https://www.proteinatlas.org/ENSG00000136280-CCM2/subcellular) reports enhanced mitochondrial localization with HPA020273 and HPA065815 across several tested human cell lines. Its summary and antibody/cell-line table were checked; images were not independently reanalysed. This supports retaining the microscopy-derived IDA as non-core. Cytoplasmic signaling does not exclude this pool, and no mitochondrial catalytic function is inferred.

Summary: The specific integrin-pathway attribution requires the original detailed evidence.

Reason: The available PMID:16037064 abstract compares CCM1/CCM2 binding with CCM1/ICAP1 and beta1-integrin interactions, but that analogy does not directly establish CCM2 participation in integrin-initiated signaling. The full original article was unavailable. Preserve the TAS assertion and leave it undecided rather than reject it or infer a pathway from the analogy.

Summary: Retain the conserved heart-development role as a developmental context.

Reason: Mouse and zebrafish evidence supports a conserved cardiovascular requirement. The PAINT assertion represents phylogenetic inference, not a donor-count vote; there is no established human-specific loss. Heart development is a downstream developmental context of the adaptor rather than a separate defining molecular function.

Summary: Complex membership is correct but this component term is nonspecific.

Reason: The Ensembl orthology transfer agrees with direct evidence for CCM2-containing signaling assemblies. Retain protein-containing complex without guessing a named complex identifier or treating generic membership as its core biochemical activity.

Summary: Retain angiogenesis regulation as a vascular outcome of CCM signaling.

Reason: PMID:17657516 places CCM2-associated complexes in vascular development. The NAS attribution is preserved without upgrading its accessible abstract to a direct angiogenesis assay. This broader vascular regulation is retained as non-core context; the core process is supported by direct human endothelial tube-formation experiments.

Summary: Retain the reported stress-MAPK connection with its ortholog and experimental-context limits.

Reason: PMID:16037064 links CCM2 to the murine OSM pathway. The original PMID:14634666 study describes a Rac-OSM-MEKK3-MKK3 scaffold in sorbitol-induced p38 activation. Retain the existing TAS as conserved, non-core pathway context; the mouse OSM construct is not a direct human endothelial assay and CCM2 is not a kinase. The endothelial MEKK3-KLF2/4 mechanism is assessed separately.

Summary: Human CCM2 depletion impairs formation of endothelial tube lumens.

Reason: The selected primary Results in PMID:19151727 compare CCM2-specific and scrambled-control shRNAs in HUVEC fibrin-bead assays. CCM2 depletion reduced visible lumen formation while cord length, cell size, proliferation and migration were retained. This directly supports the existing human endothelial tube-morphogenesis assertion. The separate tagged CCM2/KRIT1 biochemical constructs in the same paper are mouse proteins and are not presented as human experiments. The source qualifier remains acts_upstream_of_or_within. Interaction-dependent KRIT1 localization and barrier rescue in human endothelial cells (PMID:20308363) independently establish signaling work by CCM2; the core combines that adaptor mechanism with the measured lumen phenotype, rather than relying on necessity alone.