CC2D1A

Summary: An inherited sequence-specific cis-regulatory DNA-binding role is supported by conserved binding experiments and human promoter repression.

Reason: The PAINT assertion represents an ancestral-node judgment. Rodent Freud-1 binds the Htr1a regulatory element in PMID:12917378, while independent human CC2D1A experiments in PMID:27914010 support promoter association and repression. ChIP does not independently establish direct DNA contact, but the combined evidence is consistent with the inherited function. Target self-inclusion among PAINT descendant evidence is expected and is not circular. The historical human mapping of the separate IDA row remains a different question.

Summary: Retain sequence-specific cis-regulatory DNA binding with curator deference and independent human functional support.

Reason: PMID:12917378 directly demonstrates FRE-selective binding by the rodent Freud-1 construct, with competitor and antibody controls. Independently inspected human PMID:27914010 Methods and Results identify human Freud-1 in HEK-293/SK-N-SH cells, HTR1A promoter association and functional repression. Together with the conserved activity and reviewed UniProt assignment, these support retaining the human function rather than treating the historical construct question as evidence against it. Human ChIP is not purified direct DNA-contact evidence. The 2003 mouse-brain 595-residue construct and rat reporters remain distinct from the current human products; ACCEPT does not certify that the original experiment directly tested either current human isoform.

Summary: CC2D1A has a conserved RNA polymerase II transcription-factor role.

Reason: Retain the PAINT ancestral judgment, supported by sequence-dependent rodent repression and human HTR1A promoter association/depletion experiments. Repression is a supported specialization of the broader transcription-factor activity. Neither the short descendant list nor the target's own experimental contribution weakens the phylogenetic assertion. This retention does not claim that each current human isoform was tested in the older study.

Summary: Retain DNA-binding transcriptional repression with independent human corroboration while preserving the original construct caveat.

Reason: The original FRE-dependent rodent reporter experiments and independent human promoter-association/depletion results in PMID:27914010 support the same repressor activity. Retain the experimentally curated annotation with deference to the curator, consistently with the inherited/family-based assertions and the nuclear core. This is a judgment about the supported human function, not a retrospective reassignment of the mouse-brain 595-residue Freud-1 construct to a current human isoform. The human experiments show cell-dependent chromatin-partner requirements; neither ChIP alone nor repression transfers Brg1 or HDAC catalytic activity to CC2D1A.

Summary: The family-based transcriptional-repressor inference agrees with independent human functional evidence.

Reason: The InterPro mapping is consistent with the conserved Freud-1 transcriptional role and human HTR1A repression experiments. Human promoter ChIP and cell-dependent depletion responses, together with conserved sequence-specific binding evidence, support the repressor synthesis. The function is not inferred merely from the presence of a C2 domain, nor are Brg1 ATPase or HDAC catalytic activities assigned to CC2D1A.

Summary: Retain the curated CC2D1A–CHMP4B interaction as a non-core association.

Reason: This IPI assertion names CHMP4B (UniProtKB:Q9H444), the exact partner independently recorded for Q6P1N0 in the reviewed UniProt interaction section. The PMID:16730941 cache describes human CHMP interaction experiments but is abstract-only; the target-specific original assay and controls were not independently inspected. Qualitative curator corroboration supports retention under the project's binding policy without claiming direct full-length binding, defined stoichiometry or a complete ESCRT mechanism. The interaction does not justify replacing this row with the unrelated PDK1–Akt adaptor activity.

Summary: Retain the CHMP4B interaction from the quantitative human interactome as a non-core association.

Reason: The exact Q6P1N0–Q9H444 edge is corroborated by the reviewed UniProt interaction record. PMID:26496610 reports tagged HeLa-cell quantitative interaction proteomics, but its cached abstract does not expose the CC2D1A-specific measurements or controls. Retention respects the experimental curation and independent partner corroboration; it does not equate co-purification with a purified direct interface or establish every ESCRT process. No more specific molecular function follows from this screen alone.

Summary: Retain the OpenCell CHMP4B association as a supported non-core interaction.

Reason: OpenCell combines endogenous tagging and IP–mass spectrometry in human cells. The exact CHMP4B partner is independently present in the reviewed UniProt record, supporting qualified retention. The available cached prose describes the platform and its limitations, but the individual CC2D1A target table, tag effect and reciprocal controls were not independently examined. This is not a claim of direct binding, isoform specificity or an established physiological ESCRT role.

Summary: Nuclear localization agrees with the inherited transcriptional role and human nuclear experiments.

Reason: Retain the PAINT location judgment. Human endogenous Freud-1 was recovered from nuclear extracts, and promoter ChIP/depletion experiments place its transcriptional activity in the nucleus. These target experiments corroborate the location without treating an ancestral donor count as an evidence score or assigning a specific current isoform.

Summary: The UniProt nuclear-location mapping is corroborated by human transcription experiments.

Reason: Human CC2D1A nuclear extracts, reciprocal association and HTR1A promoter experiments support this location. The conservative electronic location agrees with the synthesized transcriptional role; it does not imply constitutive residence of all protein molecules or resolve every isoform.

Summary: Cytoplasmic localization is consistent with independent human fractionation and signaling experiments.

Reason: The original experimental localization is retained with curator deference. PMID:16033914 is abstract-only in the normal cache, so its complete localization assay has not been independently read. The reviewed UniProt location and independent human fractionation/signaling work in PMID:18662999 corroborate the broad cytoplasmic assignment. That corroboration supports the location without pretending to have inspected the original microscopy controls.

Summary: The conservative cytoplasmic mapping agrees with CC2D1A signaling coordination.

Reason: Human CC2D1A coordinates PDK1 and Akt in cytoplasmic signaling experiments, and fractionation supports a cytoplasmic pool. Retain the UniProt location mapping. This broad component assignment does not establish every membrane-associated proteomics row or a secreted function.

Summary: Retain the independently supported centrosomal localization.

Reason: The reviewed UniProt subcellular-location mapping cites PMID:20171170, whose primary abstract explicitly reports centrosomal Aki1 and whose visible Methods identify human HeLa/293T experiments. This is sufficient corroboration for the conservative location mapping. Centrosomal localization is independent of the PDK1–Akt signaling mechanism and is not placed on that core activity merely to cover an accepted component. The available source does not warrant a new cohesion process or a stronger site-specific recruitment mechanism here.

Summary: The curator-assessed cytosolic pool is consistent with independent human localization and signaling evidence.

Reason: Retain the immunofluorescence curation with independent human fractionation and cytosolic signaling evidence. The original HPA images were not re-scored, and no current isoform-specific localization is inferred. Cytosol is the supported location of the adaptor synthesis; separate centrosomal localization is not used to move the Akt mechanism to the centrosome.

Summary: The inherited RNA polymerase II regulatory process agrees with human HTR1A repression.

Reason: CC2D1A participates in repression of a protein-coding target through promoter association and cell-dependent cooperation with chromatin regulators. These human data corroborate the PAINT process judgment, together with conserved rodent sequence-dependent repression. Retaining this general Pol II regulatory process does not establish the distinct snRNA-specific assertion.

Summary: Recovered in a membrane-fraction proteome without protein-specific evidence that it associates with membranes.

Reason: UniProt: cytoplasm (ECO:0000269), nucleus, centrosome; no membrane association on record. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: UNDECIDED.)

Summary: CC2D1A expression can promote canonical NF-kappaB signaling in human-cell experimental contexts.

Reason: The original human cDNA overexpression screen is independently supported by targeted PMID:20529849 experiments with human CC2D1A, reporter and target-transcript measurements, IKK-immunoprecipitate activity and pathway perturbations. These establish a context-dependent positive pathway effect. Ubc13 depletion/rescue tests dependence on Ubc13, not endogenous CC2D1A necessity. The experiments do not establish CC2D1A kinase/E3 chemistry, direct TRAF2/TAK1 recruitment or a universal physiological stimulus. The original screen's target table remains uninspected; the independent target evidence supports non-core retention.

Summary: Cadherin-binding activity remains unresolved because the target-specific supporting assay has not been established.

Reason: The official GO definition requires cadherin binding. BioID proximity and junctional colocalization alone do not establish that molecular activity, but a method-level limitation does not show that every curated target lacks additional binding evidence. Newly read PMC author-manuscript Results and Methods describe E-cadherin-BirA proximity, localization and predicted networks. That manuscript differs from the published cached abstract, which additionally describes adhesion-plaque proteomics. The CC2D1A-specific supplementary record and complete version-of-record assay context remain inaccessible. Therefore the experimental HDA row remains UNDECIDED; neither corpus action frequencies nor an uninspected target table establishes an over-annotation. No direct-negative binding claim or universal purified-binary-assay requirement is imposed.

Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions.

Reason: Cytoplasmic protein that binds ESCRT-III. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: UNDECIDED.)

Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions.

Reason: Cytoplasmic protein that binds ESCRT-III. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: UNDECIDED.)

Summary: Generalize the repression process to negative regulation of transcription by RNA polymerase II.

Reason: GO:1905381 specifically narrows the regulated RNA to snRNA; its parent GO:0000122 retains the demonstrated negative Pol II regulation without that RNA-class commitment. Selected original Methods and Results in the externally accessed PMID:12917378 reproduction test rat Htr1a promoter-luciferase and FRE/SV40 reporter constructs, with FRE mutation and expression controls. Independent human PMID:27914010 shows HTR1A repression. These positive target and reporter identities support the broader replacement rather than an snRNA-specific interpretation. This does not assert that CC2D1A cannot regulate snRNA or resolve the original human-product mapping; the machine term, reference, evidence and qualifier remain unchanged.

Proposed replacements: negative regulation of transcription by RNA polymerase II

Summary: CC2D1A coordinates PDK1 and Akt through a noncatalytic signaling-adaptor mechanism.

Reason: Actual human Aki1 experiments show partner association, sequential recovery of an Aki1–PDK1–Akt complex, depletion-sensitive PDK1–Akt association and biochemical phosphorylation assays. Intrinsic PDK1 activity and Akt membrane-recruitment controls distinguish coordination from upstream activation or kinase chemistry supplied by CC2D1A. EGF versus IGF-1/PDGF and concentration-dependent effects bound the mechanism. GO:0035591 fits bringing signaling partners together; it is not already asserted or proposed as a replacement, and no redundant broader adaptor MF or new biological process is added. The binding assay uses translated/immunopurified Aki1 rather than a fully purified binary reconstitution. In the separately accessed primary Results, immunoprecipitated Aki1 accelerates recombinant PDK1-mediated Akt phosphorylation in the presence of PIP3. This biochemical kinase assay does not constitute a CC2D1A depletion-rescue experiment; the immutable normal cache is abstract-only.