FLNC

Summary: Human FLNC fragments bind the Z-disc cytoskeletal component myotilin in biochemical and yeast assays.

Reason: PMID:11038172 recombinant-fragment reciprocal immunoprecipitation and yeast assays establish the human FLNC–myotilin interaction. In the same primary work myotilin targets developing/mature Z-discs and its truncated fragment disrupts myofibrillar organization; official UniProt independently identifies it as a component of an actin cross-linking protein complex. This establishes the partner cytoskeletal-component class beyond a name or mere coincident localization. Refine the existing assertion to cytoskeletal protein binding without transferring myotilin function to FLNC or claiming a minimal isolated repeat-20 interface; the original autoactivation and construct/product limits remain. The developmental localization and myotilin-fragment perturbation experiments used mouse C2C12 host cells, separate from the recombinant human binding assay.

Proposed replacements: cytoskeletal protein binding

Summary: The FLNC C-terminal region binds the beta1A integrin subunit.

Reason: MODIFY to integrin binding (GO:0005178). The authentic PMID:16076904 abstract explicitly reports binding of the FLNC C-terminal region to the beta1A integrin subunit, in addition to its comparisons with other filamins. This target-specific interaction supports the integrin-binding class rather than merely a subtype inferred from the ITGB1 partner name. The exact pair-specific Methods and receptor/filamin construct boundaries were not independently recovered; the empty current IntAct exact-pair result is not negative evidence. Preserve the original human FLNC and P05556 source context without assigning integrin activation, ligand agonism, full-length cellular affinity or equal binding by both natural FLNC products.

Proposed replacements: integrin binding

Summary: The FLNC C-terminal region binds the FATZ-family protein MYOZ1.

Reason: The authentic PMID:16076904 abstract explicitly reports FATZ1/MYOZ1 binding to the FLNC C-terminal region and identifies FATZ1 among sarcomeric Z-disc proteins. Official GO:0051373 specifically covers binding to FATZ-family/calsarcin proteins and is a descendant of GO:0008092. Refine the existing same-partner assertion to FATZ binding, rather than stopping at the broader cytoskeletal-protein class. Full pair-specific Methods and precise reagent/affinity allocation remain unrecovered; no calcineurin regulation, sarcomere process or universal natural-product binding is inferred for FLNC.

Proposed replacements: FATZ binding

Summary: FLNC binds myotilin, a documented Z-disc cytoskeletal component.

Reason: The authentic PMID:16076904 abstract explicitly reports myotilin binding to FLNC, and original PMID:11038172 independently establishes this human pair with biochemical and yeast assays and myotilin association with myofibrillar organization. Myotilin is a documented cytoskeletal/Z-disc component, so cytoskeletal protein binding is an evidence-backed class refinement. Keep PMID:16076904 as the original source; PMID:11038172 supplies corroboration and is not a reconstruction of the former paper's assay. Do not transfer partner function or all-natural-product affinity.

Proposed replacements: cytoskeletal protein binding

Summary: FLNC associates with Xin/XIRP1 in myofibrillar attachment complexes.

Reason: The authentic PMID:16631741 abstract identifies Xin/XIRP1 as an FLNC-binding constituent of myofibrillar attachment/remodeling complexes. Exact human-pair Y2H and far-western records support the interaction; the microscopy record is separate colocalization evidence. Official UniProt independently corroborates XIRP1 actin-filament protection/organization and association with actin stress fibers, supporting the cytoskeletal-component class rather than inferring it solely from the name. Refine to cytoskeletal protein binding while preserving occurs_in GO:0014704 and the original partner. This does not transfer XIRP1 actin protection or EVH1-partner binding to FLNC, establish all Xin/FLNC products, or claim the full primary Methods were read.

Proposed replacements: cytoskeletal protein binding

Summary: FLNC peptides bind the ABL1 SH3-domain construct in an in-vitro array assay.

Reason: MODIFY to SH3 domain binding (GO:0017124). Two exact positive PMID:17474147 IntAct records identify in-vitro peptide-array binding of human ABL1 residues 61-121 to FLNC peptides 260-273 and 1749-1762. Official UniProt identifies the ABL1 construct region as its SH3 domain. Thus the existing measured peptide/domain interaction supports this specific binding class; it does not establish an endogenous full-length FLNC-ABL1 complex or FLNC kinase activity. The original abstract verifies the domain-peptide screening strategy but does not individually enumerate ABL1 in its protein list, so the exact pair/construct evidence remains attributed to IntAct. The reported validation rate for PLCgamma1 interactions is not transferred to this pair, and no natural-product-specific affinity is inferred. The tested 1749-1762 peptide falls within the annotated 1734-1766 deletion of Q14315-2, whereas the separately positive 260-273 peptide is outside that deletion. This sequence difference is not a demonstration that the full-length second product loses all binding.

Proposed replacements: SH3 domain binding

Summary: An FLNC peptide binds CRK SH3-region constructs in an in-vitro array assay.

Reason: MODIFY to SH3 domain binding (GO:0017124). Two exact positive PMID:17474147 IntAct records document in-vitro binding of CRK constructs 132-192 and 256-296 to FLNC peptide 260-273. Official UniProt maps 132-192 to the first SH3 domain and 235-296 to the second; the 256-296 assay construct is therefore only part of that second annotated domain. The observed SH3-region interaction supports the narrower class while preserving these fragment limits. It does not demonstrate an endogenous full-length complex, a physiological signaling route or equal binding by all natural FLNC products. Pair-specific details come from curated records rather than an independently recovered full primary target table; no validation rate from other partners is transferred.

Proposed replacements: SH3 domain binding

Summary: FLNC peptides bind the second GRB2 SH3-domain construct in an in-vitro array assay.

Reason: MODIFY to SH3 domain binding (GO:0017124). Two exact positive PMID:17474147 IntAct records identify in-vitro peptide-array binding of the human GRB2 construct 156-215 to FLNC peptides 260-273 and 1749-1762. Official UniProt identifies 156-215 as the second SH3 domain. This supports the specific domain-binding class for the existing peptide interaction. The original abstract establishes the screening strategy, while exact target/construct details remain attributed to IntAct because the complete primary target table was not independently recovered. The assays do not establish an endogenous full-length complex, a growth-factor pathway mechanism, universal affinity or binding by every natural FLNC product. The tested 1749-1762 peptide falls within the annotated 1734-1766 deletion of Q14315-2, whereas the separately positive 260-273 peptide is outside that deletion. This sequence difference is not a demonstration that the full-length second product loses all binding.

Proposed replacements: SH3 domain binding

Summary: FLNC interacts with the muscle ankyrin-G OTBD region.

Reason: MODIFY to ankyrin binding (GO:0030506), the specific class already present for PMID:21223964 in the original FLNC annotation set. The authentic abstract explicitly identifies FLNC in an ankyrin-G OTBD yeast-two-hybrid interaction study and reports muscle co-immunoprecipitation and costamere colocalization. This supports the ankyrin-binding class without inferring it solely from a partner name. Preserve the original partner O70511-7, a rat Ank3 product. Complete primary Methods and the correspondence between the tested OTBD construct and that exact natural splice product were not recovered; no molecular mass, purified full-length affinity, all-Ank3-isoform equivalence or natural FLNC-product assignment is inferred. The empty current IntAct response is a retrieval limit, not contrary evidence.

Proposed replacements: ankyrin binding

Summary: FLNC is a reported FBXL22-associated degradation target, without acquiring ubiquitin-ligase activity.

Reason: The original PMID:22972877 abstract identifies FLNC as a potential FBXL22 substrate and reports dose-dependent FLNC degradation after FBXL22 overexpression, attenuated by proteasome inhibition. Together with the curated experimental IPI record, this supports retaining the FBXL22 association as non-core. The complete pair-specific construct/species and binding assay details were not recovered; the abstract explicitly assigns confirmed co-immunoprecipitation to SKP1/CUL1, so that assay is not silently reassigned to FLNC. FLNC is the substrate in this context, not an E3 ligase or a proteasome component. The absence of a pair in the present IntAct retrieval is not contrary evidence.

Summary: FLNC associates with RTF2-containing affinity-purified complexes in human cell lines.

Reason: Two exact human-pair IntAct records from the PMID:33961781 interaction survey identify FLNC with tagged RTF2 bait in HCT116 and HEK293T cells. Both are anti-tag affinity-purification associations; the HEK293T edge is explicitly a spoke expansion. Retain this contextual co-complex association as non-core. The evidence does not establish direct binary binding, a replication mechanism for FLNC, or a constitutive nuclear function. No independent spectrum reanalysis or full target-specific primary Methods audit is claimed.

Summary: The broad cytoplasm location is covered by independently supported, more specific compartments.

Reason: Cytoplasm is correct and entailed by retained cytosol and muscle compartments. A FLNC-specific assay was not independently recovered from the selected PMID:12393796 sections; independent PMID:11038172/PMID:25351925 target evidence supports the compartment. Preserve the original experimental context and avoid a title-based misattribution claim.

Summary: Human FLNC expressed in rat cardiac cells has an actin-associated cytoplasmic pool.

Reason: Actual PMID:25351925 uses tagged full-length human NM001458 FLNC in rat cardiac cells, where wild type is cytoplasmic and actin-associated. The correct broad compartment is entailed by retained cytosol/muscle locations; preserve source and evidence code, with no claim of human-host or all-product assays.

Summary: Cytoplasm is correct and is entailed by the retained cytosol localization.

Reason: Cytoplasm is correct but is entailed by retained cytosol GO:0005829 through the official is_a/part_of ancestor graph, with more informative muscle compartments independently supported. Retain the original UniProt localization source rather than duplicating a replacement annotation.

Summary: Curated human cytosol localization is consistent with the intracellular FLNC pool.

Reason: Retain the curated HPA cytosol IDA, consistent with independently supported intracellular FLNC pools. No new HPA antibody/image audit or exclusive natural-product assignment is claimed.

Summary: The Reactome association event supports the retained cytosolic context.

Reason: The existing human Reactome filamin/migfilin association event places this context in cytosol, consistent with independent FLNC localization. The current detailed entity API was inaccessible, so retain the curated compartment without claiming reconstructed FLNC complex membership or stoichiometry.

Summary: FLNC localizes with actin structures, supporting the more specific actin cytoskeleton compartment.

Reason: The general cytoskeleton assertion is correct, but GO:0015629 specifies the actin-associated framework and includes its associated proteins. Actual PMID:25351925 Results report that tagged wild-type full-length human FLNC expressed in rat neonatal cardiomyocytes is cytoplasmic and mainly associated with actin fibres; endogenous human muscle localization in PMID:11038172 independently supports its structural muscle context. This is localization evidence beyond actin-binding activity alone. Refine the inherited compartment without treating the rat host as an endogenous human experiment or assigning this observation to every natural product. No Z-disc/costamere-to-cytoskeleton ancestry is assumed.

Proposed replacements: actin cytoskeleton

Summary: Human fibroblast focal-adhesion proteomics identifies a contextual FLNC pool.

Reason: The actual PMID:21423176 Results explicitly identify filamin-C in human HFF1 focal adhesion fractions with myosin-II-dependent enrichment. Retain this contextual fibroblast localization and the original CL:0000057 extension, without turning fraction proteomics into target-specific microscopy, a force-sensing mechanism or the dominant muscle localization.

Summary: FLNC binds the cytoskeletal partner nebulette in the reported interaction study.

Reason: The original PMID:17987659 abstract directly supports nebulette-FLNC interaction; retain this specialized cytoskeletal partner association as non-core. Full pair-specific construct details for O76041 were not recovered, and the original human partner field remains unchanged.

Summary: The separate cross-species nebulette partner context supports contextual cytoskeletal protein binding.

Reason: The original PMID:17987659 abstract supports the nebulette-FLNC relationship. Preserve the separate Q90684 partner context and its cross-species scope; exact pair-specific construct details remain unverified. No wrong-organism rejection or invented binding subtype follows from limited full-text access.

Summary: The broad membrane location is covered by the retained sarcolemma annotation.

Reason: Membrane includes associated peripheral proteins, so this is not a false transmembrane claim. Retained sarcolemma GO:0042383 is a verified is_a/part_of descendant of membrane, providing the existing more informative muscle membrane localization.

Summary: Transferred rat evidence and independent human muscle experiments support sarcoplasmic FLNC.

Reason: The rat D3ZHA0 donor has IDA PMID:21223964 for sarcoplasm; independent PMID:11038172 actual human muscle sections support the endogenous FLNC sarcoplasmic pool with antibody-specificity controls. Preserve the transfer source and do not equate sarcoplasm only with soluble cytosol.

Summary: Endogenous human muscle FLNC localizes to Z-discs.

Reason: Actual PMID:11038172 human muscle sections and differentiating cultures establish FLNC at Z-discs with paralog-aware antibody controls. Human FLNC fragment targeting was additionally studied in rat/mouse host cells; those constructs are corroboration, not a claim that all natural products were independently localized.

Summary: FLNC contributes actin-associated structure to cytoskeletal organization.

Reason: FLNC supplies actin-associated structural connections, and human FLNC-null cardiomyocytes show disordered actin bundles and defective sarcomere organization in PMID:34405687. The InterPro/ARBA assertion fits the protein's core work, without assigning every secondary transcriptional effect as a direct mechanism. The retained core process GO:0045214 sarcomere organization is_a GO:0031032 actomyosin structure organization is_a GO:0030036, so the core already represents this accepted broader role without a redundant process entry.

Summary: Rat donor evidence supports conserved ankyrin binding as a contextual muscle interaction.

Reason: Rat D3ZHA0 retains an experimental PMID:21223964 ankyrin-binding annotation. Together with the positive original report and existing human annotation this supports conserved ankyrin interaction, treated as a specific contextual connection rather than an additional core activity. Preserve the Ensembl donor context.

Summary: The reported ankyrin-G interaction supports specialized binding with the original rat partner preserved.

Reason: PMID:21223964 reports a positive ankyrin-G OTBD screen and corroborating association. O70511 is rat Ank3, so retain that partner and the curated IPI scope without relabeling it human or claiming all isoforms were assayed. This supports a contextual ankyrin-binding relationship.

Summary: The retained source and independent human muscle evidence support sarcolemmal FLNC.

Reason: The positive PMID:21223964 abstract reports muscle-fiber costamere localization and association, while independent PMID:11038172 directly supports human FLNC at sarcolemma. Preserve the supplied human IDA source context; full source-specific construct/image species were not replayed and must not be invented.

Summary: Rat transfer and independent human target evidence support peripheral sarcolemmal localization.

Reason: Rat D3ZHA0 retains PMID:21223964 sarcolemma IDA, and independent PMID:11038172 provides actual human muscle sarcolemmal FLNC evidence. The conserved peripheral muscle-membrane localization is a supported part of the structural scaffold, without membrane-spanning or universal-isoform claims.

Summary: The reported adult-muscle costamere localization supports this structural compartment.

Reason: PMID:21223964 explicitly reports costamere colocalization in adult muscle fibers, supporting the existing TAS location. Its limited colocalization during nascent assembly does not justify a new costamere-assembly process claim. The exact tissue/construct limits are retained in the source note.

Summary: Human FLNC loss disrupts cardiomyocyte sarcomere organization.

Reason: Actual PMID:34405687 Methods/Results show isogenic human FLNC-null hiPSC cardiomyocytes with reduced sarcomere content and disorganization persisting on patterned matrices. FLNC contributes the underlying actin-associated structure. Do not generalize the null phenotype to heterozygous variants, whose sarcomere structure remained largely preserved in these assays.

Summary: Actin filament binding underlies FLNC structural function in muscle.

Reason: The conserved FLNC actin-binding domain and actin-associated structural role support actin filament binding as the molecular core. Human FLNC loss disrupts actin bundles/sarcomere structure in PMID:34405687, and human wild-type FLNC associates with actin fibers in PMID:25351925; these contextual experiments supplement rather than masquerade as isolated binding kinetics.

Summary: Mouse donor experiments support muscle-cell maturation as a developmental extension of the structural role.

Reason: The actual mouse donor Q8VHX6 carries IDA PMID:16914736; its original abstract reports defective C2C12 differentiation/fusion and disrupted myogenesis in Flnc-deficient mice. This is positive muscle-cell maturation evidence, retained as a developmental consequence of the structural role rather than an early cell-fate mechanism or human-specific experiment.