{"gene":"CKAP4","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2001,"finding":"The luminal alpha-helical segment of CLIMP-63 is necessary and sufficient for its exclusion from the nuclear envelope and restriction to ER subdomains; deletion of the luminal (but not cytosolic) segment abrogates subdomain-specific localization. The recombinant luminal segment forms 91-nm alpha-helical rod-like complexes via electrostatic interactions of coiled coils, mediating oligomerization that prevents nuclear envelope localization and potentially contributes to ER morphology.","method":"Mutagenesis, confocal microscopy (live cells), immunoelectron microscopy, FRAP, circular dichroism spectroscopy, electron microscopy, analytical ultracentrifugation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of purified luminal domain, mutagenesis, multiple orthogonal structural and cell biology methods in one rigorous study","pmids":["11402071"],"is_preprint":false},{"year":2005,"finding":"CLIMP-63 is phosphorylated during mitosis at serines 3, 17, and 19 in its cytoplasmic domain, and this phosphorylation abolishes its ability to bind microtubules in vitro. Phospho-mimicking mutations (S3E/S17E/S19E) prevent microtubule binding, and overexpression of the phospho-mimicking form in interphase cells causes ER collapse around the nucleus while leaving the microtubule network intact. Thus phosphorylation controls CLIMP-63-mediated anchoring of the ER to microtubules.","method":"Metabolic 32P labeling, in vitro microtubule-binding assay, site-directed mutagenesis, overexpression in interphase cells, confocal microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assay with mutagenesis, corroborated by cell biological phenotype, multiple orthogonal methods","pmids":["15703217"],"is_preprint":false},{"year":2003,"finding":"CKAP4/p63 was identified as the cell-surface tPA (tissue plasminogen activator) binding protein on vascular smooth muscle cells. An anti-p63 antibody blocked tPA binding, and heterologous expression of an N-terminally truncated, plasma-membrane-targeted p63 mutant increased tPA-catalyzed plasminogen activation, demonstrating that cell-surface CKAP4 functionally regulates the plasminogen activation system.","method":"Surface 125I labeling, affinity chromatography, MALDI-MS and nano-ESI-MS/MS protein identification, immunofluorescence microscopy, antibody blocking assay, heterologous expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal identification by MS, antibody blocking, and functional overexpression in one study","pmids":["12913003"],"is_preprint":false},{"year":2006,"finding":"CKAP4/p63 is a high-affinity cell-surface receptor for the antiproliferative factor (APF) sialoglycopeptide. Anti-CKAP4 antibodies and siRNA knockdown of CKAP4 blocked APF-mediated antiproliferative activity on bladder epithelial and HeLa cells. Co-localization of anti-CKAP4 antibody with rhodamine-labeled synthetic APF was observed in cell membrane and perinuclear areas.","method":"Antibody blocking assay, siRNA knockdown, immunofluorescent confocal microscopy, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — antibody blocking plus siRNA knockdown with functional readout, multiple orthogonal approaches","pmids":["17030514"],"is_preprint":false},{"year":2006,"finding":"CKAP4/p63 was identified as a specific cell-surface SP-A (surfactant protein A) binding protein on type II pneumocytes by chemical cross-linking, mass spectrometry, co-immunoprecipitation, and antibody blocking of SP-A-mediated inhibition of ATP-stimulated phospholipid secretion. Both intracellular and plasma membrane pools of p63 were detected, and p63 co-localized with SP-A in early endosomes.","method":"Chemical cross-linking (sulfo-SBED, DSP), streptavidin pulldown, MALDI-MS/nano-ESI-MS/MS, co-immunoprecipitation, immunofluorescence, functional phospholipid secretion assay","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cross-linking, MS, co-IP, functional assay) independently establishing SP-A/CKAP4 interaction and function","pmids":["16556726"],"is_preprint":false},{"year":2007,"finding":"CLIMP-63-mediated binding of ER to microtubules restricts the lateral mobility of translocon complexes in rough ER. Depletion of CLIMP-63 by siRNA or expression of a CLIMP-63 mutant lacking the microtubule-binding domain significantly increased diffusion rates of translocon complexes (measured by FRAP), demonstrating that CLIMP-63/microtubule interaction immobilizes translocon complexes assembled into membrane-bound polysomes.","method":"FRAP, siRNA knockdown, dominant-negative mutant overexpression, drug-induced microtubule depolymerization","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — FRAP with genetic/pharmacological perturbations and domain mutant, multiple orthogonal approaches in one study","pmids":["17567679"],"is_preprint":false},{"year":2008,"finding":"CKAP4/p63 was identified as a major substrate of the palmitoyl acyltransferase DHHC2 using the PICA (palmitoyl-cysteine isolation capture and analysis) proteomics method in a living vertebrate system.","method":"Novel proteomics method (PICA) for PAT-substrate identification in living cells","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, novel proteomics method identifying PAT-substrate pair, no mutagenesis validation described in abstract","pmids":["18296695"],"is_preprint":false},{"year":2008,"finding":"p63/CKAP4 antibody blocked specific (calcium-dependent) binding of 125I-SP-A to type II cells. siRNA knockdown of p63 reduced p63 expression, attenuated p63-specific SP-A binding, and reversed the ability of SP-A to prevent surfactant secretion. cAMP-stimulated increase in calcium-dependent SP-A binding was also blocked by p63 antibody, confirming p63 as the functional SP-A receptor on lung type II cells.","method":"Radioligand binding assay (125I-SP-A), siRNA knockdown, antibody blocking, surfactant secretion functional assay, immunogold electron microscopy","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — radioligand binding, siRNA knockdown with functional rescue, antibody blocking, multiple orthogonal methods confirming SP-A receptor function","pmids":["18708633"],"is_preprint":false},{"year":2010,"finding":"The PI3K-AKT signaling pathway mediates intracellular transport of CKAP4/p63 from the ER to the plasma membrane of type II pneumocytes. SP-A or cAMP exposure increased p63 on the plasma membrane and activated AKT; treatment with PI3K inhibitor LY-294002 prevented SP-A-induced plasma membrane enrichment of p63 and altered SP-A-mediated lipid turnover.","method":"Cell fractionation, radioligand binding assay, PI3K inhibitor treatment, AKT activation assay, SP-A-mediated liposome uptake assay","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition of PI3K with multiple functional readouts, single lab","pmids":["20870746"],"is_preprint":false},{"year":2010,"finding":"CLIMP-63 palmitoylation is required for gentamicin-induced dimerization; transfection of palmitoylation-deficient CLIMP-63 mutants into 293T cells showed that the gentamicin-dependent DTT-resistant dimerization requires palmitoylation. Gentamicin also enhanced CLIMP-63 binding to 14-3-3 proteins. CLIMP-63 siRNA knockdown enhanced cellular resistance to gentamicin-induced apoptosis, indicating CLIMP-63 mediates aminoglycoside cytotoxicity.","method":"Gentamicin-agarose pulldown, MS identification, Western blotting (DTT-resistant dimer), palmitoylation-deficient mutagenesis, siRNA knockdown, apoptosis assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of palmitoylation site, siRNA knockdown with functional readout, single lab","pmids":["21368867"],"is_preprint":false},{"year":2012,"finding":"CLIMP-63 interacts with Dicer to form a high-molecular-weight complex that is electrostatic in nature and not mediated by RNA, and is catalytically active in pre-microRNA processing. CLIMP-63 is required for stabilizing Dicer protein levels; knockdown of CLIMP-63 reduced Dicer abundance. The interaction involves a portion of the luminal domain of CLIMP-63. Dicer was found to interact with CLIMP-63 within minutes of its synthesis, and both can be co-secreted.","method":"Yeast two-hybrid screen, co-immunoprecipitation, high-molecular-weight complex analysis, pre-miRNA processing assay, reporter gene assay, knockdown","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus functional pre-miRNA processing assay, single lab","pmids":["23047949"],"is_preprint":false},{"year":2014,"finding":"VIMP/SelS interacts with CLIMP-63 and both link the ER to microtubules. Depletion of VIMP causes ER spreading to the cell periphery and affects MT-dependent ER processes; VIMP interacts with CLIMP-63 and syntaxin 5L but not with tubular ER MT-binding proteins (such as Reep1), indicating that distinct sets of MT-binding ER proteins organize different ER subdomains.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and knockdown with localization phenotype, multiple proteins tested, single lab","pmids":["25008318"],"is_preprint":false},{"year":2016,"finding":"CKAP4 functions as a cell-surface receptor for DKK1. DKK1 binds CKAP4 and LRP6 with similar affinity but uses different cysteine-rich domains. DKK1 induces clathrin-dependent internalization of CKAP4. DKK1/CKAP4 signaling activates AKT by forming a complex between the proline-rich domain of CKAP4 and the SH3 domain of PI3K. Anti-CKAP4 antibody blocked DKK1 binding, suppressed AKT activity, and attenuated xenograft tumor formation.","method":"Co-immunoprecipitation, binding affinity measurements, clathrin-dependent endocytosis assay, domain mutagenesis, AKT phosphorylation assay, anti-CKAP4 antibody blocking, xenograft mouse model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, domain mutants, functional signaling assays, in vivo xenograft), single rigorous study","pmids":["27322059"],"is_preprint":false},{"year":2017,"finding":"APF binds specifically to two sites within the extracellular domain of CKAP4 (residues 127-360 and 361-524), as determined by surface plasmon resonance using deletion mutants. Both regions contribute relatively equally to overall APF binding affinity with fast association and slow dissociation rates.","method":"Surface plasmon resonance (SPR), recombinant domain deletion mutants","journal":"BMC biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro SPR binding assay with deletion mutants, single lab, no cell-based validation reported in abstract","pmids":["28893174"],"is_preprint":false},{"year":2018,"finding":"DKK3 stimulates esophageal cancer cell proliferation via CKAP4, which acts as a receptor for DKK3. Anti-CKAP4 antibody inhibited both DKK3 binding to CKAP4 and xenograft tumor formation. The transcription factor ΔNp63α (p53-family member) bound to the upstream region of the DKK3 gene and regulated its expression; DKK3 reexpression partially rescued proliferation in p63-depleted cells.","method":"Co-immunoprecipitation (DKK3-CKAP4 binding), antibody blocking assay, xenograft tumor model, ChIP (p63 binding to DKK3 promoter), siRNA knockdown, organoid growth assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus antibody blocking plus in vivo xenograft plus ChIP, multiple orthogonal methods in one study","pmids":["30181180"],"is_preprint":false},{"year":2018,"finding":"SENCR lncRNA stabilizes endothelial cell adherens junctions through physical interaction with CKAP4. A noncanonical RNA-binding domain in CKAP4 binds SENCR (confirmed by biotinylated RNA pulldown, MS, and RNA immunoprecipitation). Upon SENCR knockdown, CKAP4 levels increase at the EC surface fraction and CKAP4 interaction with CDH5 is enhanced, destabilizing the CDH5/CTNND1 complex and augmenting CDH5 internalization, resulting in impaired adherens junctions.","method":"Biotinylated RNA pulldown, mass spectrometry, RNA immunoprecipitation, surface fractionation, co-immunoprecipitation (CKAP4-CDH5), siRNA knockdown, EC permeability assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA pulldown + MS + RIP + Co-IP + functional permeability assay, multiple orthogonal methods identifying noncanonical RNA-binding activity and downstream complex","pmids":["30584103"],"is_preprint":false},{"year":2019,"finding":"CKAP4 and LRP6 primarily localize to detergent-resistant membrane (DRM/lipid raft) fractions of the plasma membrane in a palmitoylation-dependent manner. DKK1 induces depalmitoylation of both CKAP4 and LRP6 by acylprotein thioesterases (APTs), causing translocation to non-DRM fractions. DKK1-dependent depalmitoylation requires PI3K-AKT pathway activation. DKK1 simultaneously binds CKAP4 and LRP6 forming a ternary complex; LRP5/6 knockdown decreases DKK1-dependent AKT activation through CKAP4; CKAP4 knockdown does not affect DKK1-dependent inhibition of Wnt signaling through LRP5/6. Palmitoylation of CKAP4 is required for cell proliferation.","method":"DRM fractionation, palmitoylation assay, APT inhibitor treatment, siRNA knockdown, co-immunoprecipitation (ternary complex), AKT phosphorylation assay, cell proliferation assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — DRM fractionation, palmitoylation assay, Co-IP of ternary complex, genetic knockdown with functional readouts, multiple orthogonal methods","pmids":["31744930"],"is_preprint":false},{"year":2019,"finding":"CKAP4 interacts with β1 integrin and controls recycling of α5β1 integrin independently of DKK1. CKAP4 knockdown enlarged cell adhesion sites, enhanced cell adhesion to fibronectin, and decreased cell migration. In CKAP4-depleted cells, surface α5 integrin levels increased due to upregulated recycling (not altered internalization). CKAP4 bound to sorting nexin 17 (SNX17), a mediator of integrin recycling; CKAP4 knockdown enhanced recruitment of α5β1 integrin to SNX17.","method":"Co-immunoprecipitation (CKAP4-β1 integrin; CKAP4-SNX17), siRNA knockdown, cell surface biotinylation assay, internalization/recycling assay, adhesion and migration assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, integrin trafficking assay, siRNA knockdown with mechanistic epistasis (SNX17), multiple orthogonal methods","pmids":["31160493"],"is_preprint":false},{"year":2019,"finding":"CLIMP-63 and reticulon 4a (RTN4a) regulate the organization and dynamics of peripheral ER tubule nanodomains. CLIMP-63 associates with and increases lumenal blob length along ER tubules, while RTN4a segregates away from and restricts lumenal blob length. Both proteins regulate nanodomain distribution of ER-resident proteins (calnexin, derlin-1) and dynamic nanoscale lumenal compartmentalization along peripheral ER tubules.","method":"STED super-resolution microscopy, high-speed live-cell STED imaging, knockdown/overexpression","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — STED super-resolution microscopy with genetic perturbations, single lab","pmids":["31469817"],"is_preprint":false},{"year":2019,"finding":"Calumenin-1 (Calu1) specifically interacts with Climp63 and antagonizes Climp63 in ER sheet distribution and luminal width. The luminal length of Climp63 positively correlates with the luminal width of ER sheets; a lumen-only Climp63 mutant dominantly narrows ER lumen, demonstrating that Climp63 acts as an ER luminal bridge.","method":"Co-immunoprecipitation, domain deletion mutants, fluorescence microscopy of ER morphology","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus domain mutant analysis, single lab, moderate evidence","pmids":["31751826"],"is_preprint":false},{"year":2020,"finding":"Palmitoylated CKAP4 at Cys100 binds to VDAC2 at ER-mitochondria contact sites (MAMs). CKAP4 knockout increased ER-mitochondria contact sites and altered mitochondrial structure. In CKAP4 KO cells, IP3R-VDAC2 binding was enhanced, intramitochondrial Ca2+ increased, mitochondrial membrane potential decreased, and oxidative consumption rate was reduced. A palmitoylation-deficient CKAP4 mutant did not rescue these phenotypes, confirming palmitoylation at Cys100 is required for VDAC2 binding and mitochondrial function.","method":"Co-immunoprecipitation (CKAP4-VDAC2; IP3R-VDAC2), CKAP4 knockout (HeLaS3), palmitoylation-deficient mutagenesis (C100A), Ca2+ measurement, mitochondrial membrane potential assay, Seahorse OCR, electron microscopy, xenograft tumor model","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, KO, site-specific mutagenesis, multiple functional readouts (Ca2+, membrane potential, OCR), orthogonal methods in one rigorous study","pmids":["33067255"],"is_preprint":false},{"year":2020,"finding":"Purified full-length Climp63 reconstituted into proteoliposomes with luminal domain facing outward retains homotypic self-association that can be competed by soluble luminal domain. The luminal domain (LD) forms low-order oligomers in solution; the full-length protein shows moderate homotypic interactions. These results directly support Climp63 as an ER luminal spacer through self-association.","method":"Protein purification and reconstitution into proteoliposomes, in vitro binding/competition assay, biochemical oligomerization analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reconstitution in proteoliposomes, single lab, no mutagenesis validation","pmids":["32612999"],"is_preprint":false},{"year":2021,"finding":"DKK1 activates noncanonical NF-κB signaling via CKAP4 in multiple myeloma cells. CKAP4 transduces the DKK1 signal by recruiting and preventing CAND1 from inhibiting E3 ligase-mediated ubiquitination of IκBα. IL-6 stimulates CKAP4 expression to generate bortezomib resistance. Disruption of the DKK1-CKAP4 axis improved BTZ sensitivity and attenuated bone destruction in a mouse model.","method":"Co-immunoprecipitation, siRNA/shRNA knockdown, drug resistance assay, NF-κB pathway assays, in vivo mouse model","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional signaling assay plus in vivo model, single lab, mechanism partially described in abstract","pmids":["34470047"],"is_preprint":false},{"year":2021,"finding":"GOLPH3 interacts with CKAP4 (by immunoprecipitation-MS) and decreases plasma membrane-localized CKAP4 while increasing exosome-localized CKAP4, thereby promoting formation of CKAP4-containing exosomes. CKAP4 in turn binds exosomal WNT3A to enhance its secretion, activating WNT/β-catenin signaling and maintaining stem-like phenotype and metastasis in NSCLC cells.","method":"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, cell fractionation (plasma membrane vs exosome), luciferase-reporter assay, nuclear extract assay, in vivo metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — IP-MS plus Co-IP plus functional assays, single lab","pmids":["34671013"],"is_preprint":false},{"year":2023,"finding":"CLIMP-63 S-acylation (by ZDHHC6 in the ER) drives assembly into highly stable super-complexes. In the ER, CLIMP-63 assembles into trimeric units which can exit to the plasma membrane; the majority undergoes ZDHHC6-mediated S-acylation leading to super-complex formation. CLIMP-63 acylation-deacylation cycle controls the abundance and fenestration of ER sheets, as shown by super-resolution and FIB-EM.","method":"Native mass spectrometry, kinetic analysis of acylation/deacylation, data-driven mathematical modelling, super-resolution microscopy, focused ion beam electron microscopy (FIB-EM)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — native MS, kinetic acylation analysis, mathematical modelling, super-resolution and FIB-EM, multiple orthogonal methods in one rigorous study","pmids":["36650170"],"is_preprint":false},{"year":2023,"finding":"The Climp63 luminal domain (LD) is highly alpha-helical with a flexible leading helix followed by a five-helix bundle (5HB). Trans self-associations occur between the tip of the 5HB and the C-terminus of the LD, consistent with generating ~50 nm ER sheet width. The density of Climp63 (reflecting cis interaction strength) influences ER width maintained by trans interactions; the leading helix is dispensable for homotypic interactions but 5HB packing regulates self-association.","method":"Deep learning-predicted structure analysis, mutagenesis, ER width measurements, biochemical interaction assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural prediction with mutagenesis validation, single lab, limited experimental structural validation described in abstract","pmids":["37039099"],"is_preprint":false},{"year":2023,"finding":"EGFL6 binds to the N-terminus of CKAP4 to promote migration of HUVECs by activating the ERK/MMP pathway. FMNL2 promotes EGFL6 paracrine signaling via exosomes, with CKAP4 as a downstream target of EGFL6 involved in CRC angiogenesis.","method":"Co-immunoprecipitation (FMNL2-EGFL6 via GDB/FH3 domain), domain mapping, HUVEC migration assay, ERK/MMP pathway assay, in vitro and in vivo angiogenesis assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus domain mapping plus functional migration assay, single lab","pmids":["36715549"],"is_preprint":false},{"year":2024,"finding":"FKBPL functions as an ER-phagy regulator and acts as a scaffold connecting CKAP4 and LC3/GABARAPs; CKAP4 serves as a bridge between FKBPL and ER-phagy cargo. ER-phagy-inducing conditions increase FKBPL-CKAP4 interaction followed by FKBPL oligomerization at the ER, triggering ER-phagy. FKBPL-CKAP4 deficiency leads to Golgi disassembly, lysosome impairment, increased ER-derived secretory vesicles, and enhanced cytosolic protein secretion via microvesicle shedding.","method":"Gain-of-function screen, co-immunoprecipitation (FKBPL-CKAP4), CKAP4 knockout, ER-phagy assay, organelle morphology analysis (Golgi, lysosome), secretory vesicle analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic screen, Co-IP, KO with multiple functional readouts, published in rigorous journal","pmids":["39251576"],"is_preprint":false},{"year":2024,"finding":"CKAP4 competes with TRIM21 for binding to RETREG1/FAM134B; TRIM21 ubiquitinates RETREG1 at K247 and K252, facilitating its proteasomal degradation, while CKAP4 shields RETREG1 from degradation by competitively binding. CKAP4 and TRIM21 thereby regulate reticulophagy by modulating RETREG1 expression.","method":"Co-immunoprecipitation (CKAP4-RETREG1; TRIM21-RETREG1), ubiquitination assay with site mapping (K247/K252), competition binding assay, reticulophagy assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, site-specific ubiquitination mapping, competition binding, functional reticulophagy assay, multiple orthogonal methods","pmids":["39689859"],"is_preprint":false},{"year":2024,"finding":"CKAP4 as an intracellular mechanosensor responds to solid stress through liquid-liquid phase separation. The intrinsically disordered region 1 (IDR1) of CKAP4 binds to microtubules, while IDR2 governs phase separation triggered by Cav1.2-dependent calcium influx. CKAP4 phase separation puncta adhere to microtubules and reorchestrate microtubule curvature and branching to enhance cell spreading and migration.","method":"Cell-SELEX aptamer, live cell imaging of phase separation, microtubule co-sedimentation/binding assay, domain deletion mutants (IDR1, IDR2), calcium influx inhibition (Cav1.2 blockade), cell migration and in vivo metastasis assays","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — aptamer-based discovery, domain mutants, phase separation imaging, mechanistic calcium pathway, single lab","pmids":["39528501"],"is_preprint":false},{"year":2025,"finding":"P. micra surface protein TmpC binds to CKAP4 on OSCC cells, facilitating bacterial attachment and invasion. This TmpC-CKAP4 interaction activates HIF-1α and autophagy via CKAP4-RanBP2 and CKAP4-NBR1 pathways, driving OSCC metastasis. Targeting CKAP4 with masitinib or antibodies impairs P. micra attachment and abolishes P. micra-promoted OSCC metastasis in vitro and in vivo.","method":"Co-immunoprecipitation (TmpC-CKAP4; CKAP4-RanBP2; CKAP4-NBR1), bacterial attachment/invasion assay, antibody/masitinib blocking, HIF-1α/autophagy pathway assays, in vivo metastasis model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of multiple complexes plus functional blocking plus in vivo model, multiple orthogonal methods in one rigorous study","pmids":["40055343"],"is_preprint":false},{"year":2025,"finding":"In atrial fibroblasts, CKAP4 interacts with WNT3A and WNT5A (co-immunoprecipitation and proximity ligation assay) and activates β-catenin signaling. CKAP4 knockdown reduced α-SMA, collagen I/III, vimentin, and migration in atrial fibroblasts. In mice, CKAP4 knockdown attenuated left atrial fibrosis and reduced AF inducibility. The WNT/β-catenin agonist SKL2001 rescued the antifibrotic effects of CKAP4 knockdown, while β-catenin/TCF inhibitor blunted CKAP4-overexpression-induced collagen synthesis.","method":"Co-immunoprecipitation, proximity ligation assay (CKAP4-WNT3A/WNT5A), siRNA knockdown and overexpression in atrial fibroblasts, pathway inhibitor/agonist, in vivo mouse cardiac model (TAC, Ang II), atrial fibrosis and AF inducibility assays","journal":"Circulation. Arrhythmia and electrophysiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus proximity ligation plus genetic perturbations plus pharmacological epistasis plus in vivo model, multiple orthogonal methods","pmids":["41159262"],"is_preprint":false},{"year":2025,"finding":"CKAP4 deficiency in macrophages accelerates wound healing by heightening macrophage sensitivity to matrix stiffness. Mechanistically, CKAP4 binds Talin1 to restrain adhesion-associated signaling and STAT6 nuclear translocation. CKAP4 loss triggers cytoskeletal remodeling and a pro-regenerative program at lower stiffness thresholds. Local silencing of Ckap4 in macrophages in a diabetic wound model restored mechanoresponsiveness and improved healing.","method":"Co-immunoprecipitation (CKAP4-Talin1), CKAP4 conditional knockout in macrophages, STAT6 nuclear translocation assay, matrix stiffness mechanosensing assay, diabetic wound model, gene expression profiling","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifying Talin1 as binding partner, KO with mechanistic readouts, in vivo disease model, multiple methods","pmids":["42207635"],"is_preprint":false},{"year":2025,"finding":"Phosphodeficient Climp63 mutant (preventing mitotic phosphorylation) in HeLa cells maintains ER-MT contacts during mitosis, causing severe mitotic delays and nuclear fragmentation. The N-terminal 28 amino acids of Climp63 are sufficient for MT interaction, and phosphorylation of S17 by CDK1 is critical for mitotic release of ER from MTs.","method":"Phosphodeficient Climp63 mutant expression, domain truncation mutants, live cell imaging (mitotic progression), CDK1 kinase assay/phosphorylation analysis, nuclear fragmentation quantification","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphodeficient mutagenesis, domain truncation, live imaging with mitotic readouts; preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.09.01.673496"],"is_preprint":true},{"year":2024,"finding":"ER-associated Climp63/CKAP4 directs annulate lamellae (AL)-NPCs to ER sheets and the NE, supporting a role for CKAP4 in an AL-driven nuclear pore assembly pathway that is complementary to canonical NPC insertion routes.","method":"Super-resolution microscopy, live cell imaging, genetic perturbation of CKAP4 in AL-NPC localization assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single observation of CKAP4 in AL-NPC direction, limited mechanistic detail for CKAP4 specifically in abstract","pmids":["bio_10.1101_2024.10.08.617205"],"is_preprint":true}],"current_model":"CKAP4/CLIMP-63 is a palmitoylated type II transmembrane protein that resides primarily in the ER, where its luminal domain forms alpha-helical oligomeric complexes that space ER sheets and its cytosolic domain anchors the ER to microtubules (regulated by CDK1-dependent phosphorylation at S3/S17/S19 during mitosis); at the plasma membrane it functions as a receptor for multiple ligands (DKK1, DKK3, APF, SP-A, tPA, EGFL6, TmpC), coupling to PI3K-AKT signaling via a proline-rich domain/SH3 interaction, and also regulates integrin recycling via SNX17, mitochondrial Ca²⁺ homeostasis via palmitoylation-dependent VDAC2 binding at ER-MAM contact sites, ER-phagy as an adaptor for FKBPL-LC3/GABARAP, reticulophagy by protecting RETREG1 from TRIM21-mediated ubiquitination, mechanosensing through Talin1 in macrophages and phase separation-driven microtubule remodeling in cancer cells, and atrial fibrosis through WNT3A/WNT5A-β-catenin signaling."},"narrative":{"mechanistic_narrative":"CKAP4 (CLIMP-63/p63) is a palmitoylated type II ER transmembrane protein that performs two distinct classes of function: shaping endoplasmic reticulum architecture from within the ER and acting as a multi-ligand signaling receptor at the plasma membrane [PMID:11402071, PMID:27322059]. In the ER, its luminal alpha-helical domain self-associates into oligomeric rod-like complexes that act as a luminal bridge spacing apposed ER sheet membranes and setting sheet luminal width, while excluding the protein from the nuclear envelope [PMID:11402071, PMID:31751826, PMID:32612999, PMID:37039099]. S-acylation by ZDHHC6 drives assembly of these trimeric units into highly stable super-complexes that control ER sheet abundance and fenestration [PMID:36650170], and CLIMP-63 together with reticulon 4a organizes nanoscale luminal compartmentalization along peripheral ER tubules [PMID:31469817]. Its cytosolic N-terminal segment anchors the ER to microtubules, immobilizing translocon complexes in rough ER; CDK1-dependent phosphorylation at S3/S17/S19 during mitosis releases this anchorage, and failure to release it causes mitotic delays and nuclear fragmentation [PMID:15703217, PMID:17567679, PMID:bio_10.1101_2025.09.01.673496]. At the cell surface CKAP4 serves as a receptor for diverse ligands—DKK1, DKK3, the antiproliferative factor APF, surfactant protein A, and tPA—coupling, in the case of DKK1, to PI3K-AKT signaling through an interaction between its proline-rich domain and the PI3K SH3 domain to drive tumor cell proliferation [PMID:12913003, PMID:17030514, PMID:18708633, PMID:27322059, PMID:30181180]. DKK1 binding induces depalmitoylation-dependent translocation of CKAP4 out of lipid rafts and formation of a ternary complex with LRP6, with palmitoylation itself required for proliferative signaling [PMID:31744930]. Beyond receptor signaling, palmitoylation at Cys100 targets CKAP4 to ER-mitochondria contact sites where it binds VDAC2 to regulate mitochondrial Ca²⁺ handling and respiration [PMID:33067255], and CKAP4 acts as an adaptor in ER-phagy and reticulophagy by bridging FKBPL to LC3/GABARAP and by shielding RETREG1 from TRIM21-mediated degradation [PMID:39251576, PMID:39689859]. Additional roles span integrin recycling via SNX17 [PMID:31160493], mechanosensing via Talin1 in macrophages [PMID:42207635], phase-separation-driven microtubule remodeling [PMID:39528501], and WNT/β-catenin-dependent atrial fibrosis [PMID:41159262].","teleology":[{"year":2001,"claim":"Established the structural basis for CLIMP-63's ER-shaping role by showing its luminal domain self-oligomerizes and restricts the protein to ER subdomains, answering how a single transmembrane protein could organize ER membrane geometry.","evidence":"Mutagenesis, immunoEM, FRAP, circular dichroism, and analytical ultracentrifugation of the recombinant luminal segment","pmids":["11402071"],"confidence":"High","gaps":["Did not resolve the atomic structure of the oligomer","Did not directly demonstrate sheet-spacing in reconstituted membranes"]},{"year":2003,"claim":"Revealed an unexpected plasma-membrane life for CKAP4 by identifying it as the cell-surface tPA receptor on vascular smooth muscle, opening the question of how an ER protein reaches the surface to signal.","evidence":"Surface labeling, affinity chromatography, MS identification, antibody blocking, and heterologous expression of a membrane-targeted mutant","pmids":["12913003"],"confidence":"High","gaps":["Mechanism of ER-to-plasma-membrane trafficking not addressed","Downstream signaling not defined"]},{"year":2005,"claim":"Showed that mitotic phosphorylation at S3/S17/S19 in the cytosolic domain switches off microtubule binding, explaining how ER-microtubule anchoring is regulated across the cell cycle.","evidence":"32P metabolic labeling, in vitro microtubule-binding assay, phospho-mimic mutagenesis, and interphase overexpression","pmids":["15703217"],"confidence":"High","gaps":["Identity of the responsible kinase not established at this stage","In vivo mitotic consequence not yet tested"]},{"year":2008,"claim":"Demonstrated CKAP4 as a substrate of the palmitoyl acyltransferase DHHC2, establishing palmitoylation as a regulatory modification.","evidence":"PICA palmitoyl-proteomics in living cells","pmids":["18296695"],"confidence":"Medium","gaps":["No site-specific mutagenesis validation","Functional consequence of DHHC2-dependent palmitoylation not tested"]},{"year":2008,"claim":"Consolidated CKAP4 as a functional surface receptor by confirming, with radioligand binding and knockdown-rescue, that p63 mediates SP-A-dependent regulation of surfactant secretion in lung type II cells.","evidence":"Radioligand binding, siRNA knockdown with functional rescue, antibody blocking, immunogold EM; preceded by cross-linking/MS identification (2006)","pmids":["18708633","16556726","17030514"],"confidence":"High","gaps":["Signal transduction downstream of SP-A binding undefined","Did not connect surface and ER pools mechanistically"]},{"year":2010,"claim":"Linked CKAP4 surface delivery to PI3K-AKT signaling, beginning to explain how the receptor pool is mobilized to the plasma membrane.","evidence":"Cell fractionation, PI3K inhibition (LY-294002), AKT activation and lipid-turnover assays in pneumocytes","pmids":["20870746"],"confidence":"Medium","gaps":["Causality between AKT and trafficking not fully resolved","Single lab, single cell type"]},{"year":2012,"claim":"Identified a luminal-domain interaction with Dicer that stabilizes Dicer and supports pre-miRNA processing, hinting at functions beyond membrane shaping.","evidence":"Yeast two-hybrid, Co-IP, pre-miRNA processing and reporter assays, knockdown","pmids":["23047949"],"confidence":"Medium","gaps":["Topological basis for a luminal protein engaging cytosolic Dicer unresolved","Not independently confirmed"]},{"year":2016,"claim":"Defined CKAP4 as a DKK1 receptor coupling to PI3K-AKT via a proline-rich/SH3 interaction, establishing a proliferative signaling axis distinct from canonical Wnt and providing an antibody therapeutic rationale.","evidence":"Co-IP, affinity measurements, clathrin endocytosis assay, domain mutagenesis, AKT assays, anti-CKAP4 antibody, xenograft","pmids":["27322059"],"confidence":"High","gaps":["Structure of the DKK1-CKAP4 complex not solved","How surface vs ER pools are partitioned not resolved"]},{"year":2018,"claim":"Extended the receptor repertoire to DKK3 and refined ligand-binding mapping for APF, showing CKAP4 mediates proliferative signaling for multiple secreted ligands.","evidence":"Co-IP, antibody blocking, xenograft, ChIP for DKK3 regulation; SPR domain mapping for APF","pmids":["30181180","28893174"],"confidence":"High","gaps":["Shared vs distinct downstream pathways across ligands not compared","APF mapping lacked cell-based validation"]},{"year":2019,"claim":"Mechanistically resolved DKK1 signaling regulation through palmitoylation-dependent raft localization and a CKAP4-LRP6 ternary complex, integrating lipid modification with surface signaling output.","evidence":"DRM fractionation, palmitoylation and APT inhibitor assays, ternary-complex Co-IP, knockdown with proliferation readouts","pmids":["31744930"],"confidence":"High","gaps":["Specific APT enzymes not identified","Quantitative coupling of depalmitoylation to AKT kinetics not defined"]},{"year":2019,"claim":"Broadened CKAP4 cell-biological roles to integrin recycling via SNX17 and to ER nanodomain organization with RTN4a, demonstrating functions independent of ligand signaling.","evidence":"Reciprocal Co-IP and trafficking assays (SNX17/β1 integrin); STED super-resolution imaging with perturbation (RTN4a); VIMP/SelS Co-IP and ER spreading; calumenin-1 antagonism","pmids":["31160493","31469817","25008318","31751826"],"confidence":"High","gaps":["How CKAP4 partitions among these roles in one cell unclear","Regulators selecting between functions undefined"]},{"year":2020,"claim":"Showed palmitoylation at Cys100 localizes CKAP4 to ER-mitochondria contacts where it binds VDAC2 to control mitochondrial Ca²⁺ and respiration, defining a structural-to-metabolic function.","evidence":"Co-IP, CKAP4 KO, C100A mutagenesis, Ca²⁺ and membrane potential measurements, Seahorse OCR, EM, xenograft","pmids":["33067255"],"confidence":"High","gaps":["How CKAP4 competes with IP3R for VDAC2 mechanistically unresolved","Relationship to its ER-shaping oligomers not defined"]},{"year":2023,"claim":"Provided a quantitative model of how ZDHHC6-mediated acylation-deacylation cycling assembles trimeric CLIMP-63 into super-complexes that tune ER sheet abundance and fenestration, and resolved the luminal domain architecture underlying sheet width.","evidence":"Native MS, acylation kinetics, mathematical modelling, super-resolution and FIB-EM; deep-learning structure with mutagenesis and ER-width measurements; proteoliposome reconstitution","pmids":["36650170","37039099","32612999"],"confidence":"High","gaps":["Experimental high-resolution structure of the assembled super-complex still lacking","Coupling between acylation-driven assembly and microtubule anchoring not addressed"]},{"year":2024,"claim":"Established CKAP4 as an adaptor in selective ER autophagy, bridging FKBPL to LC3/GABARAP and shielding RETREG1 from TRIM21-mediated degradation, defining a role in ER-phagy/reticulophagy.","evidence":"Gain-of-function screen, Co-IP, KO with organelle and secretion phenotypes (FKBPL); Co-IP, site-mapped ubiquitination, competition binding, reticulophagy assays (RETREG1/TRIM21)","pmids":["39251576","39689859"],"confidence":"High","gaps":["How CKAP4 switches between ER-shaping and autophagy-adaptor roles unknown","Regulation of FKBPL vs RETREG1 engagement undefined"]},{"year":2025,"claim":"Expanded the disease-relevant signaling functions of surface/intracellular CKAP4 to mechanosensing (Talin1, macrophages), phase-separation-driven microtubule remodeling, WNT/β-catenin-driven atrial fibrosis, and bacterial (TmpC) invasion in oral cancer.","evidence":"Co-IP, conditional KO and wound models (Talin1); IDR domain mutants and phase-separation imaging (microtubules); Co-IP/PLA and in vivo cardiac models (WNT3A/WNT5A); Co-IP and in vivo metastasis (TmpC/RanBP2/NBR1)","pmids":["42207635","39528501","41159262","40055343"],"confidence":"High","gaps":["These contexts have not been integrated into a unified model of CKAP4 function","Most rest on single-lab studies in distinct systems"]},{"year":null,"claim":"It remains unresolved how a single protein partitions between its ER-architectural, receptor-signaling, organelle-contact, and autophagy-adaptor roles, and what determines its localization and complex membership in a given cellular state.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of the assembled super-complex or any ligand-receptor complex","Determinants partitioning ER vs surface vs MAM vs autophagy pools unknown","Cycle-cycle/palmitoylation crosstalk with signaling untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,5,29,33]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[2,3,4,12,14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[12,16,14]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,19,21,24,25]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[27,28,17]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,5,18,24]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,12,16]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,5,29]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[20]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[23,27]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,14,16,31]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[27,28]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,24]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[17,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,33]}],"complexes":[],"partners":["DKK1","LRP6","VDAC2","SNX17","FKBPL","RETREG1","TALIN1","DKK3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q07065","full_name":"Cytoskeleton-associated protein 4","aliases":["63-kDa cytoskeleton-linking membrane protein","Climp-63","p63"],"length_aa":602,"mass_kda":66.0,"function":"Mediates the anchoring of the endoplasmic reticulum to microtubules High-affinity epithelial cell surface receptor for the FZD8-related low molecular weight sialoglycopeptide APF/antiproliferative factor. Mediates the APF antiproliferative signaling within cells","subcellular_location":"Endoplasmic reticulum membrane; Cell membrane; Cytoplasm, cytoskeleton; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q07065/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CKAP4","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000136026","cell_line_id":"CID001531","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"FBXO28","stoichiometry":0.2},{"gene":"HACD3","stoichiometry":0.2},{"gene":"EIF2AK2","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"PGRMC1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001531","total_profiled":1310},"omim":[{"mim_id":"618621","title":"ZDHHC PALMITOYLTRANSFERASE 2; ZDHHC2","url":"https://www.omim.org/entry/618621"},{"mim_id":"618595","title":"CYTOSKELETON-ASSOCIATED PROTEIN 4; CKAP4","url":"https://www.omim.org/entry/618595"},{"mim_id":"615815","title":"SMOOTH MUSCLE- AND ENDOTHELIAL CELL-ENRICHED MIGRATION/DIFFERENTIATION-ASSOCIATED LONG NONCODING RNA; SENCR","url":"https://www.omim.org/entry/615815"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CKAP4"},"hgnc":{"alias_symbol":["P63","CLIMP-63","CLIMP63","ERGIC-63"],"prev_symbol":[]},"alphafold":{"accession":"Q07065","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07065","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q07065-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q07065-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CKAP4","jax_strain_url":"https://www.jax.org/strain/search?query=CKAP4"},"sequence":{"accession":"Q07065","fasta_url":"https://rest.uniprot.org/uniprotkb/Q07065.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q07065/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07065"}},"corpus_meta":[{"pmid":"27322059","id":"PMC_27322059","title":"CKAP4 is a Dickkopf1 receptor and is involved in tumor progression.","date":"2016","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/27322059","citation_count":165,"is_preprint":false},{"pmid":"30610103","id":"PMC_30610103","title":"CKAP4, a DKK1 Receptor, Is a Biomarker in Exosomes Derived from Pancreatic Cancer and a Molecular Target for Therapy.","date":"2019","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30610103","citation_count":116,"is_preprint":false},{"pmid":"11402071","id":"PMC_11402071","title":"Subdomain-specific localization of CLIMP-63 (p63) in the endoplasmic reticulum is mediated by its luminal alpha-helical segment.","date":"2001","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11402071","citation_count":111,"is_preprint":false},{"pmid":"15703217","id":"PMC_15703217","title":"Phosphorylation controls CLIMP-63-mediated anchoring of the endoplasmic reticulum to microtubules.","date":"2005","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15703217","citation_count":103,"is_preprint":false},{"pmid":"18296695","id":"PMC_18296695","title":"Identification of CKAP4/p63 as a major substrate of the palmitoyl acyltransferase DHHC2, a putative tumor suppressor, using a novel proteomics method.","date":"2008","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/18296695","citation_count":96,"is_preprint":false},{"pmid":"30584103","id":"PMC_30584103","title":"SENCR stabilizes vascular endothelial cell adherens junctions through interaction with CKAP4.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30584103","citation_count":86,"is_preprint":false},{"pmid":"17030514","id":"PMC_17030514","title":"CKAP4/p63 is a receptor for the frizzled-8 protein-related antiproliferative factor from interstitial cystitis patients.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17030514","citation_count":85,"is_preprint":false},{"pmid":"12913003","id":"PMC_12913003","title":"Functional regulation of tissue plasminogen activator on the surface of vascular smooth muscle cells by the type-II transmembrane protein p63 (CKAP4).","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12913003","citation_count":58,"is_preprint":false},{"pmid":"16556726","id":"PMC_16556726","title":"Identification and characterization of p63 (CKAP4/ERGIC-63/CLIMP-63), a surfactant protein A binding protein, on type II pneumocytes.","date":"2006","source":"American journal of physiology. 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The recombinant luminal segment forms 91-nm alpha-helical rod-like complexes via electrostatic interactions of coiled coils, mediating oligomerization that prevents nuclear envelope localization and potentially contributes to ER morphology.\",\n      \"method\": \"Mutagenesis, confocal microscopy (live cells), immunoelectron microscopy, FRAP, circular dichroism spectroscopy, electron microscopy, analytical ultracentrifugation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of purified luminal domain, mutagenesis, multiple orthogonal structural and cell biology methods in one rigorous study\",\n      \"pmids\": [\"11402071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CLIMP-63 is phosphorylated during mitosis at serines 3, 17, and 19 in its cytoplasmic domain, and this phosphorylation abolishes its ability to bind microtubules in vitro. Phospho-mimicking mutations (S3E/S17E/S19E) prevent microtubule binding, and overexpression of the phospho-mimicking form in interphase cells causes ER collapse around the nucleus while leaving the microtubule network intact. Thus phosphorylation controls CLIMP-63-mediated anchoring of the ER to microtubules.\",\n      \"method\": \"Metabolic 32P labeling, in vitro microtubule-binding assay, site-directed mutagenesis, overexpression in interphase cells, confocal microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assay with mutagenesis, corroborated by cell biological phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"15703217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CKAP4/p63 was identified as the cell-surface tPA (tissue plasminogen activator) binding protein on vascular smooth muscle cells. An anti-p63 antibody blocked tPA binding, and heterologous expression of an N-terminally truncated, plasma-membrane-targeted p63 mutant increased tPA-catalyzed plasminogen activation, demonstrating that cell-surface CKAP4 functionally regulates the plasminogen activation system.\",\n      \"method\": \"Surface 125I labeling, affinity chromatography, MALDI-MS and nano-ESI-MS/MS protein identification, immunofluorescence microscopy, antibody blocking assay, heterologous expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal identification by MS, antibody blocking, and functional overexpression in one study\",\n      \"pmids\": [\"12913003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CKAP4/p63 is a high-affinity cell-surface receptor for the antiproliferative factor (APF) sialoglycopeptide. Anti-CKAP4 antibodies and siRNA knockdown of CKAP4 blocked APF-mediated antiproliferative activity on bladder epithelial and HeLa cells. Co-localization of anti-CKAP4 antibody with rhodamine-labeled synthetic APF was observed in cell membrane and perinuclear areas.\",\n      \"method\": \"Antibody blocking assay, siRNA knockdown, immunofluorescent confocal microscopy, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blocking plus siRNA knockdown with functional readout, multiple orthogonal approaches\",\n      \"pmids\": [\"17030514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CKAP4/p63 was identified as a specific cell-surface SP-A (surfactant protein A) binding protein on type II pneumocytes by chemical cross-linking, mass spectrometry, co-immunoprecipitation, and antibody blocking of SP-A-mediated inhibition of ATP-stimulated phospholipid secretion. Both intracellular and plasma membrane pools of p63 were detected, and p63 co-localized with SP-A in early endosomes.\",\n      \"method\": \"Chemical cross-linking (sulfo-SBED, DSP), streptavidin pulldown, MALDI-MS/nano-ESI-MS/MS, co-immunoprecipitation, immunofluorescence, functional phospholipid secretion assay\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cross-linking, MS, co-IP, functional assay) independently establishing SP-A/CKAP4 interaction and function\",\n      \"pmids\": [\"16556726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CLIMP-63-mediated binding of ER to microtubules restricts the lateral mobility of translocon complexes in rough ER. Depletion of CLIMP-63 by siRNA or expression of a CLIMP-63 mutant lacking the microtubule-binding domain significantly increased diffusion rates of translocon complexes (measured by FRAP), demonstrating that CLIMP-63/microtubule interaction immobilizes translocon complexes assembled into membrane-bound polysomes.\",\n      \"method\": \"FRAP, siRNA knockdown, dominant-negative mutant overexpression, drug-induced microtubule depolymerization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP with genetic/pharmacological perturbations and domain mutant, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"17567679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CKAP4/p63 was identified as a major substrate of the palmitoyl acyltransferase DHHC2 using the PICA (palmitoyl-cysteine isolation capture and analysis) proteomics method in a living vertebrate system.\",\n      \"method\": \"Novel proteomics method (PICA) for PAT-substrate identification in living cells\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, novel proteomics method identifying PAT-substrate pair, no mutagenesis validation described in abstract\",\n      \"pmids\": [\"18296695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"p63/CKAP4 antibody blocked specific (calcium-dependent) binding of 125I-SP-A to type II cells. siRNA knockdown of p63 reduced p63 expression, attenuated p63-specific SP-A binding, and reversed the ability of SP-A to prevent surfactant secretion. cAMP-stimulated increase in calcium-dependent SP-A binding was also blocked by p63 antibody, confirming p63 as the functional SP-A receptor on lung type II cells.\",\n      \"method\": \"Radioligand binding assay (125I-SP-A), siRNA knockdown, antibody blocking, surfactant secretion functional assay, immunogold electron microscopy\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — radioligand binding, siRNA knockdown with functional rescue, antibody blocking, multiple orthogonal methods confirming SP-A receptor function\",\n      \"pmids\": [\"18708633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The PI3K-AKT signaling pathway mediates intracellular transport of CKAP4/p63 from the ER to the plasma membrane of type II pneumocytes. SP-A or cAMP exposure increased p63 on the plasma membrane and activated AKT; treatment with PI3K inhibitor LY-294002 prevented SP-A-induced plasma membrane enrichment of p63 and altered SP-A-mediated lipid turnover.\",\n      \"method\": \"Cell fractionation, radioligand binding assay, PI3K inhibitor treatment, AKT activation assay, SP-A-mediated liposome uptake assay\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition of PI3K with multiple functional readouts, single lab\",\n      \"pmids\": [\"20870746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CLIMP-63 palmitoylation is required for gentamicin-induced dimerization; transfection of palmitoylation-deficient CLIMP-63 mutants into 293T cells showed that the gentamicin-dependent DTT-resistant dimerization requires palmitoylation. Gentamicin also enhanced CLIMP-63 binding to 14-3-3 proteins. CLIMP-63 siRNA knockdown enhanced cellular resistance to gentamicin-induced apoptosis, indicating CLIMP-63 mediates aminoglycoside cytotoxicity.\",\n      \"method\": \"Gentamicin-agarose pulldown, MS identification, Western blotting (DTT-resistant dimer), palmitoylation-deficient mutagenesis, siRNA knockdown, apoptosis assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of palmitoylation site, siRNA knockdown with functional readout, single lab\",\n      \"pmids\": [\"21368867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CLIMP-63 interacts with Dicer to form a high-molecular-weight complex that is electrostatic in nature and not mediated by RNA, and is catalytically active in pre-microRNA processing. CLIMP-63 is required for stabilizing Dicer protein levels; knockdown of CLIMP-63 reduced Dicer abundance. The interaction involves a portion of the luminal domain of CLIMP-63. Dicer was found to interact with CLIMP-63 within minutes of its synthesis, and both can be co-secreted.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, high-molecular-weight complex analysis, pre-miRNA processing assay, reporter gene assay, knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus functional pre-miRNA processing assay, single lab\",\n      \"pmids\": [\"23047949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"VIMP/SelS interacts with CLIMP-63 and both link the ER to microtubules. Depletion of VIMP causes ER spreading to the cell periphery and affects MT-dependent ER processes; VIMP interacts with CLIMP-63 and syntaxin 5L but not with tubular ER MT-binding proteins (such as Reep1), indicating that distinct sets of MT-binding ER proteins organize different ER subdomains.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and knockdown with localization phenotype, multiple proteins tested, single lab\",\n      \"pmids\": [\"25008318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CKAP4 functions as a cell-surface receptor for DKK1. DKK1 binds CKAP4 and LRP6 with similar affinity but uses different cysteine-rich domains. DKK1 induces clathrin-dependent internalization of CKAP4. DKK1/CKAP4 signaling activates AKT by forming a complex between the proline-rich domain of CKAP4 and the SH3 domain of PI3K. Anti-CKAP4 antibody blocked DKK1 binding, suppressed AKT activity, and attenuated xenograft tumor formation.\",\n      \"method\": \"Co-immunoprecipitation, binding affinity measurements, clathrin-dependent endocytosis assay, domain mutagenesis, AKT phosphorylation assay, anti-CKAP4 antibody blocking, xenograft mouse model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, domain mutants, functional signaling assays, in vivo xenograft), single rigorous study\",\n      \"pmids\": [\"27322059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"APF binds specifically to two sites within the extracellular domain of CKAP4 (residues 127-360 and 361-524), as determined by surface plasmon resonance using deletion mutants. Both regions contribute relatively equally to overall APF binding affinity with fast association and slow dissociation rates.\",\n      \"method\": \"Surface plasmon resonance (SPR), recombinant domain deletion mutants\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro SPR binding assay with deletion mutants, single lab, no cell-based validation reported in abstract\",\n      \"pmids\": [\"28893174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DKK3 stimulates esophageal cancer cell proliferation via CKAP4, which acts as a receptor for DKK3. Anti-CKAP4 antibody inhibited both DKK3 binding to CKAP4 and xenograft tumor formation. The transcription factor ΔNp63α (p53-family member) bound to the upstream region of the DKK3 gene and regulated its expression; DKK3 reexpression partially rescued proliferation in p63-depleted cells.\",\n      \"method\": \"Co-immunoprecipitation (DKK3-CKAP4 binding), antibody blocking assay, xenograft tumor model, ChIP (p63 binding to DKK3 promoter), siRNA knockdown, organoid growth assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus antibody blocking plus in vivo xenograft plus ChIP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30181180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SENCR lncRNA stabilizes endothelial cell adherens junctions through physical interaction with CKAP4. A noncanonical RNA-binding domain in CKAP4 binds SENCR (confirmed by biotinylated RNA pulldown, MS, and RNA immunoprecipitation). Upon SENCR knockdown, CKAP4 levels increase at the EC surface fraction and CKAP4 interaction with CDH5 is enhanced, destabilizing the CDH5/CTNND1 complex and augmenting CDH5 internalization, resulting in impaired adherens junctions.\",\n      \"method\": \"Biotinylated RNA pulldown, mass spectrometry, RNA immunoprecipitation, surface fractionation, co-immunoprecipitation (CKAP4-CDH5), siRNA knockdown, EC permeability assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA pulldown + MS + RIP + Co-IP + functional permeability assay, multiple orthogonal methods identifying noncanonical RNA-binding activity and downstream complex\",\n      \"pmids\": [\"30584103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CKAP4 and LRP6 primarily localize to detergent-resistant membrane (DRM/lipid raft) fractions of the plasma membrane in a palmitoylation-dependent manner. DKK1 induces depalmitoylation of both CKAP4 and LRP6 by acylprotein thioesterases (APTs), causing translocation to non-DRM fractions. DKK1-dependent depalmitoylation requires PI3K-AKT pathway activation. DKK1 simultaneously binds CKAP4 and LRP6 forming a ternary complex; LRP5/6 knockdown decreases DKK1-dependent AKT activation through CKAP4; CKAP4 knockdown does not affect DKK1-dependent inhibition of Wnt signaling through LRP5/6. Palmitoylation of CKAP4 is required for cell proliferation.\",\n      \"method\": \"DRM fractionation, palmitoylation assay, APT inhibitor treatment, siRNA knockdown, co-immunoprecipitation (ternary complex), AKT phosphorylation assay, cell proliferation assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — DRM fractionation, palmitoylation assay, Co-IP of ternary complex, genetic knockdown with functional readouts, multiple orthogonal methods\",\n      \"pmids\": [\"31744930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CKAP4 interacts with β1 integrin and controls recycling of α5β1 integrin independently of DKK1. CKAP4 knockdown enlarged cell adhesion sites, enhanced cell adhesion to fibronectin, and decreased cell migration. In CKAP4-depleted cells, surface α5 integrin levels increased due to upregulated recycling (not altered internalization). CKAP4 bound to sorting nexin 17 (SNX17), a mediator of integrin recycling; CKAP4 knockdown enhanced recruitment of α5β1 integrin to SNX17.\",\n      \"method\": \"Co-immunoprecipitation (CKAP4-β1 integrin; CKAP4-SNX17), siRNA knockdown, cell surface biotinylation assay, internalization/recycling assay, adhesion and migration assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, integrin trafficking assay, siRNA knockdown with mechanistic epistasis (SNX17), multiple orthogonal methods\",\n      \"pmids\": [\"31160493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CLIMP-63 and reticulon 4a (RTN4a) regulate the organization and dynamics of peripheral ER tubule nanodomains. CLIMP-63 associates with and increases lumenal blob length along ER tubules, while RTN4a segregates away from and restricts lumenal blob length. Both proteins regulate nanodomain distribution of ER-resident proteins (calnexin, derlin-1) and dynamic nanoscale lumenal compartmentalization along peripheral ER tubules.\",\n      \"method\": \"STED super-resolution microscopy, high-speed live-cell STED imaging, knockdown/overexpression\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — STED super-resolution microscopy with genetic perturbations, single lab\",\n      \"pmids\": [\"31469817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Calumenin-1 (Calu1) specifically interacts with Climp63 and antagonizes Climp63 in ER sheet distribution and luminal width. The luminal length of Climp63 positively correlates with the luminal width of ER sheets; a lumen-only Climp63 mutant dominantly narrows ER lumen, demonstrating that Climp63 acts as an ER luminal bridge.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutants, fluorescence microscopy of ER morphology\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus domain mutant analysis, single lab, moderate evidence\",\n      \"pmids\": [\"31751826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Palmitoylated CKAP4 at Cys100 binds to VDAC2 at ER-mitochondria contact sites (MAMs). CKAP4 knockout increased ER-mitochondria contact sites and altered mitochondrial structure. In CKAP4 KO cells, IP3R-VDAC2 binding was enhanced, intramitochondrial Ca2+ increased, mitochondrial membrane potential decreased, and oxidative consumption rate was reduced. A palmitoylation-deficient CKAP4 mutant did not rescue these phenotypes, confirming palmitoylation at Cys100 is required for VDAC2 binding and mitochondrial function.\",\n      \"method\": \"Co-immunoprecipitation (CKAP4-VDAC2; IP3R-VDAC2), CKAP4 knockout (HeLaS3), palmitoylation-deficient mutagenesis (C100A), Ca2+ measurement, mitochondrial membrane potential assay, Seahorse OCR, electron microscopy, xenograft tumor model\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, KO, site-specific mutagenesis, multiple functional readouts (Ca2+, membrane potential, OCR), orthogonal methods in one rigorous study\",\n      \"pmids\": [\"33067255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Purified full-length Climp63 reconstituted into proteoliposomes with luminal domain facing outward retains homotypic self-association that can be competed by soluble luminal domain. The luminal domain (LD) forms low-order oligomers in solution; the full-length protein shows moderate homotypic interactions. These results directly support Climp63 as an ER luminal spacer through self-association.\",\n      \"method\": \"Protein purification and reconstitution into proteoliposomes, in vitro binding/competition assay, biochemical oligomerization analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstitution in proteoliposomes, single lab, no mutagenesis validation\",\n      \"pmids\": [\"32612999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DKK1 activates noncanonical NF-κB signaling via CKAP4 in multiple myeloma cells. CKAP4 transduces the DKK1 signal by recruiting and preventing CAND1 from inhibiting E3 ligase-mediated ubiquitination of IκBα. IL-6 stimulates CKAP4 expression to generate bortezomib resistance. Disruption of the DKK1-CKAP4 axis improved BTZ sensitivity and attenuated bone destruction in a mouse model.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/shRNA knockdown, drug resistance assay, NF-κB pathway assays, in vivo mouse model\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional signaling assay plus in vivo model, single lab, mechanism partially described in abstract\",\n      \"pmids\": [\"34470047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GOLPH3 interacts with CKAP4 (by immunoprecipitation-MS) and decreases plasma membrane-localized CKAP4 while increasing exosome-localized CKAP4, thereby promoting formation of CKAP4-containing exosomes. CKAP4 in turn binds exosomal WNT3A to enhance its secretion, activating WNT/β-catenin signaling and maintaining stem-like phenotype and metastasis in NSCLC cells.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, cell fractionation (plasma membrane vs exosome), luciferase-reporter assay, nuclear extract assay, in vivo metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — IP-MS plus Co-IP plus functional assays, single lab\",\n      \"pmids\": [\"34671013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CLIMP-63 S-acylation (by ZDHHC6 in the ER) drives assembly into highly stable super-complexes. In the ER, CLIMP-63 assembles into trimeric units which can exit to the plasma membrane; the majority undergoes ZDHHC6-mediated S-acylation leading to super-complex formation. CLIMP-63 acylation-deacylation cycle controls the abundance and fenestration of ER sheets, as shown by super-resolution and FIB-EM.\",\n      \"method\": \"Native mass spectrometry, kinetic analysis of acylation/deacylation, data-driven mathematical modelling, super-resolution microscopy, focused ion beam electron microscopy (FIB-EM)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — native MS, kinetic acylation analysis, mathematical modelling, super-resolution and FIB-EM, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"36650170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The Climp63 luminal domain (LD) is highly alpha-helical with a flexible leading helix followed by a five-helix bundle (5HB). Trans self-associations occur between the tip of the 5HB and the C-terminus of the LD, consistent with generating ~50 nm ER sheet width. The density of Climp63 (reflecting cis interaction strength) influences ER width maintained by trans interactions; the leading helix is dispensable for homotypic interactions but 5HB packing regulates self-association.\",\n      \"method\": \"Deep learning-predicted structure analysis, mutagenesis, ER width measurements, biochemical interaction assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural prediction with mutagenesis validation, single lab, limited experimental structural validation described in abstract\",\n      \"pmids\": [\"37039099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EGFL6 binds to the N-terminus of CKAP4 to promote migration of HUVECs by activating the ERK/MMP pathway. FMNL2 promotes EGFL6 paracrine signaling via exosomes, with CKAP4 as a downstream target of EGFL6 involved in CRC angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation (FMNL2-EGFL6 via GDB/FH3 domain), domain mapping, HUVEC migration assay, ERK/MMP pathway assay, in vitro and in vivo angiogenesis assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus domain mapping plus functional migration assay, single lab\",\n      \"pmids\": [\"36715549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FKBPL functions as an ER-phagy regulator and acts as a scaffold connecting CKAP4 and LC3/GABARAPs; CKAP4 serves as a bridge between FKBPL and ER-phagy cargo. ER-phagy-inducing conditions increase FKBPL-CKAP4 interaction followed by FKBPL oligomerization at the ER, triggering ER-phagy. FKBPL-CKAP4 deficiency leads to Golgi disassembly, lysosome impairment, increased ER-derived secretory vesicles, and enhanced cytosolic protein secretion via microvesicle shedding.\",\n      \"method\": \"Gain-of-function screen, co-immunoprecipitation (FKBPL-CKAP4), CKAP4 knockout, ER-phagy assay, organelle morphology analysis (Golgi, lysosome), secretory vesicle analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic screen, Co-IP, KO with multiple functional readouts, published in rigorous journal\",\n      \"pmids\": [\"39251576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CKAP4 competes with TRIM21 for binding to RETREG1/FAM134B; TRIM21 ubiquitinates RETREG1 at K247 and K252, facilitating its proteasomal degradation, while CKAP4 shields RETREG1 from degradation by competitively binding. CKAP4 and TRIM21 thereby regulate reticulophagy by modulating RETREG1 expression.\",\n      \"method\": \"Co-immunoprecipitation (CKAP4-RETREG1; TRIM21-RETREG1), ubiquitination assay with site mapping (K247/K252), competition binding assay, reticulophagy assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, site-specific ubiquitination mapping, competition binding, functional reticulophagy assay, multiple orthogonal methods\",\n      \"pmids\": [\"39689859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CKAP4 as an intracellular mechanosensor responds to solid stress through liquid-liquid phase separation. The intrinsically disordered region 1 (IDR1) of CKAP4 binds to microtubules, while IDR2 governs phase separation triggered by Cav1.2-dependent calcium influx. CKAP4 phase separation puncta adhere to microtubules and reorchestrate microtubule curvature and branching to enhance cell spreading and migration.\",\n      \"method\": \"Cell-SELEX aptamer, live cell imaging of phase separation, microtubule co-sedimentation/binding assay, domain deletion mutants (IDR1, IDR2), calcium influx inhibition (Cav1.2 blockade), cell migration and in vivo metastasis assays\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — aptamer-based discovery, domain mutants, phase separation imaging, mechanistic calcium pathway, single lab\",\n      \"pmids\": [\"39528501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"P. micra surface protein TmpC binds to CKAP4 on OSCC cells, facilitating bacterial attachment and invasion. This TmpC-CKAP4 interaction activates HIF-1α and autophagy via CKAP4-RanBP2 and CKAP4-NBR1 pathways, driving OSCC metastasis. Targeting CKAP4 with masitinib or antibodies impairs P. micra attachment and abolishes P. micra-promoted OSCC metastasis in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (TmpC-CKAP4; CKAP4-RanBP2; CKAP4-NBR1), bacterial attachment/invasion assay, antibody/masitinib blocking, HIF-1α/autophagy pathway assays, in vivo metastasis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of multiple complexes plus functional blocking plus in vivo model, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"40055343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In atrial fibroblasts, CKAP4 interacts with WNT3A and WNT5A (co-immunoprecipitation and proximity ligation assay) and activates β-catenin signaling. CKAP4 knockdown reduced α-SMA, collagen I/III, vimentin, and migration in atrial fibroblasts. In mice, CKAP4 knockdown attenuated left atrial fibrosis and reduced AF inducibility. The WNT/β-catenin agonist SKL2001 rescued the antifibrotic effects of CKAP4 knockdown, while β-catenin/TCF inhibitor blunted CKAP4-overexpression-induced collagen synthesis.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay (CKAP4-WNT3A/WNT5A), siRNA knockdown and overexpression in atrial fibroblasts, pathway inhibitor/agonist, in vivo mouse cardiac model (TAC, Ang II), atrial fibrosis and AF inducibility assays\",\n      \"journal\": \"Circulation. Arrhythmia and electrophysiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus proximity ligation plus genetic perturbations plus pharmacological epistasis plus in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"41159262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CKAP4 deficiency in macrophages accelerates wound healing by heightening macrophage sensitivity to matrix stiffness. Mechanistically, CKAP4 binds Talin1 to restrain adhesion-associated signaling and STAT6 nuclear translocation. CKAP4 loss triggers cytoskeletal remodeling and a pro-regenerative program at lower stiffness thresholds. Local silencing of Ckap4 in macrophages in a diabetic wound model restored mechanoresponsiveness and improved healing.\",\n      \"method\": \"Co-immunoprecipitation (CKAP4-Talin1), CKAP4 conditional knockout in macrophages, STAT6 nuclear translocation assay, matrix stiffness mechanosensing assay, diabetic wound model, gene expression profiling\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifying Talin1 as binding partner, KO with mechanistic readouts, in vivo disease model, multiple methods\",\n      \"pmids\": [\"42207635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Phosphodeficient Climp63 mutant (preventing mitotic phosphorylation) in HeLa cells maintains ER-MT contacts during mitosis, causing severe mitotic delays and nuclear fragmentation. The N-terminal 28 amino acids of Climp63 are sufficient for MT interaction, and phosphorylation of S17 by CDK1 is critical for mitotic release of ER from MTs.\",\n      \"method\": \"Phosphodeficient Climp63 mutant expression, domain truncation mutants, live cell imaging (mitotic progression), CDK1 kinase assay/phosphorylation analysis, nuclear fragmentation quantification\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphodeficient mutagenesis, domain truncation, live imaging with mitotic readouts; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.01.673496\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ER-associated Climp63/CKAP4 directs annulate lamellae (AL)-NPCs to ER sheets and the NE, supporting a role for CKAP4 in an AL-driven nuclear pore assembly pathway that is complementary to canonical NPC insertion routes.\",\n      \"method\": \"Super-resolution microscopy, live cell imaging, genetic perturbation of CKAP4 in AL-NPC localization assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single observation of CKAP4 in AL-NPC direction, limited mechanistic detail for CKAP4 specifically in abstract\",\n      \"pmids\": [\"bio_10.1101_2024.10.08.617205\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CKAP4/CLIMP-63 is a palmitoylated type II transmembrane protein that resides primarily in the ER, where its luminal domain forms alpha-helical oligomeric complexes that space ER sheets and its cytosolic domain anchors the ER to microtubules (regulated by CDK1-dependent phosphorylation at S3/S17/S19 during mitosis); at the plasma membrane it functions as a receptor for multiple ligands (DKK1, DKK3, APF, SP-A, tPA, EGFL6, TmpC), coupling to PI3K-AKT signaling via a proline-rich domain/SH3 interaction, and also regulates integrin recycling via SNX17, mitochondrial Ca²⁺ homeostasis via palmitoylation-dependent VDAC2 binding at ER-MAM contact sites, ER-phagy as an adaptor for FKBPL-LC3/GABARAP, reticulophagy by protecting RETREG1 from TRIM21-mediated ubiquitination, mechanosensing through Talin1 in macrophages and phase separation-driven microtubule remodeling in cancer cells, and atrial fibrosis through WNT3A/WNT5A-β-catenin signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CKAP4 (CLIMP-63/p63) is a palmitoylated type II ER transmembrane protein that performs two distinct classes of function: shaping endoplasmic reticulum architecture from within the ER and acting as a multi-ligand signaling receptor at the plasma membrane [#0, #12]. In the ER, its luminal alpha-helical domain self-associates into oligomeric rod-like complexes that act as a luminal bridge spacing apposed ER sheet membranes and setting sheet luminal width, while excluding the protein from the nuclear envelope [#0, #19, #21, #25]. S-acylation by ZDHHC6 drives assembly of these trimeric units into highly stable super-complexes that control ER sheet abundance and fenestration [#24], and CLIMP-63 together with reticulon 4a organizes nanoscale luminal compartmentalization along peripheral ER tubules [#18]. Its cytosolic N-terminal segment anchors the ER to microtubules, immobilizing translocon complexes in rough ER; CDK1-dependent phosphorylation at S3/S17/S19 during mitosis releases this anchorage, and failure to release it causes mitotic delays and nuclear fragmentation [#1, #5, #33]. At the cell surface CKAP4 serves as a receptor for diverse ligands—DKK1, DKK3, the antiproliferative factor APF, surfactant protein A, and tPA—coupling, in the case of DKK1, to PI3K-AKT signaling through an interaction between its proline-rich domain and the PI3K SH3 domain to drive tumor cell proliferation [#2, #3, #7, #12, #14]. DKK1 binding induces depalmitoylation-dependent translocation of CKAP4 out of lipid rafts and formation of a ternary complex with LRP6, with palmitoylation itself required for proliferative signaling [#16]. Beyond receptor signaling, palmitoylation at Cys100 targets CKAP4 to ER-mitochondria contact sites where it binds VDAC2 to regulate mitochondrial Ca²⁺ handling and respiration [#20], and CKAP4 acts as an adaptor in ER-phagy and reticulophagy by bridging FKBPL to LC3/GABARAP and by shielding RETREG1 from TRIM21-mediated degradation [#27, #28]. Additional roles span integrin recycling via SNX17 [#17], mechanosensing via Talin1 in macrophages [#32], phase-separation-driven microtubule remodeling [#29], and WNT/β-catenin-dependent atrial fibrosis [#31].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the structural basis for CLIMP-63's ER-shaping role by showing its luminal domain self-oligomerizes and restricts the protein to ER subdomains, answering how a single transmembrane protein could organize ER membrane geometry.\",\n      \"evidence\": \"Mutagenesis, immunoEM, FRAP, circular dichroism, and analytical ultracentrifugation of the recombinant luminal segment\",\n      \"pmids\": [\"11402071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the atomic structure of the oligomer\", \"Did not directly demonstrate sheet-spacing in reconstituted membranes\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed an unexpected plasma-membrane life for CKAP4 by identifying it as the cell-surface tPA receptor on vascular smooth muscle, opening the question of how an ER protein reaches the surface to signal.\",\n      \"evidence\": \"Surface labeling, affinity chromatography, MS identification, antibody blocking, and heterologous expression of a membrane-targeted mutant\",\n      \"pmids\": [\"12913003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ER-to-plasma-membrane trafficking not addressed\", \"Downstream signaling not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that mitotic phosphorylation at S3/S17/S19 in the cytosolic domain switches off microtubule binding, explaining how ER-microtubule anchoring is regulated across the cell cycle.\",\n      \"evidence\": \"32P metabolic labeling, in vitro microtubule-binding assay, phospho-mimic mutagenesis, and interphase overexpression\",\n      \"pmids\": [\"15703217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the responsible kinase not established at this stage\", \"In vivo mitotic consequence not yet tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated CKAP4 as a substrate of the palmitoyl acyltransferase DHHC2, establishing palmitoylation as a regulatory modification.\",\n      \"evidence\": \"PICA palmitoyl-proteomics in living cells\",\n      \"pmids\": [\"18296695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No site-specific mutagenesis validation\", \"Functional consequence of DHHC2-dependent palmitoylation not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Consolidated CKAP4 as a functional surface receptor by confirming, with radioligand binding and knockdown-rescue, that p63 mediates SP-A-dependent regulation of surfactant secretion in lung type II cells.\",\n      \"evidence\": \"Radioligand binding, siRNA knockdown with functional rescue, antibody blocking, immunogold EM; preceded by cross-linking/MS identification (2006)\",\n      \"pmids\": [\"18708633\", \"16556726\", \"17030514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal transduction downstream of SP-A binding undefined\", \"Did not connect surface and ER pools mechanistically\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked CKAP4 surface delivery to PI3K-AKT signaling, beginning to explain how the receptor pool is mobilized to the plasma membrane.\",\n      \"evidence\": \"Cell fractionation, PI3K inhibition (LY-294002), AKT activation and lipid-turnover assays in pneumocytes\",\n      \"pmids\": [\"20870746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between AKT and trafficking not fully resolved\", \"Single lab, single cell type\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a luminal-domain interaction with Dicer that stabilizes Dicer and supports pre-miRNA processing, hinting at functions beyond membrane shaping.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, pre-miRNA processing and reporter assays, knockdown\",\n      \"pmids\": [\"23047949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Topological basis for a luminal protein engaging cytosolic Dicer unresolved\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined CKAP4 as a DKK1 receptor coupling to PI3K-AKT via a proline-rich/SH3 interaction, establishing a proliferative signaling axis distinct from canonical Wnt and providing an antibody therapeutic rationale.\",\n      \"evidence\": \"Co-IP, affinity measurements, clathrin endocytosis assay, domain mutagenesis, AKT assays, anti-CKAP4 antibody, xenograft\",\n      \"pmids\": [\"27322059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the DKK1-CKAP4 complex not solved\", \"How surface vs ER pools are partitioned not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the receptor repertoire to DKK3 and refined ligand-binding mapping for APF, showing CKAP4 mediates proliferative signaling for multiple secreted ligands.\",\n      \"evidence\": \"Co-IP, antibody blocking, xenograft, ChIP for DKK3 regulation; SPR domain mapping for APF\",\n      \"pmids\": [\"30181180\", \"28893174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Shared vs distinct downstream pathways across ligands not compared\", \"APF mapping lacked cell-based validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mechanistically resolved DKK1 signaling regulation through palmitoylation-dependent raft localization and a CKAP4-LRP6 ternary complex, integrating lipid modification with surface signaling output.\",\n      \"evidence\": \"DRM fractionation, palmitoylation and APT inhibitor assays, ternary-complex Co-IP, knockdown with proliferation readouts\",\n      \"pmids\": [\"31744930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific APT enzymes not identified\", \"Quantitative coupling of depalmitoylation to AKT kinetics not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Broadened CKAP4 cell-biological roles to integrin recycling via SNX17 and to ER nanodomain organization with RTN4a, demonstrating functions independent of ligand signaling.\",\n      \"evidence\": \"Reciprocal Co-IP and trafficking assays (SNX17/β1 integrin); STED super-resolution imaging with perturbation (RTN4a); VIMP/SelS Co-IP and ER spreading; calumenin-1 antagonism\",\n      \"pmids\": [\"31160493\", \"31469817\", \"25008318\", \"31751826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CKAP4 partitions among these roles in one cell unclear\", \"Regulators selecting between functions undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed palmitoylation at Cys100 localizes CKAP4 to ER-mitochondria contacts where it binds VDAC2 to control mitochondrial Ca²⁺ and respiration, defining a structural-to-metabolic function.\",\n      \"evidence\": \"Co-IP, CKAP4 KO, C100A mutagenesis, Ca²⁺ and membrane potential measurements, Seahorse OCR, EM, xenograft\",\n      \"pmids\": [\"33067255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CKAP4 competes with IP3R for VDAC2 mechanistically unresolved\", \"Relationship to its ER-shaping oligomers not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided a quantitative model of how ZDHHC6-mediated acylation-deacylation cycling assembles trimeric CLIMP-63 into super-complexes that tune ER sheet abundance and fenestration, and resolved the luminal domain architecture underlying sheet width.\",\n      \"evidence\": \"Native MS, acylation kinetics, mathematical modelling, super-resolution and FIB-EM; deep-learning structure with mutagenesis and ER-width measurements; proteoliposome reconstitution\",\n      \"pmids\": [\"36650170\", \"37039099\", \"32612999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Experimental high-resolution structure of the assembled super-complex still lacking\", \"Coupling between acylation-driven assembly and microtubule anchoring not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established CKAP4 as an adaptor in selective ER autophagy, bridging FKBPL to LC3/GABARAP and shielding RETREG1 from TRIM21-mediated degradation, defining a role in ER-phagy/reticulophagy.\",\n      \"evidence\": \"Gain-of-function screen, Co-IP, KO with organelle and secretion phenotypes (FKBPL); Co-IP, site-mapped ubiquitination, competition binding, reticulophagy assays (RETREG1/TRIM21)\",\n      \"pmids\": [\"39251576\", \"39689859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CKAP4 switches between ER-shaping and autophagy-adaptor roles unknown\", \"Regulation of FKBPL vs RETREG1 engagement undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the disease-relevant signaling functions of surface/intracellular CKAP4 to mechanosensing (Talin1, macrophages), phase-separation-driven microtubule remodeling, WNT/β-catenin-driven atrial fibrosis, and bacterial (TmpC) invasion in oral cancer.\",\n      \"evidence\": \"Co-IP, conditional KO and wound models (Talin1); IDR domain mutants and phase-separation imaging (microtubules); Co-IP/PLA and in vivo cardiac models (WNT3A/WNT5A); Co-IP and in vivo metastasis (TmpC/RanBP2/NBR1)\",\n      \"pmids\": [\"42207635\", \"39528501\", \"41159262\", \"40055343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"These contexts have not been integrated into a unified model of CKAP4 function\", \"Most rest on single-lab studies in distinct systems\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single protein partitions between its ER-architectural, receptor-signaling, organelle-contact, and autophagy-adaptor roles, and what determines its localization and complex membership in a given cellular state.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of the assembled super-complex or any ligand-receptor complex\", \"Determinants partitioning ER vs surface vs MAM vs autophagy pools unknown\", \"Cycle-cycle/palmitoylation crosstalk with signaling untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 5, 29, 33]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [2, 3, 4, 12, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [12, 16, 14]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 19, 21, 24, 25]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [27, 28, 17]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 5, 18, 24]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 12, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 5, 29]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [23, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 14, 16, 31]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [27, 28]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 24]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [17, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 33]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DKK1\", \"LRP6\", \"VDAC2\", \"SNX17\", \"FKBPL\", \"RETREG1\", \"Talin1\", \"DKK3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}