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Showing CKAP4 — P63 is a alias.

CKAP4

Cytoskeleton-associated protein 4 · UniProt Q07065

Length
602 aa
Mass
66.0 kDa
Annotated
2026-06-09
70 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    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

    PMID:11402071

    Open questions at the time
    • Did not resolve the atomic structure of the oligomer
    • Did not directly demonstrate sheet-spacing in reconstituted membranes
  2. 2003 High

    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

    PMID:12913003

    Open questions at the time
    • Mechanism of ER-to-plasma-membrane trafficking not addressed
    • Downstream signaling not defined
  3. 2005 High

    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

    PMID:15703217

    Open questions at the time
    • Identity of the responsible kinase not established at this stage
    • In vivo mitotic consequence not yet tested
  4. 2008 Medium

    Demonstrated CKAP4 as a substrate of the palmitoyl acyltransferase DHHC2, establishing palmitoylation as a regulatory modification.

    Evidence PICA palmitoyl-proteomics in living cells

    PMID:18296695

    Open questions at the time
    • No site-specific mutagenesis validation
    • Functional consequence of DHHC2-dependent palmitoylation not tested
  5. 2008 High

    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)

    PMID:16556726 PMID:17030514 PMID:18708633

    Open questions at the time
    • Signal transduction downstream of SP-A binding undefined
    • Did not connect surface and ER pools mechanistically
  6. 2010 Medium

    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

    PMID:20870746

    Open questions at the time
    • Causality between AKT and trafficking not fully resolved
    • Single lab, single cell type
  7. 2012 Medium

    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

    PMID:23047949

    Open questions at the time
    • Topological basis for a luminal protein engaging cytosolic Dicer unresolved
    • Not independently confirmed
  8. 2016 High

    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

    PMID:27322059

    Open questions at the time
    • Structure of the DKK1-CKAP4 complex not solved
    • How surface vs ER pools are partitioned not resolved
  9. 2018 High

    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

    PMID:28893174 PMID:30181180

    Open questions at the time
    • Shared vs distinct downstream pathways across ligands not compared
    • APF mapping lacked cell-based validation
  10. 2019 High

    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

    PMID:31744930

    Open questions at the time
    • Specific APT enzymes not identified
    • Quantitative coupling of depalmitoylation to AKT kinetics not defined
  11. 2019 High

    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

    PMID:25008318 PMID:31160493 PMID:31469817 PMID:31751826

    Open questions at the time
    • How CKAP4 partitions among these roles in one cell unclear
    • Regulators selecting between functions undefined
  12. 2020 High

    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

    PMID:33067255

    Open questions at the time
    • How CKAP4 competes with IP3R for VDAC2 mechanistically unresolved
    • Relationship to its ER-shaping oligomers not defined
  13. 2023 High

    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

    PMID:32612999 PMID:36650170 PMID:37039099

    Open questions at the time
    • Experimental high-resolution structure of the assembled super-complex still lacking
    • Coupling between acylation-driven assembly and microtubule anchoring not addressed
  14. 2024 High

    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)

    PMID:39251576 PMID:39689859

    Open questions at the time
    • How CKAP4 switches between ER-shaping and autophagy-adaptor roles unknown
    • Regulation of FKBPL vs RETREG1 engagement undefined
  15. 2025 High

    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)

    PMID:39528501 PMID:40055343 PMID:41159262 PMID:42207635

    Open questions at the time
    • These contexts have not been integrated into a unified model of CKAP4 function
    • Most rest on single-lab studies in distinct systems

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 5 GO:0005198 structural molecule activity 5 GO:0008092 cytoskeletal protein binding 4 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0003723 RNA binding 1
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 3 GO:0031410 cytoplasmic vesicle 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9609507 Protein localization 2 R-HSA-9612973 Autophagy 2
Partners
DKK1DKK3FKBPLLRP6RETREG1SNX17TALIN1VDAC2

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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. Mutagenesis, confocal microscopy (live cells), immunoelectron microscopy, FRAP, circular dichroism spectroscopy, electron microscopy, analytical ultracentrifugation The Journal of cell biology High 11402071
2005 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. Metabolic 32P labeling, in vitro microtubule-binding assay, site-directed mutagenesis, overexpression in interphase cells, confocal microscopy Molecular biology of the cell High 15703217
2003 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. Surface 125I labeling, affinity chromatography, MALDI-MS and nano-ESI-MS/MS protein identification, immunofluorescence microscopy, antibody blocking assay, heterologous expression The Journal of biological chemistry High 12913003
2006 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. Antibody blocking assay, siRNA knockdown, immunofluorescent confocal microscopy, cell proliferation assay The Journal of biological chemistry High 17030514
2006 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. Chemical cross-linking (sulfo-SBED, DSP), streptavidin pulldown, MALDI-MS/nano-ESI-MS/MS, co-immunoprecipitation, immunofluorescence, functional phospholipid secretion assay American journal of physiology. Lung cellular and molecular physiology High 16556726
2007 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. FRAP, siRNA knockdown, dominant-negative mutant overexpression, drug-induced microtubule depolymerization Journal of cell science High 17567679
2008 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. Novel proteomics method (PICA) for PAT-substrate identification in living cells Molecular & cellular proteomics : MCP Medium 18296695
2008 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. Radioligand binding assay (125I-SP-A), siRNA knockdown, antibody blocking, surfactant secretion functional assay, immunogold electron microscopy American journal of physiology. Lung cellular and molecular physiology High 18708633
2010 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. Cell fractionation, radioligand binding assay, PI3K inhibitor treatment, AKT activation assay, SP-A-mediated liposome uptake assay American journal of physiology. Lung cellular and molecular physiology Medium 20870746
2010 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. Gentamicin-agarose pulldown, MS identification, Western blotting (DTT-resistant dimer), palmitoylation-deficient mutagenesis, siRNA knockdown, apoptosis assay Cell death & disease Medium 21368867
2012 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. Yeast two-hybrid screen, co-immunoprecipitation, high-molecular-weight complex analysis, pre-miRNA processing assay, reporter gene assay, knockdown Nucleic acids research Medium 23047949
2014 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. Co-immunoprecipitation, siRNA knockdown, immunofluorescence microscopy The Journal of biological chemistry Medium 25008318
2016 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. Co-immunoprecipitation, binding affinity measurements, clathrin-dependent endocytosis assay, domain mutagenesis, AKT phosphorylation assay, anti-CKAP4 antibody blocking, xenograft mouse model The Journal of clinical investigation High 27322059
2017 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. Surface plasmon resonance (SPR), recombinant domain deletion mutants BMC biochemistry Medium 28893174
2018 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. Co-immunoprecipitation (DKK3-CKAP4 binding), antibody blocking assay, xenograft tumor model, ChIP (p63 binding to DKK3 promoter), siRNA knockdown, organoid growth assay Cancer research High 30181180
2018 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. Biotinylated RNA pulldown, mass spectrometry, RNA immunoprecipitation, surface fractionation, co-immunoprecipitation (CKAP4-CDH5), siRNA knockdown, EC permeability assay Proceedings of the National Academy of Sciences of the United States of America High 30584103
2019 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. DRM fractionation, palmitoylation assay, APT inhibitor treatment, siRNA knockdown, co-immunoprecipitation (ternary complex), AKT phosphorylation assay, cell proliferation assay Science signaling High 31744930
2019 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. Co-immunoprecipitation (CKAP4-β1 integrin; CKAP4-SNX17), siRNA knockdown, cell surface biotinylation assay, internalization/recycling assay, adhesion and migration assays Molecular and cellular biology High 31160493
2019 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. STED super-resolution microscopy, high-speed live-cell STED imaging, knockdown/overexpression PLoS biology Medium 31469817
2019 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. Co-immunoprecipitation, domain deletion mutants, fluorescence microscopy of ER morphology iScience Medium 31751826
2020 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. 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 of cell science High 33067255
2020 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. Protein purification and reconstitution into proteoliposomes, in vitro binding/competition assay, biochemical oligomerization analysis Frontiers in cell and developmental biology Medium 32612999
2021 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. Co-immunoprecipitation, siRNA/shRNA knockdown, drug resistance assay, NF-κB pathway assays, in vivo mouse model Blood advances Medium 34470047
2021 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. Immunoprecipitation-mass spectrometry, co-immunoprecipitation, cell fractionation (plasma membrane vs exosome), luciferase-reporter assay, nuclear extract assay, in vivo metastasis model Cell death & disease Medium 34671013
2023 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. Native mass spectrometry, kinetic analysis of acylation/deacylation, data-driven mathematical modelling, super-resolution microscopy, focused ion beam electron microscopy (FIB-EM) Nature communications High 36650170
2023 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. Deep learning-predicted structure analysis, mutagenesis, ER width measurements, biochemical interaction assays Journal of cell science Medium 37039099
2023 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. Co-immunoprecipitation (FMNL2-EGFL6 via GDB/FH3 domain), domain mapping, HUVEC migration assay, ERK/MMP pathway assay, in vitro and in vivo angiogenesis assays Cancer science Medium 36715549
2024 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. Gain-of-function screen, co-immunoprecipitation (FKBPL-CKAP4), CKAP4 knockout, ER-phagy assay, organelle morphology analysis (Golgi, lysosome), secretory vesicle analysis Nature communications High 39251576
2024 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. Co-immunoprecipitation (CKAP4-RETREG1; TRIM21-RETREG1), ubiquitination assay with site mapping (K247/K252), competition binding assay, reticulophagy assay Autophagy High 39689859
2024 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. 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 Cell discovery Medium 39528501
2025 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. Co-immunoprecipitation (TmpC-CKAP4; CKAP4-RanBP2; CKAP4-NBR1), bacterial attachment/invasion assay, antibody/masitinib blocking, HIF-1α/autophagy pathway assays, in vivo metastasis model Nature communications High 40055343
2025 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. 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 Circulation. Arrhythmia and electrophysiology High 41159262
2025 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. Co-immunoprecipitation (CKAP4-Talin1), CKAP4 conditional knockout in macrophages, STAT6 nuclear translocation assay, matrix stiffness mechanosensing assay, diabetic wound model, gene expression profiling Cell reports High 42207635
2025 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. Phosphodeficient Climp63 mutant expression, domain truncation mutants, live cell imaging (mitotic progression), CDK1 kinase assay/phosphorylation analysis, nuclear fragmentation quantification bioRxivpreprint Medium bio_10.1101_2025.09.01.673496
2024 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. Super-resolution microscopy, live cell imaging, genetic perturbation of CKAP4 in AL-NPC localization assay bioRxivpreprint Low bio_10.1101_2024.10.08.617205

Source papers

Stage 0 corpus · 70 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 CKAP4 is a Dickkopf1 receptor and is involved in tumor progression. The Journal of clinical investigation 165 27322059
2019 CKAP4, a DKK1 Receptor, Is a Biomarker in Exosomes Derived from Pancreatic Cancer and a Molecular Target for Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 116 30610103
2001 Subdomain-specific localization of CLIMP-63 (p63) in the endoplasmic reticulum is mediated by its luminal alpha-helical segment. The Journal of cell biology 111 11402071
2005 Phosphorylation controls CLIMP-63-mediated anchoring of the endoplasmic reticulum to microtubules. Molecular biology of the cell 103 15703217
2008 Identification of CKAP4/p63 as a major substrate of the palmitoyl acyltransferase DHHC2, a putative tumor suppressor, using a novel proteomics method. Molecular & cellular proteomics : MCP 96 18296695
2018 SENCR stabilizes vascular endothelial cell adherens junctions through interaction with CKAP4. Proceedings of the National Academy of Sciences of the United States of America 86 30584103
2006 CKAP4/p63 is a receptor for the frizzled-8 protein-related antiproliferative factor from interstitial cystitis patients. The Journal of biological chemistry 85 17030514
2003 Functional regulation of tissue plasminogen activator on the surface of vascular smooth muscle cells by the type-II transmembrane protein p63 (CKAP4). The Journal of biological chemistry 58 12913003
2006 Identification and characterization of p63 (CKAP4/ERGIC-63/CLIMP-63), a surfactant protein A binding protein, on type II pneumocytes. American journal of physiology. Lung cellular and molecular physiology 53 16556726
2007 Climp-63-mediated binding of microtubules to the ER affects the lateral mobility of translocon complexes. Journal of cell science 49 17567679
2022 Elucidation of CKAP4-remodeled cell mechanics in driving metastasis of bladder cancer through aptamer-based target discovery. Proceedings of the National Academy of Sciences of the United States of America 47 35412892
2019 Reticulon and CLIMP-63 regulate nanodomain organization of peripheral ER tubules. PLoS biology 44 31469817
2019 Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6. Science signaling 44 31744930
2018 p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4. Cancer research 44 30181180
2021 GOLPH3/CKAP4 promotes metastasis and tumorigenicity by enhancing the secretion of exosomal WNT3A in non-small-cell lung cancer. Cell death & disease 40 34671013
2019 CKAP4 Regulates Cell Migration via the Interaction with and Recycling of Integrin. Molecular and cellular biology 39 31160493
2020 Palmitoylated CKAP4 regulates mitochondrial functions through an interaction with VDAC2 at ER-mitochondria contact sites. Journal of cell science 36 33067255
2012 Regulation of human Dicer by the resident ER membrane protein CLIMP-63. Nucleic acids research 36 23047949
2016 CKAP4 is identified as a receptor for Dickkopf in cancer cells. The Journal of clinical investigation 35 27322056
2010 CLIMP-63 is a gentamicin-binding protein that is involved in drug-induced cytotoxicity. Cell death & disease 35 21368867
2021 Plasmalemma vesicle-associated protein promotes angiogenesis in cholangiocarcinoma via the DKK1/CKAP4/PI3K signaling pathway. Oncogene 33 34079085
2020 The RBP1-CKAP4 axis activates oncogenic autophagy and promotes cancer progression in oral squamous cell carcinoma. Cell death & disease 32 32587255
2009 P63 (CKAP4) as an SP-A receptor: implications for surfactant turnover. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 32 20054143
2020 CDR1as/miR-7/CKAP4 axis contributes to the pathogenesis of abdominal aortic aneurysm by regulating the proliferation and apoptosis of primary vascular smooth muscle cells. Experimental and therapeutic medicine 31 32346440
2023 CKAP4 is a potential exosomal biomarker and therapeutic target for lung cancer. Translational lung cancer research 26 37057110
2019 Calumenin-1 Interacts with Climp63 to Cooperatively Determine the Luminal Width and Distribution of Endoplasmic Reticulum Sheets. iScience 26 31751826
2018 MicroRNA-671-3p promotes proliferation and migration of glioma cells via targeting CKAP4. OncoTargets and therapy 26 30288057
2015 How many lives does CLIMP-63 have? Biochemical Society transactions 26 25849921
2014 CKAP4 inhibited growth and metastasis of hepatocellular carcinoma through regulating EGFR signaling. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 22 24838946
2010 Role of the PI3-kinase signaling pathway in trafficking of the surfactant protein A receptor P63 (CKAP4) on type II pneumocytes. American journal of physiology. Lung cellular and molecular physiology 22 20870746
2021 DKK1 activates noncanonical NF-κB signaling via IL-6-induced CKAP4 receptor in multiple myeloma. Blood advances 21 34470047
2008 Role of P63 (CKAP4) in binding of surfactant protein-A to type II pneumocytes. American journal of physiology. Lung cellular and molecular physiology 21 18708633
2023 Dynamics of CLIMP-63 S-acylation control ER morphology. Nature communications 19 36650170
2023 Formin-like 2 promotes angiogenesis and metastasis of colorectal cancer by regulating the EGFL6/CKAP4/ERK axis. Cancer science 17 36715549
2014 Valosin-containing protein-interacting membrane protein (VIMP) links the endoplasmic reticulum with microtubules in concert with cytoskeleton-linking membrane protein (CLIMP)-63. The Journal of biological chemistry 17 25008318
2023 DKK1-CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness. Cancer science 16 36718957
2024 DKK1 Activates the PI3K/AKT Pathway via CKAP4 to Balance the Inhibitory Effect on Wnt/β-Catenin Signaling and Regulates Wnt3a-Induced MSC Migration. Stem cells (Dayton, Ohio) 15 38469899
2024 Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching. Cell discovery 14 39528501
2023 A network map of cytoskeleton-associated protein 4 (CKAP4) mediated signaling pathway in cancer. Journal of cell communication and signaling 13 36944905
2021 CKAP4 participates in tryptase-induced phenotypic conversion in atrial fibroblasts through PAR2/p38/JNK pathway. American journal of translational research 13 34017388
2025 Parvimonas micra promotes oral squamous cell carcinoma metastasis through TmpC-CKAP4 axis. Nature communications 12 40055343
2023 CKAP4-mediated activation of FOXM1 via phosphorylation pathways regulates malignant behavior of glioblastoma cells. Translational oncology 12 36701930
2022 CKAP4 contributes to the progression of vascular calcification (VC) in chronic kidney disease (CKD) by modulating YAP phosphorylation and MMP2 expression. Cellular signalling 11 35108641
2024 Newly developed humanized anti-CKAP4 antibody suppresses pancreatic cancer growth by inhibiting DKK1-CKAP4 signaling. Cancer science 10 39118263
2024 Cytosolic FKBPL and ER-resident CKAP4 co-regulates ER-phagy and protein secretion. Nature communications 10 39251576
2021 Cytoskeleton-associated protein 4 (CKAP4) promotes malignant progression of human gliomas through inhibition of the Hippo signaling pathway. Journal of neuro-oncology 10 34476666
2023 Circular RNA suppression of vascular smooth muscle apoptosis through the miR-545-3p/CKAP4 axis during abdominal aortic aneurysm formation. Vascular medicine (London, England) 9 36847199
2020 Self-Association of Purified Reconstituted ER Luminal Spacer Climp63. Frontiers in cell and developmental biology 8 32612999
2017 Antiproliferative factor (APF) binds specifically to sites within the cytoskeleton-associated protein 4 (CKAP4) extracellular domain. BMC biochemistry 8 28893174
2007 A new, unexpected action of olomoucine, a CDK inhibitor, on normal human cells: up-regulation of CLIMP-63, a cytoskeleton-linking membrane protein. Journal of cellular biochemistry 8 17975794
2024 Senescence Biomarkers CKAP4 and PTX3 Stratify Severe Kidney Disease Patients. Cells 7 39404377
2024 CKAP4 in hepatocellular carcinoma: competitive RETREG1/FAM134B binding, reticulophagy regulation, and cancer progression. Autophagy 7 39689859
2012 Surfactant protein A blocks recognition of Pseudomonas aeruginosa by CKAP4/P63 on airway epithelial cells. The Journal of infectious diseases 7 22966120
2021 RNA-Binding Profiles of CKAP4 as an RNA-Binding Protein in Myocardial Tissues. Frontiers in cardiovascular medicine 6 35004889
2024 The Role of Serum Dickkopf1 and CKAP4 Levels in Diagnosing Colorectal Cancer and Measuring the Disease Severity: A Prospective Study. Medicina (Kaunas, Lithuania) 4 38929550
2023 Molecular basis of Climp63-mediated ER lumen spacing. Journal of cell science 3 37039099
2023 The clinical significance and diagnostic value of serum Dickkopf1 and CKAP4 levels in patients with gastric cancer: a prospective study. European review for medical and pharmacological sciences 3 37916373
2024 LRRC59 promotes the progression of oral squamous cell carcinoma by interacting with SRP pathway components and enhancing the secretion of CKAP4-containing exosomes. Heliyon 2 38533057
2025 An electrochemical biosensor for sensitive detection of CKAP4 with application to the diagnosis of ovarian cancer. Biosensors & bioelectronics 1 40684728
2024 CKAP4 is a potential therapeutic target to overcome resistance to EGFR-TKIs in lung adenocarcinoma. Genes & genomics 1 39704929
2026 Decoding the DKK1/CKAP4 signaling Axis: A novel mechanism driving Neointimal hyperplasia in arteriovenous fistulas. International immunopharmacology 0 41865456
2026 CKAP4 Regulates ERS-Induced Apoptosis in Osteoclasts Through FOXO3 in Periodontitis. Cell proliferation 0 41969105
2026 Exploring histone acetylation in ischemic stroke: CREBBP and CKAP4 as candidate biomarkers linked to histone acetylation networks. Frontiers in pharmacology 0 42004604
2026 Thoracic perivascular adipose tissue-derived PI16 alleviates vascular calcification via CKAP4/PI3K/Akt pathway. Pharmacological research 0 42167386
2026 Targeting the macrophage mechanosensing regulator CKAP4 accelerates the inflammatory-to-proliferative transition in wound healing. Cell reports 0 42207635
2025 The Emerging Role of CKAP4 in GI Cancer: From Molecular Pathways to Clinical Applications. Current oncology (Toronto, Ont.) 0 41149482
2025 CKAP4 Promotes Atrial Fibrosis and Enhances Atrial Fibrillation Vulnerability via WNT/β-Catenin Activation. Circulation. Arrhythmia and electrophysiology 0 41159262
2025 CKAP4 in Extracellular Vesicle-Derived From Podocyte Serves as a Non-Invasive Diagnostic Biomarker for Diabetic Nephropathy and Promotes Vascular Calcification. Journal of extracellular vesicles 0 41316993
2024 Author Correction: The clinical significance and diagnostic value of serum Dickkopf1 and CKAP4 levels in patients with gastric cancer: a prospective study. European review for medical and pharmacological sciences 0 38766782
2024 Retraction: A network map of cytoskeleton-associated protein 4 (CKAP4) mediated signaling pathway in cancer. Journal of cell communication and signaling 0 39524144

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