{"gene":"AHNAK2","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2015,"finding":"AHNAK2 associates with FGF1 in a heat shock-dependent manner (identified by immunoprecipitation mass spectrometry), and both proteins translocate to the cytoskeletal fraction upon heat stress, co-localizing with F-actin near the plasma membrane. Depletion of AHNAK2 drastically reduces stress-induced FGF1 export but does not affect spontaneous FGF2 export or Notch inhibition-induced FGF1 release, placing AHNAK2 as a specific component of the nonclassical FGF1 secretion pathway.","method":"Immunoprecipitation mass spectrometry, subcellular fractionation, co-localization imaging, siRNA knockdown with FGF1 export assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal IP-MS identification plus functional knockdown with specific export readout, single lab, two orthogonal methods","pmids":["25560297"],"is_preprint":false},{"year":2010,"finding":"AHNAK2 localizes to the costameric network in mouse skeletal muscle fibers, as demonstrated by co-localization with vinculin; no AHNAK2 expression was detected in the T-tubule system.","method":"Immunofluorescence with specific AHNAK2 antibodies and co-localization with vinculin in mouse skeletal muscle sections","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with specific antibodies and functional marker co-localization, single lab","pmids":["20833135"],"is_preprint":false},{"year":2019,"finding":"AHNAK2 binds directly to periaxin (PRX), the protein encoded by the CMT4F-associated PRX gene; compound heterozygous mutations in AHNAK2 in a CMT patient family result in significantly reduced AHNAK2 mRNA and protein levels, suggesting disruption of the AHNAK2-PRX interaction impairs myelination.","method":"Linkage analysis, whole exome sequencing, direct binding assay (stated as direct binding), patient fibroblast expression analysis (qRT-PCR and western blot)","journal":"Neurogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct binding to PRX stated but method details limited in abstract; functional consequence inferred from patient data, single lab","pmids":["31011849"],"is_preprint":false},{"year":2020,"finding":"AHNAK2 knockdown in lung adenocarcinoma cells suppresses migration, invasion, and EMT, and inhibits TGF-β1-induced Smad3 phosphorylation. When p-Smad3 is pharmacologically inhibited, AHNAK2 knockdown has no additional effect, placing AHNAK2 upstream of or at the level of Smad3 phosphorylation in the TGF-β/Smad3 pathway.","method":"siRNA knockdown, wound-healing and transwell assays, western blot for p-Smad3/Smad3 and EMT markers, Smad3 phosphorylation inhibitor epistasis experiment","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic epistasis via inhibitor rescue experiment, siRNA knockdown with defined molecular readout, single lab, multiple orthogonal assays","pmids":["33363388"],"is_preprint":false},{"year":2020,"finding":"AHNAK2 knockdown in lung adenocarcinoma A549 cells decreases phosphorylation of MEK, ERK, and p90RSK, and produces effects similar to the MEK inhibitor U0126, placing AHNAK2 as a positive regulator of the MAPK (MEK/ERK) signaling pathway to promote proliferation, migration, and invasion.","method":"siRNA knockdown, western blot for p-MEK/p-ERK/p-P90RSK, pharmacological comparison with U0126 inhibitor, CCK-8, wound-healing, and transwell assays","journal":"Technology in cancer research & treatment","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA + inhibitor comparison but no direct mechanistic link established between AHNAK2 and MAPK components","pmids":["33000678"],"is_preprint":false},{"year":2021,"finding":"AHNAK2 knockdown reduces nuclear factor kappa B (NF-κB) pathway activity in thyroid carcinoma cells, as shown by decreased NF-κB signaling markers, inhibiting migration, invasion, and metastasis.","method":"siRNA knockdown, western blot for NF-κB pathway markers, migration/invasion assays, in vivo metastasis model","journal":"Life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with pathway marker readout but no direct mechanistic link between AHNAK2 and NF-κB components established","pmids":["34627772"],"is_preprint":false},{"year":2021,"finding":"AHNAK2 knockdown in thyroid carcinoma cells inhibits proliferation, metastasis, and EMT, and reduces β-catenin and cyclin D1 protein levels; AHNAK2 overexpression has the opposite effect. Rescue with LiCl (Wnt activator) or ICG-001 (Wnt inhibitor) counteracts the effects of AHNAK2 knockdown or overexpression, respectively, placing AHNAK2 as a positive regulator of the Wnt/β-catenin pathway.","method":"siRNA knockdown, overexpression, western blot for β-catenin/cyclin D1, pharmacological rescue with LiCl and ICG-001, proliferation/migration/invasion assays","journal":"Neoplasma","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement via pharmacological rescue but no direct protein interaction between AHNAK2 and Wnt components demonstrated","pmids":["34374294"],"is_preprint":false},{"year":2021,"finding":"Knockdown of AHNAK2 in ESCC cell lines increases radioresistance, and transcriptome analysis indicates AHNAK2 regulates expression of interleukins, interleukin receptors, and chemokines by inhibiting NF-κB and TNF signaling pathways, suppressing immune response in radioresistant cells.","method":"shRNA knockdown, clonogenic survival after irradiation, transcriptome sequencing/RNA-seq analysis","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, transcriptomic pathway inference without direct mechanistic validation of NF-κB/TNF pathway regulation","pmids":["33633453"],"is_preprint":false},{"year":2023,"finding":"AHNAK2 physically interacts with RUVBL1 (identified by co-immunoprecipitation and mass spectrometry); AHNAK2 knockdown causes G1/S phase cell cycle arrest in lung adenocarcinoma cells, and GSEA/RNA-seq implicate AHNAK2 in the mitotic cell cycle, DNA replication, and NF-κB signaling.","method":"shRNA knockdown, RNA sequencing, mass spectrometry, co-immunoprecipitation (Co-IP), cell cycle analysis by flow cytometry","journal":"Thoracic cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP identification of RUVBL1 interaction with functional cell cycle phenotype, single lab, two orthogonal methods (MS + Co-IP)","pmids":["37349884"],"is_preprint":false},{"year":2024,"finding":"AHNAK2 promotes pancreatic ductal adenocarcinoma progression by preventing c-MET protein degradation (post-transcriptional stabilization), maintaining persistent HGF/c-MET signaling; AHNAK2 and c-MET show significant positive correlation at the protein level but not mRNA level, and AHNAK2 knockdown reduces c-MET protein in response to HGF treatment.","method":"Lentivirus-mediated knockdown, western blot for c-MET protein levels with/without HGF, subcutaneous CDX model and KPC spontaneous mouse model, IHC, qRT-PCR","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo knockdown with post-transcriptional stabilization mechanism supported by protein vs. mRNA correlation analysis, single lab","pmids":["38751848"],"is_preprint":false},{"year":2024,"finding":"AHNAK2 knockdown in pancreatic cancer cells decreases phosphorylated p65, phosphorylated IκBα, and MMP-9 expression; NF-κB activation reverses the effects of AHNAK2 knockdown, placing AHNAK2 upstream of the NF-κB/MMP-9 axis in pancreatic cancer progression.","method":"siRNA knockdown, western blot for p-p65/p-IκBα/MMP-9, NF-κB activator rescue experiment, CCK-8, scratch, and transwell assays","journal":"Biochemical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement via pharmacological rescue but mechanism of AHNAK2 connection to NF-κB not directly established","pmids":["38864962"],"is_preprint":false},{"year":2024,"finding":"AHNAK2 promotes differentiated thyroid cancer cell proliferation, migration, and invasion; knockdown reduces phospho-PI3K p85 and phospho-AKT levels, placing AHNAK2 as a positive regulator of the PI3K/AKT signaling pathway.","method":"siRNA knockdown, western blot for p-PI3K and p-AKT, CCK-8, colony formation, migration/invasion assays, flow cytometry","journal":"Current cancer drug targets","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with downstream marker readout, no direct mechanistic link between AHNAK2 and PI3K/AKT components","pmids":["36089788"],"is_preprint":false},{"year":2025,"finding":"AHNAK2 co-localizes with Cortactin in filopodia in pancreatic cancer cell lines that show diffuse cytoplasmic AHNAK2 distribution; this co-localization increases on fibronectin, collagen substrates, and in hypoxia, and correlates with augmented cancer cell invasion. Cell lines with vesicular AHNAK2 staining do not show these changes.","method":"Immunofluorescence co-localization in cell lines, substrate-dependent culture experiments, hypoxia treatment, invasion assay","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, co-localization imaging without direct functional validation of AHNAK2-Cortactin interaction","pmids":["39849106"],"is_preprint":false},{"year":2025,"finding":"AHNAK2 knockdown in 5-FU-resistant colorectal cancer cells reduces resistance to 5-FU and suppresses PCNA, CDK4, p-AKT, and p-GSK-3β while increasing cleaved caspase-3 and E-cadherin; AHNAK2 overexpression produces opposite effects both in vitro and in vivo, placing AHNAK2 as an activator of the AKT/GSK-3β survival axis that confers chemotherapy resistance.","method":"siRNA knockdown, overexpression, western blot for AKT/GSK-3β pathway components, CCK-8, colony formation, flow cytometry, wound healing, transwell, tumor xenograft mouse model","journal":"Clinical and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional gain/loss-of-function with in vivo validation and defined molecular pathway readout, single lab","pmids":["40382757"],"is_preprint":false},{"year":2026,"finding":"AHNAK2 knockdown in gastric cancer cells reduces proliferation, invasion, and migration while increasing apoptosis; RNA sequencing and western blot analysis confirm that AHNAK2 mediates GC progression through the Wnt/β-catenin signaling pathway.","method":"shRNA knockdown, western blot, immunofluorescence, transcriptome RNA sequencing, IHC","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by transcriptomics and western blot without direct mechanistic link to Wnt components","pmids":["41655165"],"is_preprint":false}],"current_model":"AHNAK2 is a large scaffold protein that localizes to costameres in skeletal muscle and to the submembrane cytoskeletal compartment in other cell types, where it physically associates with FGF1 (during heat stress), periaxin (PRX), RUVBL1, and cortactin; it acts as a positive regulator of multiple oncogenic signaling axes—including TGF-β/Smad3, MAPK/ERK, NF-κB/MMP-9, PI3K/AKT, AKT/GSK-3β, and Wnt/β-catenin—and stabilizes c-MET protein post-transcriptionally, collectively promoting cell migration, invasion, EMT, cell cycle progression, and chemoresistance in various cancer contexts."},"narrative":{"mechanistic_narrative":"AHNAK2 is a large submembrane scaffold protein that organizes membrane-proximal cytoskeletal architecture in muscle and engages multiple signaling modules to drive tumor cell invasion and survival [PMID:20833135, PMID:38751848]. In skeletal muscle it localizes to the costameric network, co-distributing with vinculin and excluded from the T-tubule system [PMID:20833135], and it binds directly to periaxin, an interaction whose disruption by compound heterozygous AHNAK2 mutations is linked to a Charcot-Marie-Tooth-type peripheral neuropathy/myelination defect in an affected family [PMID:31011849]. AHNAK2 also functions in nonclassical FGF1 secretion: under heat stress it associates with FGF1, translocates with it to the F-actin-rich submembrane cytoskeletal compartment, and is specifically required for stress-induced FGF1 export [PMID:25560297]. In cancer, AHNAK2 acts as a positive regulator of pro-invasive and pro-survival signaling, promoting TGF-β/Smad3-driven EMT [PMID:33363388], post-transcriptionally stabilizing c-MET protein to sustain HGF/c-MET signaling [PMID:38751848], and supporting the AKT/GSK-3β survival axis that confers chemotherapy resistance [PMID:40382757]. It additionally physically interacts with RUVBL1 and is required for G1/S cell cycle progression [PMID:37349884]. Across diverse epithelial cancers AHNAK2 knockdown consistently suppresses proliferation, migration, invasion, and EMT. The biochemical mechanism by which AHNAK2 connects to these signaling cascades has not been resolved in the available corpus.","teleology":[{"year":2010,"claim":"Established where AHNAK2 resides in differentiated tissue, defining it as a costamere-associated submembrane protein rather than a T-tubule component.","evidence":"Immunofluorescence co-localization with vinculin in mouse skeletal muscle sections","pmids":["20833135"],"confidence":"Medium","gaps":["No binding partner at the costamere identified","Functional role in muscle mechanics not tested"]},{"year":2015,"claim":"Showed AHNAK2 is a specific functional component of stress-induced nonclassical FGF1 secretion, linking it to membrane-proximal cytoskeletal trafficking.","evidence":"IP-MS identification of FGF1 association, subcellular fractionation, and siRNA knockdown with FGF1 export assay","pmids":["25560297"],"confidence":"Medium","gaps":["Direct vs. indirect FGF1 binding not resolved","Mechanism of cytoskeletal translocation unknown"]},{"year":2019,"claim":"Connected AHNAK2 to peripheral myelination by demonstrating direct binding to periaxin and linking AHNAK2 mutations to a CMT-type phenotype.","evidence":"Linkage analysis, whole exome sequencing, direct binding assay, and patient fibroblast expression analysis","pmids":["31011849"],"confidence":"Medium","gaps":["Binding interface and assay details limited","Causal mechanism for myelination defect inferred, not demonstrated"]},{"year":2020,"claim":"Positioned AHNAK2 as a positive driver of EMT and motility upstream of or at Smad3 phosphorylation in the TGF-β pathway, and as a positive regulator of MEK/ERK signaling in lung adenocarcinoma.","evidence":"siRNA knockdown with inhibitor epistasis (p-Smad3 inhibitor; U0126), wound-healing/transwell assays, and pathway western blots","pmids":["33363388","33000678"],"confidence":"Medium","gaps":["No direct physical link between AHNAK2 and Smad3 or MEK/ERK components","Whether AHNAK2 acts as a scaffold or upstream activator unresolved"]},{"year":2021,"claim":"Extended AHNAK2's pro-tumor signaling role across thyroid carcinoma and ESCC, implicating NF-κB, Wnt/β-catenin, and immune/radioresistance programs.","evidence":"siRNA/shRNA knockdown, pharmacological rescue (LiCl/ICG-001), pathway marker western blots, clonogenic survival, RNA-seq, and an in vivo metastasis model","pmids":["34627772","34374294","33633453"],"confidence":"Low","gaps":["Pathway placement is inferential, no direct interaction with NF-κB or Wnt components shown","Transcriptomic regulation of cytokines not mechanistically validated"]},{"year":2023,"claim":"Identified a physical interaction partner (RUVBL1) and linked AHNAK2 to G1/S cell cycle progression, providing the first protein-interaction handle in cancer cells.","evidence":"Co-IP and mass spectrometry, shRNA knockdown, RNA-seq/GSEA, and flow cytometry cell cycle analysis","pmids":["37349884"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation in original report","Functional consequence of the RUVBL1 interaction not dissected"]},{"year":2024,"claim":"Defined a post-transcriptional mechanism whereby AHNAK2 stabilizes c-MET protein to sustain HGF/c-MET signaling, and reinforced AHNAK2's role upstream of the NF-κB/MMP-9 and PI3K/AKT axes.","evidence":"Lentiviral/siRNA knockdown, protein-vs-mRNA correlation, c-MET western blot with HGF, NF-κB activator rescue, CDX and KPC mouse models, and pathway western blots","pmids":["38751848","38864962","36089788"],"confidence":"Medium","gaps":["Molecular basis of c-MET protein stabilization not identified","Direct connection of AHNAK2 to NF-κB or PI3K/AKT components not established"]},{"year":2025,"claim":"Linked AHNAK2 to invasive cell-surface structures and chemoresistance, showing cortactin co-localization in filopodia and activation of the AKT/GSK-3β survival axis in 5-FU-resistant colorectal cancer.","evidence":"Immunofluorescence co-localization on ECM substrates and hypoxia, invasion assays, bidirectional gain/loss-of-function with western blots, and tumor xenograft model","pmids":["39849106","40382757"],"confidence":"Medium","gaps":["AHNAK2-cortactin interaction is co-localization only, not biochemically validated","Mechanism of AKT/GSK-3β activation not directly demonstrated"]},{"year":2026,"claim":"Reinforced AHNAK2 as a driver of gastric cancer progression through the Wnt/β-catenin pathway, consistent with its broad pro-tumor signaling role.","evidence":"shRNA knockdown, RNA-seq, western blot, immunofluorescence, and IHC","pmids":["41655165"],"confidence":"Low","gaps":["No direct link to Wnt pathway components","Pathway assignment based on transcriptomics and marker readout only"]},{"year":null,"claim":"The unifying biochemical mechanism by which a single large scaffold protein engages so many distinct signaling cascades (TGF-β, MAPK, NF-κB, PI3K/AKT, Wnt, c-MET) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No defined domain-level interaction map","Whether AHNAK2 acts as a direct scaffold for these pathways or via an upstream node is unknown","No structural model of AHNAK2 in any of these contexts"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,12]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,9,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8]}],"complexes":[],"partners":["FGF1","PRX","RUVBL1","CTTN","MET"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IVF2","full_name":"Protein AHNAK2","aliases":[],"length_aa":5795,"mass_kda":616.6,"function":"","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8IVF2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AHNAK2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AHNAK2","total_profiled":1310},"omim":[{"mim_id":"608570","title":"AHNAK NUCLEOPROTEIN 2; AHNAK2","url":"https://www.omim.org/entry/608570"},{"mim_id":"103390","title":"AHNAK NUCLEOPROTEIN; AHNAK","url":"https://www.omim.org/entry/103390"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":294.4}],"url":"https://www.proteinatlas.org/search/AHNAK2"},"hgnc":{"alias_symbol":[],"prev_symbol":["C14orf78"]},"alphafold":{"accession":"Q8IVF2","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IVF2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IVF2-2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IVF2-2-F1-predicted_aligned_error_v6.png","plddt_mean":44.78},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AHNAK2","jax_strain_url":"https://www.jax.org/strain/search?query=AHNAK2"},"sequence":{"accession":"Q8IVF2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IVF2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IVF2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IVF2"}},"corpus_meta":[{"pmid":"33363388","id":"PMC_33363388","title":"AHNAK2 Promotes Migration, Invasion, and Epithelial-Mesenchymal Transition in Lung Adenocarcinoma Cells via the TGF-β/Smad3 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immunoprecipitation mass spectrometry), and both proteins translocate to the cytoskeletal fraction upon heat stress, co-localizing with F-actin near the plasma membrane. Depletion of AHNAK2 drastically reduces stress-induced FGF1 export but does not affect spontaneous FGF2 export or Notch inhibition-induced FGF1 release, placing AHNAK2 as a specific component of the nonclassical FGF1 secretion pathway.\",\n      \"method\": \"Immunoprecipitation mass spectrometry, subcellular fractionation, co-localization imaging, siRNA knockdown with FGF1 export assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal IP-MS identification plus functional knockdown with specific export readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"25560297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AHNAK2 localizes to the costameric network in mouse skeletal muscle fibers, as demonstrated by co-localization with vinculin; no AHNAK2 expression was detected in the T-tubule system.\",\n      \"method\": \"Immunofluorescence with specific AHNAK2 antibodies and co-localization with vinculin in mouse skeletal muscle sections\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with specific antibodies and functional marker co-localization, single lab\",\n      \"pmids\": [\"20833135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AHNAK2 binds directly to periaxin (PRX), the protein encoded by the CMT4F-associated PRX gene; compound heterozygous mutations in AHNAK2 in a CMT patient family result in significantly reduced AHNAK2 mRNA and protein levels, suggesting disruption of the AHNAK2-PRX interaction impairs myelination.\",\n      \"method\": \"Linkage analysis, whole exome sequencing, direct binding assay (stated as direct binding), patient fibroblast expression analysis (qRT-PCR and western blot)\",\n      \"journal\": \"Neurogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct binding to PRX stated but method details limited in abstract; functional consequence inferred from patient data, single lab\",\n      \"pmids\": [\"31011849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AHNAK2 knockdown in lung adenocarcinoma cells suppresses migration, invasion, and EMT, and inhibits TGF-β1-induced Smad3 phosphorylation. When p-Smad3 is pharmacologically inhibited, AHNAK2 knockdown has no additional effect, placing AHNAK2 upstream of or at the level of Smad3 phosphorylation in the TGF-β/Smad3 pathway.\",\n      \"method\": \"siRNA knockdown, wound-healing and transwell assays, western blot for p-Smad3/Smad3 and EMT markers, Smad3 phosphorylation inhibitor epistasis experiment\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic epistasis via inhibitor rescue experiment, siRNA knockdown with defined molecular readout, single lab, multiple orthogonal assays\",\n      \"pmids\": [\"33363388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AHNAK2 knockdown in lung adenocarcinoma A549 cells decreases phosphorylation of MEK, ERK, and p90RSK, and produces effects similar to the MEK inhibitor U0126, placing AHNAK2 as a positive regulator of the MAPK (MEK/ERK) signaling pathway to promote proliferation, migration, and invasion.\",\n      \"method\": \"siRNA knockdown, western blot for p-MEK/p-ERK/p-P90RSK, pharmacological comparison with U0126 inhibitor, CCK-8, wound-healing, and transwell assays\",\n      \"journal\": \"Technology in cancer research & treatment\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA + inhibitor comparison but no direct mechanistic link established between AHNAK2 and MAPK components\",\n      \"pmids\": [\"33000678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AHNAK2 knockdown reduces nuclear factor kappa B (NF-κB) pathway activity in thyroid carcinoma cells, as shown by decreased NF-κB signaling markers, inhibiting migration, invasion, and metastasis.\",\n      \"method\": \"siRNA knockdown, western blot for NF-κB pathway markers, migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with pathway marker readout but no direct mechanistic link between AHNAK2 and NF-κB components established\",\n      \"pmids\": [\"34627772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AHNAK2 knockdown in thyroid carcinoma cells inhibits proliferation, metastasis, and EMT, and reduces β-catenin and cyclin D1 protein levels; AHNAK2 overexpression has the opposite effect. Rescue with LiCl (Wnt activator) or ICG-001 (Wnt inhibitor) counteracts the effects of AHNAK2 knockdown or overexpression, respectively, placing AHNAK2 as a positive regulator of the Wnt/β-catenin pathway.\",\n      \"method\": \"siRNA knockdown, overexpression, western blot for β-catenin/cyclin D1, pharmacological rescue with LiCl and ICG-001, proliferation/migration/invasion assays\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement via pharmacological rescue but no direct protein interaction between AHNAK2 and Wnt components demonstrated\",\n      \"pmids\": [\"34374294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of AHNAK2 in ESCC cell lines increases radioresistance, and transcriptome analysis indicates AHNAK2 regulates expression of interleukins, interleukin receptors, and chemokines by inhibiting NF-κB and TNF signaling pathways, suppressing immune response in radioresistant cells.\",\n      \"method\": \"shRNA knockdown, clonogenic survival after irradiation, transcriptome sequencing/RNA-seq analysis\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, transcriptomic pathway inference without direct mechanistic validation of NF-κB/TNF pathway regulation\",\n      \"pmids\": [\"33633453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AHNAK2 physically interacts with RUVBL1 (identified by co-immunoprecipitation and mass spectrometry); AHNAK2 knockdown causes G1/S phase cell cycle arrest in lung adenocarcinoma cells, and GSEA/RNA-seq implicate AHNAK2 in the mitotic cell cycle, DNA replication, and NF-κB signaling.\",\n      \"method\": \"shRNA knockdown, RNA sequencing, mass spectrometry, co-immunoprecipitation (Co-IP), cell cycle analysis by flow cytometry\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP identification of RUVBL1 interaction with functional cell cycle phenotype, single lab, two orthogonal methods (MS + Co-IP)\",\n      \"pmids\": [\"37349884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AHNAK2 promotes pancreatic ductal adenocarcinoma progression by preventing c-MET protein degradation (post-transcriptional stabilization), maintaining persistent HGF/c-MET signaling; AHNAK2 and c-MET show significant positive correlation at the protein level but not mRNA level, and AHNAK2 knockdown reduces c-MET protein in response to HGF treatment.\",\n      \"method\": \"Lentivirus-mediated knockdown, western blot for c-MET protein levels with/without HGF, subcutaneous CDX model and KPC spontaneous mouse model, IHC, qRT-PCR\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo knockdown with post-transcriptional stabilization mechanism supported by protein vs. mRNA correlation analysis, single lab\",\n      \"pmids\": [\"38751848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AHNAK2 knockdown in pancreatic cancer cells decreases phosphorylated p65, phosphorylated IκBα, and MMP-9 expression; NF-κB activation reverses the effects of AHNAK2 knockdown, placing AHNAK2 upstream of the NF-κB/MMP-9 axis in pancreatic cancer progression.\",\n      \"method\": \"siRNA knockdown, western blot for p-p65/p-IκBα/MMP-9, NF-κB activator rescue experiment, CCK-8, scratch, and transwell assays\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement via pharmacological rescue but mechanism of AHNAK2 connection to NF-κB not directly established\",\n      \"pmids\": [\"38864962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AHNAK2 promotes differentiated thyroid cancer cell proliferation, migration, and invasion; knockdown reduces phospho-PI3K p85 and phospho-AKT levels, placing AHNAK2 as a positive regulator of the PI3K/AKT signaling pathway.\",\n      \"method\": \"siRNA knockdown, western blot for p-PI3K and p-AKT, CCK-8, colony formation, migration/invasion assays, flow cytometry\",\n      \"journal\": \"Current cancer drug targets\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with downstream marker readout, no direct mechanistic link between AHNAK2 and PI3K/AKT components\",\n      \"pmids\": [\"36089788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AHNAK2 co-localizes with Cortactin in filopodia in pancreatic cancer cell lines that show diffuse cytoplasmic AHNAK2 distribution; this co-localization increases on fibronectin, collagen substrates, and in hypoxia, and correlates with augmented cancer cell invasion. Cell lines with vesicular AHNAK2 staining do not show these changes.\",\n      \"method\": \"Immunofluorescence co-localization in cell lines, substrate-dependent culture experiments, hypoxia treatment, invasion assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, co-localization imaging without direct functional validation of AHNAK2-Cortactin interaction\",\n      \"pmids\": [\"39849106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AHNAK2 knockdown in 5-FU-resistant colorectal cancer cells reduces resistance to 5-FU and suppresses PCNA, CDK4, p-AKT, and p-GSK-3β while increasing cleaved caspase-3 and E-cadherin; AHNAK2 overexpression produces opposite effects both in vitro and in vivo, placing AHNAK2 as an activator of the AKT/GSK-3β survival axis that confers chemotherapy resistance.\",\n      \"method\": \"siRNA knockdown, overexpression, western blot for AKT/GSK-3β pathway components, CCK-8, colony formation, flow cytometry, wound healing, transwell, tumor xenograft mouse model\",\n      \"journal\": \"Clinical and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional gain/loss-of-function with in vivo validation and defined molecular pathway readout, single lab\",\n      \"pmids\": [\"40382757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"AHNAK2 knockdown in gastric cancer cells reduces proliferation, invasion, and migration while increasing apoptosis; RNA sequencing and western blot analysis confirm that AHNAK2 mediates GC progression through the Wnt/β-catenin signaling pathway.\",\n      \"method\": \"shRNA knockdown, western blot, immunofluorescence, transcriptome RNA sequencing, IHC\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by transcriptomics and western blot without direct mechanistic link to Wnt components\",\n      \"pmids\": [\"41655165\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AHNAK2 is a large scaffold protein that localizes to costameres in skeletal muscle and to the submembrane cytoskeletal compartment in other cell types, where it physically associates with FGF1 (during heat stress), periaxin (PRX), RUVBL1, and cortactin; it acts as a positive regulator of multiple oncogenic signaling axes—including TGF-β/Smad3, MAPK/ERK, NF-κB/MMP-9, PI3K/AKT, AKT/GSK-3β, and Wnt/β-catenin—and stabilizes c-MET protein post-transcriptionally, collectively promoting cell migration, invasion, EMT, cell cycle progression, and chemoresistance in various cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AHNAK2 is a large submembrane scaffold protein that organizes membrane-proximal cytoskeletal architecture in muscle and engages multiple signaling modules to drive tumor cell invasion and survival [#1, #9]. In skeletal muscle it localizes to the costameric network, co-distributing with vinculin and excluded from the T-tubule system [#1], and it binds directly to periaxin, an interaction whose disruption by compound heterozygous AHNAK2 mutations is linked to a Charcot-Marie-Tooth-type peripheral neuropathy/myelination defect in an affected family [#2]. AHNAK2 also functions in nonclassical FGF1 secretion: under heat stress it associates with FGF1, translocates with it to the F-actin-rich submembrane cytoskeletal compartment, and is specifically required for stress-induced FGF1 export [#0]. In cancer, AHNAK2 acts as a positive regulator of pro-invasive and pro-survival signaling, promoting TGF-\\u03b2/Smad3-driven EMT [#3], post-transcriptionally stabilizing c-MET protein to sustain HGF/c-MET signaling [#9], and supporting the AKT/GSK-3\\u03b2 survival axis that confers chemotherapy resistance [#13]. It additionally physically interacts with RUVBL1 and is required for G1/S cell cycle progression [#8]. Across diverse epithelial cancers AHNAK2 knockdown consistently suppresses proliferation, migration, invasion, and EMT. The biochemical mechanism by which AHNAK2 connects to these signaling cascades has not been resolved in the available corpus.\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established where AHNAK2 resides in differentiated tissue, defining it as a costamere-associated submembrane protein rather than a T-tubule component.\",\n      \"evidence\": \"Immunofluorescence co-localization with vinculin in mouse skeletal muscle sections\",\n      \"pmids\": [\"20833135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No binding partner at the costamere identified\", \"Functional role in muscle mechanics not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed AHNAK2 is a specific functional component of stress-induced nonclassical FGF1 secretion, linking it to membrane-proximal cytoskeletal trafficking.\",\n      \"evidence\": \"IP-MS identification of FGF1 association, subcellular fractionation, and siRNA knockdown with FGF1 export assay\",\n      \"pmids\": [\"25560297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect FGF1 binding not resolved\", \"Mechanism of cytoskeletal translocation unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected AHNAK2 to peripheral myelination by demonstrating direct binding to periaxin and linking AHNAK2 mutations to a CMT-type phenotype.\",\n      \"evidence\": \"Linkage analysis, whole exome sequencing, direct binding assay, and patient fibroblast expression analysis\",\n      \"pmids\": [\"31011849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface and assay details limited\", \"Causal mechanism for myelination defect inferred, not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned AHNAK2 as a positive driver of EMT and motility upstream of or at Smad3 phosphorylation in the TGF-\\u03b2 pathway, and as a positive regulator of MEK/ERK signaling in lung adenocarcinoma.\",\n      \"evidence\": \"siRNA knockdown with inhibitor epistasis (p-Smad3 inhibitor; U0126), wound-healing/transwell assays, and pathway western blots\",\n      \"pmids\": [\"33363388\", \"33000678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct physical link between AHNAK2 and Smad3 or MEK/ERK components\", \"Whether AHNAK2 acts as a scaffold or upstream activator unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended AHNAK2's pro-tumor signaling role across thyroid carcinoma and ESCC, implicating NF-\\u03baB, Wnt/\\u03b2-catenin, and immune/radioresistance programs.\",\n      \"evidence\": \"siRNA/shRNA knockdown, pharmacological rescue (LiCl/ICG-001), pathway marker western blots, clonogenic survival, RNA-seq, and an in vivo metastasis model\",\n      \"pmids\": [\"34627772\", \"34374294\", \"33633453\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement is inferential, no direct interaction with NF-\\u03baB or Wnt components shown\", \"Transcriptomic regulation of cytokines not mechanistically validated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a physical interaction partner (RUVBL1) and linked AHNAK2 to G1/S cell cycle progression, providing the first protein-interaction handle in cancer cells.\",\n      \"evidence\": \"Co-IP and mass spectrometry, shRNA knockdown, RNA-seq/GSEA, and flow cytometry cell cycle analysis\",\n      \"pmids\": [\"37349884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation in original report\", \"Functional consequence of the RUVBL1 interaction not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a post-transcriptional mechanism whereby AHNAK2 stabilizes c-MET protein to sustain HGF/c-MET signaling, and reinforced AHNAK2's role upstream of the NF-\\u03baB/MMP-9 and PI3K/AKT axes.\",\n      \"evidence\": \"Lentiviral/siRNA knockdown, protein-vs-mRNA correlation, c-MET western blot with HGF, NF-\\u03baB activator rescue, CDX and KPC mouse models, and pathway western blots\",\n      \"pmids\": [\"38751848\", \"38864962\", \"36089788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of c-MET protein stabilization not identified\", \"Direct connection of AHNAK2 to NF-\\u03baB or PI3K/AKT components not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked AHNAK2 to invasive cell-surface structures and chemoresistance, showing cortactin co-localization in filopodia and activation of the AKT/GSK-3\\u03b2 survival axis in 5-FU-resistant colorectal cancer.\",\n      \"evidence\": \"Immunofluorescence co-localization on ECM substrates and hypoxia, invasion assays, bidirectional gain/loss-of-function with western blots, and tumor xenograft model\",\n      \"pmids\": [\"39849106\", \"40382757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AHNAK2-cortactin interaction is co-localization only, not biochemically validated\", \"Mechanism of AKT/GSK-3\\u03b2 activation not directly demonstrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Reinforced AHNAK2 as a driver of gastric cancer progression through the Wnt/\\u03b2-catenin pathway, consistent with its broad pro-tumor signaling role.\",\n      \"evidence\": \"shRNA knockdown, RNA-seq, western blot, immunofluorescence, and IHC\",\n      \"pmids\": [\"41655165\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct link to Wnt pathway components\", \"Pathway assignment based on transcriptomics and marker readout only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying biochemical mechanism by which a single large scaffold protein engages so many distinct signaling cascades (TGF-\\u03b2, MAPK, NF-\\u03baB, PI3K/AKT, Wnt, c-MET) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No defined domain-level interaction map\", \"Whether AHNAK2 acts as a direct scaffold for these pathways or via an upstream node is unknown\", \"No structural model of AHNAK2 in any of these contexts\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 9, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FGF1\", \"PRX\", \"RUVBL1\", \"CTTN\", \"MET\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}