Affinage

AHNAK2

Protein AHNAK2 · UniProt Q8IVF2

Length
5795 aa
Mass
616.6 kDa
Annotated
2026-06-09
22 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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.

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2010 Medium

    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

    PMID:20833135

    Open questions at the time
    • No binding partner at the costamere identified
    • Functional role in muscle mechanics not tested
  2. 2015 Medium

    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

    PMID:25560297

    Open questions at the time
    • Direct vs. indirect FGF1 binding not resolved
    • Mechanism of cytoskeletal translocation unknown
  3. 2019 Medium

    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

    PMID:31011849

    Open questions at the time
    • Binding interface and assay details limited
    • Causal mechanism for myelination defect inferred, not demonstrated
  4. 2020 Medium

    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

    PMID:33000678 PMID:33363388

    Open questions at the time
    • No direct physical link between AHNAK2 and Smad3 or MEK/ERK components
    • Whether AHNAK2 acts as a scaffold or upstream activator unresolved
  5. 2021 Low

    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

    PMID:33633453 PMID:34374294 PMID:34627772

    Open questions at the time
    • Pathway placement is inferential, no direct interaction with NF-κB or Wnt components shown
    • Transcriptomic regulation of cytokines not mechanistically validated
  6. 2023 Medium

    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

    PMID:37349884

    Open questions at the time
    • Single Co-IP without reciprocal validation in original report
    • Functional consequence of the RUVBL1 interaction not dissected
  7. 2024 Medium

    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

    PMID:36089788 PMID:38751848 PMID:38864962

    Open questions at the time
    • Molecular basis of c-MET protein stabilization not identified
    • Direct connection of AHNAK2 to NF-κB or PI3K/AKT components not established
  8. 2025 Medium

    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

    PMID:39849106 PMID:40382757

    Open questions at the time
    • AHNAK2-cortactin interaction is co-localization only, not biochemically validated
    • Mechanism of AKT/GSK-3β activation not directly demonstrated
  9. 2026 Low

    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

    PMID:41655165

    Open questions at the time
    • No direct link to Wnt pathway components
    • Pathway assignment based on transcriptomics and marker readout only

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 1

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 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. Immunoprecipitation mass spectrometry, subcellular fractionation, co-localization imaging, siRNA knockdown with FGF1 export assay Journal of cellular biochemistry Medium 25560297
2010 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. Immunofluorescence with specific AHNAK2 antibodies and co-localization with vinculin in mouse skeletal muscle sections Biochemical and biophysical research communications Medium 20833135
2019 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. Linkage analysis, whole exome sequencing, direct binding assay (stated as direct binding), patient fibroblast expression analysis (qRT-PCR and western blot) Neurogenetics Medium 31011849
2020 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. siRNA knockdown, wound-healing and transwell assays, western blot for p-Smad3/Smad3 and EMT markers, Smad3 phosphorylation inhibitor epistasis experiment OncoTargets and therapy Medium 33363388
2020 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. siRNA knockdown, western blot for p-MEK/p-ERK/p-P90RSK, pharmacological comparison with U0126 inhibitor, CCK-8, wound-healing, and transwell assays Technology in cancer research & treatment Low 33000678
2021 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. siRNA knockdown, western blot for NF-κB pathway markers, migration/invasion assays, in vivo metastasis model Life sciences Low 34627772
2021 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. siRNA knockdown, overexpression, western blot for β-catenin/cyclin D1, pharmacological rescue with LiCl and ICG-001, proliferation/migration/invasion assays Neoplasma Low 34374294
2021 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. shRNA knockdown, clonogenic survival after irradiation, transcriptome sequencing/RNA-seq analysis OncoTargets and therapy Low 33633453
2023 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. shRNA knockdown, RNA sequencing, mass spectrometry, co-immunoprecipitation (Co-IP), cell cycle analysis by flow cytometry Thoracic cancer Medium 37349884
2024 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. Lentivirus-mediated knockdown, western blot for c-MET protein levels with/without HGF, subcutaneous CDX model and KPC spontaneous mouse model, IHC, qRT-PCR Cancer management and research Medium 38751848
2024 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. siRNA knockdown, western blot for p-p65/p-IκBα/MMP-9, NF-κB activator rescue experiment, CCK-8, scratch, and transwell assays Biochemical genetics Low 38864962
2024 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. siRNA knockdown, western blot for p-PI3K and p-AKT, CCK-8, colony formation, migration/invasion assays, flow cytometry Current cancer drug targets Low 36089788
2025 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. Immunofluorescence co-localization in cell lines, substrate-dependent culture experiments, hypoxia treatment, invasion assay Scientific reports Low 39849106
2025 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. siRNA knockdown, overexpression, western blot for AKT/GSK-3β pathway components, CCK-8, colony formation, flow cytometry, wound healing, transwell, tumor xenograft mouse model Clinical and experimental medicine Medium 40382757
2026 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. shRNA knockdown, western blot, immunofluorescence, transcriptome RNA sequencing, IHC Discover oncology Low 41655165

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 AHNAK2 Promotes Migration, Invasion, and Epithelial-Mesenchymal Transition in Lung Adenocarcinoma Cells via the TGF-β/Smad3 Pathway. OncoTargets and therapy 34 33363388
2010 AHNAK1 and AHNAK2 are costameric proteins: AHNAK1 affects transverse skeletal muscle fiber stiffness. Biochemical and biophysical research communications 27 20833135
2022 The Obscure Potential of AHNAK2. Cancers 26 35158796
2015 AHNAK2 Participates in the Stress-Induced Nonclassical FGF1 Secretion Pathway. Journal of cellular biochemistry 26 25560297
2021 AHNAK2 promotes thyroid carcinoma progression by activating the NF-κB pathway. Life sciences 22 34627772
2020 Down-Regulation of AHNAK2 Inhibits Cell Proliferation, Migration and Invasion Through Inactivating the MAPK Pathway in Lung Adenocarcinoma. Technology in cancer research & treatment 20 33000678
2019 Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family. Neurogenetics 13 31011849
2022 Deleterious AHNAK2 Mutation as a Novel Biomarker for Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer. Frontiers in oncology 10 35359393
2024 AHNAK2 Promotes the Progression of Differentiated Thyroid Cancer through PI3K/AKT Signaling Pathway. Current cancer drug targets 9 36089788
2021 Silencing of AHNAK2 restricts thyroid carcinoma progression by inhibiting the Wnt/β-catenin pathway. Neoplasma 9 34374294
2021 Identification and Functional Validation of Radioresistance-Related Genes AHNAK2 and EVPL in Esophageal Squamous Cell Carcinoma by Exome and Transcriptome Sequencing Analyses. OncoTargets and therapy 8 33633453
2023 Downregulation of AHNAK2 inhibits cell cycle of lung adenocarcinoma cells by interacting with RUVBL1. Thoracic cancer 7 37349884
2022 AHNAK2 is a biomarker and a potential therapeutic target of adenocarcinomas. Acta biochimica et biophysica Sinica 7 36017889
2024 AHNAK2 Promotes the Progression of Pancreatic Ductal Adenocarcinoma by Maintaining the Stability of c-MET. Cancer management and research 4 38751848
2024 AHNAK2 Regulates NF-κB/MMP-9 Signaling to Promote Pancreatic Cancer Progression. Biochemical genetics 3 38864962
2025 AHNAK2: a potential diagnostic biomarker for pancreatic cancer related to cellular motility. Scientific reports 2 39849106
2022 Exome sequencing in a child with neurodevelopmental disorder and epilepsy: Variant analysis of the AHNAK2 gene. Molecular genetics & genomic medicine 2 35789128
2025 AHNAK2 confers 5-fluorouracil resistance in colorectal cancer via activation of the AKT/GSK-3β signaling axis. Clinical and experimental medicine 1 40382757
2026 AHNAK2 is a novel diagnostic biomarker for gallbladder adenocarcinoma. Histology and histopathology 0 41527812
2026 AHNAK2 exacerbates the malignant phenotype of gastric cancer through activation of the Wnt/β-catenin signaling pathway. Discover oncology 0 41655165
2025 Diagnostic value of AHNAK2 immunohistochemical expression in papillary thyroid carcinoma: an immunohistochemical study. Diagnostic pathology 0 41188896
2025 Exploration of the correlation between AHNAK2 and pancreatic cancer and its role in the tumor microenvironment based on bioinformatics: Computational pharmacology. Medicine 0 41465903

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