{"gene":"PXN","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2023,"finding":"ULK1/2 directly phosphorylate PXN (paxillin) at S32 and S119, which weakens homotypic PXN interactions and liquid-liquid phase separation of PXN, thereby impairing focal adhesion assembly and inhibiting actin stress fiber formation, cell contraction, and migration. ULK1/2 and FAK/Src have opposing functions on PXN-dependent mechanotransduction, competing for phosphorylation of adjacent serine and tyrosine residues.","method":"In vitro kinase assay, site-directed mutagenesis (S32/S119), phase separation assay, focal adhesion assembly imaging, loss-of-function (KO/KD) with migration and mechanical phenotype readouts","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct substrate identification with mutagenesis, in vitro phosphorylation assay, phase separation assay, and functional migration/FA phenotype, single lab but multiple orthogonal methods","pmids":["37846507"],"is_preprint":false},{"year":2025,"finding":"The disordered N-terminal domain of PXN undergoes significant conformational compaction upon binding the C-terminal focal adhesion targeting (FAT) domain of FAK, forming a 48-kDa multi-modal fuzzy complex with four major interconverting states. Each state has unique sets of contacts involving disordered regions. This PXN–FAT interaction is necessary and sufficient for localizing FAK to focal adhesions.","method":"NMR spectroscopy, small-angle X-ray scattering (SAXS), ensemble analysis of disordered complex","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural characterization (NMR + SAXS) with conformational state resolution, single preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.01.01.630265"],"is_preprint":true},{"year":2021,"finding":"Substrate stiffness regulates FAK and PXN phosphorylation at focal adhesions in endothelial cells, which promotes Rac1 activation (GDP→GTP transition), subsequent YAP nuclear translocation, and tip cell specification during angiogenesis. Phosphorylated PXN also loosens intercellular connections, further facilitating tip cell formation.","method":"Tunable hydrogel substrates, phospho-specific western blotting, Rac1 GTP-pulldown, YAP localization imaging, loss-of-function","journal":"Bioactive materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (phospho-WB, GTP-pulldown, imaging) in single lab establishing p-PXN→Rac1→YAP pathway","pmids":["34466738"],"is_preprint":false},{"year":2018,"finding":"Cytoplasmic LIF (bearing signal peptide mutation) enhances cancer cell invasion and vascular dissemination mechanistically through modulation of YAP1-FAK/PXN signaling in nasopharyngeal carcinoma, reprogramming collective to mesenchymal invasion mode.","method":"IHC correlation, functional invasion assays, pharmacological inhibition (AZD0530/dasatinib), signaling pathway analysis by western blot","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (YAP1-FAK/PXN) established with pharmacological reversal and multiple functional assays in single lab","pmids":["30504771"],"is_preprint":false},{"year":2014,"finding":"LSD1 (lysine-specific demethylase 1) controls transcription of PXN (paxillin) in androgen-independent prostate cancer cells. Upon LSD1 depletion, enhanced LPAR6 signaling promotes cell migration with concomitant phosphorylation of PXN, establishing a LSD1→PXN phosphorylation→migration axis.","method":"Transcriptome and cistrome (ChIP-seq) analysis, siRNA knockdown, migration/invasion assays, phospho-PXN western blot","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cistrome + transcriptome plus functional migration assays establish LSD1 regulation of PXN, single lab with two orthogonal genomic/functional methods","pmids":["25285406"],"is_preprint":false},{"year":2023,"finding":"ANGPTL4 binding to NRP1 receptor leads to ABL1 tyrosine kinase-dependent phosphorylation of PXN, driving HNSCC tumor cell migration. Pharmacological inhibition of ABL1 (dasatinib) or siRNA silencing of NRP1 or ABL1 blocks PXN phosphorylation and migration.","method":"Co-receptor binding assay, siRNA knockdown of NRP1/ABL1, pharmacological inhibition (dasatinib), phospho-PXN western blot, migration assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor–kinase–substrate axis (NRP1/ABL1/PXN phosphorylation) established with pharmacological + genetic perturbation and phospho-readout, single lab","pmids":["37169211"],"is_preprint":false},{"year":2024,"finding":"CXCL5 activates phosphorylation of PXN/AKT signaling cascade in lung cancer cells, leading to upregulation of PD-L1 expression and formation of a positive feedback loop that promotes immune evasion.","method":"Gene silencing, western blotting for p-PXN and p-AKT, flow cytometry for PD-L1, in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CXCL5→p-PXN→AKT→PD-L1 pathway established by gene silencing with phospho-readouts, single lab, multiple methods","pmids":["39034411"],"is_preprint":false},{"year":2026,"finding":"STAT3 directly upregulates PXN transcription in GBM (IDH-wildtype), and PXN reciprocally activates STAT3 by regulating SRC transcription, forming a positive feedback loop. Additionally, PXN stabilizes YB-1 protein by inhibiting its ubiquitin-mediated degradation.","method":"qRT-PCR, western blotting, mRNA sequencing, functional knockdown assays, ubiquitination assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional feedback loop and ubiquitination regulation established by multiple molecular methods in single lab","pmids":["41872167"],"is_preprint":false},{"year":2015,"finding":"miR-212 directly targets the 3'UTR of PXN mRNA to suppress PXN expression; miR-212 overexpression reduces PXN mRNA and protein levels and decreases gastric cancer cell invasion and migration in vitro and in vivo. PXN restoration rescues migration/invasion in miR-212-overexpressing cells.","method":"Luciferase reporter assay (3'UTR), miRNA mimic/inhibitor transfection, rescue experiments, in vitro and in vivo invasion assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR targeting confirmed by luciferase assay, functional rescue experiments, single lab","pmids":["26693054"],"is_preprint":false},{"year":2017,"finding":"STAT3 binds to a binding site in the PXN gene promoter; nobiletin inhibits STAT3/DNA binding activity at this site and STAT3 binding to the PXN promoter, thereby suppressing PXN-mediated tumor angiogenesis in ER+ breast cancer cells downstream of Src/FAK/STAT3 signaling.","method":"EMSA, ChIP assay, western blotting, HUVEC angiogenesis assay, RT-PCR","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct STAT3–PXN promoter binding established by EMSA and ChIP, single lab, two orthogonal chromatin methods","pmids":["28468300"],"is_preprint":false},{"year":2025,"finding":"PXN knockdown in premalignant Src-activated mammary epithelial cells prevents the transient increase in tensile forces at focal adhesions and at adherens junctions, and abolishes the proliferative advantage, placing PXN functionally upstream of AJ force buildup and EGFR-ERK/MRTF-A-SRF activation during early malignant transformation.","method":"siRNA knockdown, FRET-based tension biosensors at FAs and AJs, FAK inhibition, proliferation assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — genetic epistasis with tension biosensors, preprint not peer-reviewed, single lab","pmids":["bio_10.1101_2025.07.05.663275"],"is_preprint":true},{"year":2019,"finding":"ETV4 transcription factor directly upregulates PXN (paxillin) expression; luciferase reporter assays demonstrate direct transcriptional regulation, and PXN inhibition partially abolishes cell proliferation and migration induced by ETV4 in NSCLC cells.","method":"Luciferase reporter assay, microarray, gain/loss-of-function, cell proliferation and migration assays","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional regulation confirmed by luciferase assay plus functional rescue, single lab","pmids":["31670855"],"is_preprint":false},{"year":2021,"finding":"ITGB1 (integrin β1) regulates PXN expression; siRNA knockdown of ITGB1 downregulates PXN and YWHAZ in primary HCC cells. The ITGB1/PXN/YWHAZ/AKT axis promotes HCC cell cycle progression and aggressive tumor behavior.","method":"siRNA knockdown, western blot, immunostaining, cell cycle analysis, xenograft","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — pathway placement by siRNA + downstream readouts, but mechanistic detail is limited, single lab","pmids":["34977001"],"is_preprint":false},{"year":2021,"finding":"miR-497 directly targets CDC42 and ITGB1, whose knockdown inhibits phosphorylation of FAK and PXN (paxillin) and AKT, establishing CDC42/ITGB1/FAK/PXN/AKT as a signaling cascade controlling focal adhesion and gastric cancer cell migration/invasion. CDC42 restoration counteracts miR-497-mediated suppression of this pathway.","method":"miRNA overexpression, siRNA knockdown, phospho-western blotting, migration/invasion assay, in vivo metastasis, CDC42 rescue experiment","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-PXN readout downstream of CDC42/ITGB1 with CDC42 rescue establishing pathway order, single lab, multiple methods","pmids":["34589278"],"is_preprint":false},{"year":2012,"finding":"Pxn (paxillin) is specifically expressed in pillar cells of the mouse organ of Corti during embryonic and early postnatal ages, localizing as a focal adhesion scaffold protein in the inner ear.","method":"Transcriptional and translational reporter expression analysis, in situ hybridization","journal":"Gene expression patterns","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by expression reporter, no functional consequence established, single study","pmids":["22446079"],"is_preprint":false}],"current_model":"Paxillin (PXN) is a focal adhesion scaffold protein whose disordered N-terminal domain forms a multi-state fuzzy complex with the FAT domain of FAK to localize FAK to focal adhesions; it is phosphorylated at tyrosine residues by FAK/Src (promoting focal adhesion assembly and cell migration) and at S32/S119 by ULK1/2 (opposing FA assembly by weakening PXN homotypic interactions and liquid-liquid phase separation); its transcription is regulated by STAT3 (which it reciprocally activates via SRC), ETV4, and LSD1; downstream it activates Rac1-YAP, AKT, and STAT3 signaling cascades; and upstream inputs including ITGB1, ANGPTL4/NRP1/ABL1, CXCL5, and mechanical stimuli converge on PXN phosphorylation to control cell migration, mechanotransduction, and tumor progression."},"narrative":{"mechanistic_narrative":"Paxillin (PXN) is a focal adhesion scaffold protein that couples integrin-based adhesion and mechanical inputs to actin remodeling, cell migration, and tumor progression [PMID:37846507, PMID:34466738]. Its disordered N-terminal domain undergoes conformational compaction upon binding the C-terminal FAT domain of FAK, forming a multi-state fuzzy complex that is necessary and sufficient to localize FAK to focal adhesions [PMID:bio_10.1101_2025.01.01.630265]. PXN function is gated by competing phosphorylation: FAK/Src phosphorylate tyrosine residues to promote focal adhesion assembly, while ULK1/2 directly phosphorylate S32 and S119 to weaken PXN homotypic interactions and liquid-liquid phase separation, thereby opposing focal adhesion assembly, stress fiber formation, and migration [PMID:37846507]. At adhesions, substrate stiffness drives FAK/PXN phosphorylation that activates Rac1 and downstream YAP nuclear translocation to specify endothelial tip cells, and PXN sits functionally upstream of focal-adhesion and adherens-junction tension buildup [PMID:34466738]. In cancer, multiple upstream inputs converge on PXN phosphorylation and expression to drive migration and invasion: ANGPTL4 binding NRP1 triggers ABL1-dependent PXN phosphorylation [PMID:37169211], CXCL5 activates a PXN/AKT cascade that upregulates PD-L1 for immune evasion [PMID:39034411], and integrin β1 feeds a PXN/YWHAZ/AKT axis [PMID:34977001, PMID:34589278]. PXN expression is transcriptionally controlled by STAT3, ETV4, and LSD1 and is suppressed by miR-212, while PXN reciprocally activates STAT3 via SRC and stabilizes YB-1 against ubiquitin-mediated degradation, establishing feed-forward loops in tumor cells [PMID:25285406, PMID:41872167, PMID:26693054, PMID:28468300, PMID:31670855].","teleology":[{"year":2012,"claim":"Established a tissue-specific expression context for PXN as a focal adhesion scaffold, showing it is selectively present in pillar cells of the developing organ of Corti.","evidence":"Reporter expression analysis and in situ hybridization in mouse inner ear","pmids":["22446079"],"confidence":"Low","gaps":["No functional consequence of pillar-cell expression established","No mechanism linking PXN to inner ear development","Localization-only, single study"]},{"year":2014,"claim":"Connected chromatin-level regulation to PXN, showing the demethylase LSD1 controls PXN transcription and a LSD1→PXN phosphorylation→migration axis.","evidence":"ChIP-seq, transcriptome, siRNA knockdown and migration assays in prostate cancer cells","pmids":["25285406"],"confidence":"Medium","gaps":["Whether LSD1 acts directly at the PXN locus versus indirectly not fully resolved","Kinase responsible for the downstream PXN phosphorylation not identified"]},{"year":2015,"claim":"Identified a post-transcriptional brake on PXN, demonstrating miR-212 directly targets the PXN 3'UTR to suppress invasion.","evidence":"Luciferase 3'UTR reporter, miRNA mimic/inhibitor, rescue, in vitro/in vivo invasion in gastric cancer","pmids":["26693054"],"confidence":"Medium","gaps":["Other miR-212 targets contributing to phenotype not excluded","Does not address PXN protein-level activity changes"]},{"year":2017,"claim":"Mapped a direct transcriptional input by showing STAT3 binds the PXN promoter to drive PXN-mediated tumor angiogenesis.","evidence":"EMSA and ChIP at the PXN promoter, HUVEC angiogenesis assay in ER+ breast cancer cells","pmids":["28468300"],"confidence":"Medium","gaps":["Direction of causality within Src/FAK/STAT3 loop not fully dissected","Pharmacological agent (nobiletin) may have off-target effects"]},{"year":2018,"claim":"Placed PXN within a YAP1-FAK/PXN signaling module governing the switch from collective to mesenchymal invasion.","evidence":"IHC correlation, invasion assays, Src-family inhibition in nasopharyngeal carcinoma","pmids":["30504771"],"confidence":"Medium","gaps":["PXN's specific contribution versus FAK/YAP1 not separated","Direct molecular link between cytoplasmic LIF and PXN unresolved"]},{"year":2019,"claim":"Added a second direct transcriptional activator, showing ETV4 upregulates PXN to drive proliferation and migration.","evidence":"Luciferase reporter, microarray, gain/loss-of-function in NSCLC cells","pmids":["31670855"],"confidence":"Medium","gaps":["ETV4 binding site within PXN regulatory region not mapped precisely","PXN inhibition only partially abolishes ETV4 effects"]},{"year":2021,"claim":"Defined the mechanotransduction output of PXN phosphorylation, linking substrate stiffness through FAK/PXN to Rac1 activation and YAP-driven endothelial tip cell specification.","evidence":"Tunable hydrogels, phospho-WB, Rac1 GTP-pulldown, YAP imaging, loss-of-function in endothelial cells","pmids":["34466738"],"confidence":"Medium","gaps":["Specific phospho-residues mediating Rac1 activation not defined","How p-PXN loosens intercellular junctions mechanistically unclear"]},{"year":2021,"claim":"Embedded PXN in integrin and small-GTPase signaling cascades, placing it downstream of ITGB1 and CDC42/ITGB1 in AKT-coupled migration and cell-cycle pathways.","evidence":"siRNA knockdown, phospho-WB, CDC42 rescue, migration/invasion, xenograft in HCC and gastric cancer","pmids":["34977001","34589278"],"confidence":"Medium","gaps":["Direct versus indirect regulation of PXN by ITGB1 not distinguished in HCC study (Low confidence)","Mechanism of YWHAZ involvement in the axis not detailed"]},{"year":2023,"claim":"Revealed an antagonistic regulatory logic on PXN, showing ULK1/2 directly phosphorylate S32/S119 to weaken PXN phase separation and oppose FAK/Src-driven focal adhesion assembly.","evidence":"In vitro kinase assay, S32/S119 mutagenesis, phase separation assay, FA imaging, KO/KD migration phenotypes","pmids":["37846507"],"confidence":"High","gaps":["How the ULK1/2 versus FAK/Src balance is set in cells not defined","Physiological signals controlling ULK1/2 phosphorylation of PXN unknown"]},{"year":2023,"claim":"Identified an upstream receptor-kinase route to PXN phosphorylation, showing ANGPTL4/NRP1/ABL1 drives PXN phosphorylation and migration.","evidence":"Co-receptor binding, siRNA of NRP1/ABL1, dasatinib, phospho-PXN WB, migration in HNSCC","pmids":["37169211"],"confidence":"Medium","gaps":["ABL1 phospho-target residues on PXN not mapped","dasatinib inhibits multiple kinases beyond ABL1"]},{"year":2024,"claim":"Linked PXN to immune evasion, showing CXCL5 drives a PXN/AKT cascade that upregulates PD-L1 in a positive feedback loop.","evidence":"Gene silencing, p-PXN/p-AKT WB, PD-L1 flow cytometry, xenograft in lung cancer","pmids":["39034411"],"confidence":"Medium","gaps":["Direct biochemical link between p-PXN and AKT activation not shown","Mechanism by which PXN/AKT controls PD-L1 transcription unresolved"]},{"year":2025,"claim":"Resolved the structural basis of FAK recruitment, showing the disordered PXN N-terminus forms a multi-state fuzzy complex with the FAK FAT domain that is necessary and sufficient to localize FAK to adhesions.","evidence":"NMR and SAXS ensemble analysis of the PXN–FAT disordered complex (preprint)","pmids":["bio_10.1101_2025.01.01.630265"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Functional consequence of individual fuzzy states in cells not tested","How phosphorylation reshapes the fuzzy ensemble not addressed"]},{"year":2025,"claim":"Positioned PXN upstream of force buildup in early transformation, showing PXN is required for transient FA and adherens-junction tension and the proliferative advantage of Src-activated cells.","evidence":"siRNA, FRET tension biosensors at FAs/AJs, FAK inhibition, proliferation assays (preprint)","pmids":["bio_10.1101_2025.07.05.663275"],"confidence":"Low","gaps":["Preprint, single lab, not peer-reviewed","Molecular link between PXN and adherens-junction tension not defined","Connection to EGFR-ERK/MRTF-A-SRF axis correlative"]},{"year":2026,"claim":"Established a self-reinforcing transcriptional circuit and a protein-stabilization role, showing STAT3 drives PXN, PXN reactivates STAT3 via SRC, and PXN stabilizes YB-1 against ubiquitin-mediated degradation.","evidence":"qRT-PCR, WB, mRNA-seq, knockdown, ubiquitination assay in IDH-wildtype GBM","pmids":["41872167"],"confidence":"Medium","gaps":["Whether PXN regulates YB-1 ubiquitination directly or via an intermediary unknown","Mechanism by which PXN controls SRC transcription unresolved"]},{"year":null,"claim":"How the competing FAK/Src and ULK1/2 phosphorylation inputs, the fuzzy PXN-FAT ensemble, and PXN phase separation are integrated to set adhesion dynamics in physiological versus tumor contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling phosphorylation state to fuzzy-complex conformation and phase behavior","In vivo physiological role of PXN phase separation untested","Cytoplasmic versus nuclear/transcriptional functions of PXN not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,6,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,6,7,8]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,2,10]}],"complexes":["focal adhesion"],"partners":["FAK","SRC","ABL1","STAT3","YB-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49023","full_name":"Paxillin","aliases":[],"length_aa":591,"mass_kda":64.5,"function":"Cytoskeletal protein involved in actin-membrane attachment at sites of cell adhesion to the extracellular matrix (focal adhesion). Recruits other proteins such as TRIM15 to focal adhesion","subcellular_location":"Cytoplasm, cytoskeleton; Cell junction, focal adhesion; Cytoplasm, cell cortex","url":"https://www.uniprot.org/uniprotkb/P49023/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PXN","classification":"Not Classified","n_dependent_lines":406,"n_total_lines":1208,"dependency_fraction":0.3360927152317881},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000089159","cell_line_id":"CID000545","localizations":[{"compartment":"focal_adhesions","grade":3}],"interactors":[{"gene":"DYNLL2","stoichiometry":4.0},{"gene":"ARHGEF7","stoichiometry":0.2},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"PTPN12","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000545","total_profiled":1310},"omim":[{"mim_id":"620403","title":"INKA-BOX ACTIN REGULATOR 2; INKA2","url":"https://www.omim.org/entry/620403"},{"mim_id":"618888","title":"CAS SCAFFOLD PROTEIN FAMILY, MEMBER 4; CASS4","url":"https://www.omim.org/entry/618888"},{"mim_id":"618649","title":"HECT DOMAIN E3 UBIQUITIN PROTEIN LIGASE 1; HECTD1","url":"https://www.omim.org/entry/618649"},{"mim_id":"618441","title":"ADHESION G PROTEIN-COUPLED RECEPTOR G3; ADGRG3","url":"https://www.omim.org/entry/618441"},{"mim_id":"617338","title":"NUDIX HYDROLASE 16-LIKE 1; NUDT16L1","url":"https://www.omim.org/entry/617338"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Focal adhesion sites","reliability":"Enhanced"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PXN"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P49023","domains":[{"cath_id":"2.10.110.10","chopping":"355-413","consensus_level":"medium","plddt":90.611,"start":355,"end":413},{"cath_id":"2.10.110.10","chopping":"415-472","consensus_level":"medium","plddt":93.2984,"start":415,"end":472}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49023","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49023-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49023-F1-predicted_aligned_error_v6.png","plddt_mean":65.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PXN","jax_strain_url":"https://www.jax.org/strain/search?query=PXN"},"sequence":{"accession":"P49023","fasta_url":"https://rest.uniprot.org/uniprotkb/P49023.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49023/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49023"}},"corpus_meta":[{"pmid":"28553938","id":"PMC_28553938","title":"The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1.","date":"2017","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28553938","citation_count":267,"is_preprint":false},{"pmid":"34626132","id":"PMC_34626132","title":"DDX17-regulated alternative splicing that produced an oncogenic isoform of PXN-AS1 to promote HCC metastasis.","date":"2021","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/34626132","citation_count":88,"is_preprint":false},{"pmid":"28468300","id":"PMC_28468300","title":"Nobiletin Inhibits Angiogenesis by Regulating Src/FAK/STAT3-Mediated Signaling through PXN in ER⁺ Breast Cancer Cells.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28468300","citation_count":69,"is_preprint":false},{"pmid":"31670855","id":"PMC_31670855","title":"ETV4 overexpression promotes progression of non-small cell lung cancer by upregulating PXN and MMP1 transcriptionally.","date":"2019","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31670855","citation_count":59,"is_preprint":false},{"pmid":"25285406","id":"PMC_25285406","title":"LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6.","date":"2014","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25285406","citation_count":57,"is_preprint":false},{"pmid":"29337100","id":"PMC_29337100","title":"Knockdown of long non-coding RNA XIST inhibits cell viability and invasion by regulating miR-137/PXN axis in non-small cell lung cancer.","date":"2018","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/29337100","citation_count":55,"is_preprint":false},{"pmid":"34466738","id":"PMC_34466738","title":"Matrix stiffness modulates tip cell formation through the p-PXN-Rac1-YAP signaling 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Through PXN/YWHAZ/AKT Pathways.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34977001","citation_count":37,"is_preprint":false},{"pmid":"26693054","id":"PMC_26693054","title":"MicroRNA-212 functions as an epigenetic-silenced tumor suppressor involving in tumor metastasis and invasion of gastric cancer through down-regulating PXN expression.","date":"2015","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26693054","citation_count":35,"is_preprint":false},{"pmid":"39034411","id":"PMC_39034411","title":"CXCL5 impedes CD8+ T cell immunity by upregulating PD-L1 expression in lung cancer via PXN/AKT signaling phosphorylation and neutrophil chemotaxis.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/39034411","citation_count":33,"is_preprint":false},{"pmid":"30504771","id":"PMC_30504771","title":"Cytoplasmic LIF 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ULK1/2 and FAK/Src have opposing functions on PXN-dependent mechanotransduction, competing for phosphorylation of adjacent serine and tyrosine residues.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (S32/S119), phase separation assay, focal adhesion assembly imaging, loss-of-function (KO/KD) with migration and mechanical phenotype readouts\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct substrate identification with mutagenesis, in vitro phosphorylation assay, phase separation assay, and functional migration/FA phenotype, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37846507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The disordered N-terminal domain of PXN undergoes significant conformational compaction upon binding the C-terminal focal adhesion targeting (FAT) domain of FAK, forming a 48-kDa multi-modal fuzzy complex with four major interconverting states. Each state has unique sets of contacts involving disordered regions. This PXN–FAT interaction is necessary and sufficient for localizing FAK to focal adhesions.\",\n      \"method\": \"NMR spectroscopy, small-angle X-ray scattering (SAXS), ensemble analysis of disordered complex\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural characterization (NMR + SAXS) with conformational state resolution, single preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.01.01.630265\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Substrate stiffness regulates FAK and PXN phosphorylation at focal adhesions in endothelial cells, which promotes Rac1 activation (GDP→GTP transition), subsequent YAP nuclear translocation, and tip cell specification during angiogenesis. Phosphorylated PXN also loosens intercellular connections, further facilitating tip cell formation.\",\n      \"method\": \"Tunable hydrogel substrates, phospho-specific western blotting, Rac1 GTP-pulldown, YAP localization imaging, loss-of-function\",\n      \"journal\": \"Bioactive materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (phospho-WB, GTP-pulldown, imaging) in single lab establishing p-PXN→Rac1→YAP pathway\",\n      \"pmids\": [\"34466738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cytoplasmic LIF (bearing signal peptide mutation) enhances cancer cell invasion and vascular dissemination mechanistically through modulation of YAP1-FAK/PXN signaling in nasopharyngeal carcinoma, reprogramming collective to mesenchymal invasion mode.\",\n      \"method\": \"IHC correlation, functional invasion assays, pharmacological inhibition (AZD0530/dasatinib), signaling pathway analysis by western blot\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (YAP1-FAK/PXN) established with pharmacological reversal and multiple functional assays in single lab\",\n      \"pmids\": [\"30504771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LSD1 (lysine-specific demethylase 1) controls transcription of PXN (paxillin) in androgen-independent prostate cancer cells. Upon LSD1 depletion, enhanced LPAR6 signaling promotes cell migration with concomitant phosphorylation of PXN, establishing a LSD1→PXN phosphorylation→migration axis.\",\n      \"method\": \"Transcriptome and cistrome (ChIP-seq) analysis, siRNA knockdown, migration/invasion assays, phospho-PXN western blot\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cistrome + transcriptome plus functional migration assays establish LSD1 regulation of PXN, single lab with two orthogonal genomic/functional methods\",\n      \"pmids\": [\"25285406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANGPTL4 binding to NRP1 receptor leads to ABL1 tyrosine kinase-dependent phosphorylation of PXN, driving HNSCC tumor cell migration. Pharmacological inhibition of ABL1 (dasatinib) or siRNA silencing of NRP1 or ABL1 blocks PXN phosphorylation and migration.\",\n      \"method\": \"Co-receptor binding assay, siRNA knockdown of NRP1/ABL1, pharmacological inhibition (dasatinib), phospho-PXN western blot, migration assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor–kinase–substrate axis (NRP1/ABL1/PXN phosphorylation) established with pharmacological + genetic perturbation and phospho-readout, single lab\",\n      \"pmids\": [\"37169211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CXCL5 activates phosphorylation of PXN/AKT signaling cascade in lung cancer cells, leading to upregulation of PD-L1 expression and formation of a positive feedback loop that promotes immune evasion.\",\n      \"method\": \"Gene silencing, western blotting for p-PXN and p-AKT, flow cytometry for PD-L1, in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CXCL5→p-PXN→AKT→PD-L1 pathway established by gene silencing with phospho-readouts, single lab, multiple methods\",\n      \"pmids\": [\"39034411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STAT3 directly upregulates PXN transcription in GBM (IDH-wildtype), and PXN reciprocally activates STAT3 by regulating SRC transcription, forming a positive feedback loop. Additionally, PXN stabilizes YB-1 protein by inhibiting its ubiquitin-mediated degradation.\",\n      \"method\": \"qRT-PCR, western blotting, mRNA sequencing, functional knockdown assays, ubiquitination assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional feedback loop and ubiquitination regulation established by multiple molecular methods in single lab\",\n      \"pmids\": [\"41872167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-212 directly targets the 3'UTR of PXN mRNA to suppress PXN expression; miR-212 overexpression reduces PXN mRNA and protein levels and decreases gastric cancer cell invasion and migration in vitro and in vivo. PXN restoration rescues migration/invasion in miR-212-overexpressing cells.\",\n      \"method\": \"Luciferase reporter assay (3'UTR), miRNA mimic/inhibitor transfection, rescue experiments, in vitro and in vivo invasion assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR targeting confirmed by luciferase assay, functional rescue experiments, single lab\",\n      \"pmids\": [\"26693054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STAT3 binds to a binding site in the PXN gene promoter; nobiletin inhibits STAT3/DNA binding activity at this site and STAT3 binding to the PXN promoter, thereby suppressing PXN-mediated tumor angiogenesis in ER+ breast cancer cells downstream of Src/FAK/STAT3 signaling.\",\n      \"method\": \"EMSA, ChIP assay, western blotting, HUVEC angiogenesis assay, RT-PCR\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct STAT3–PXN promoter binding established by EMSA and ChIP, single lab, two orthogonal chromatin methods\",\n      \"pmids\": [\"28468300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PXN knockdown in premalignant Src-activated mammary epithelial cells prevents the transient increase in tensile forces at focal adhesions and at adherens junctions, and abolishes the proliferative advantage, placing PXN functionally upstream of AJ force buildup and EGFR-ERK/MRTF-A-SRF activation during early malignant transformation.\",\n      \"method\": \"siRNA knockdown, FRET-based tension biosensors at FAs and AJs, FAK inhibition, proliferation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis with tension biosensors, preprint not peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.07.05.663275\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ETV4 transcription factor directly upregulates PXN (paxillin) expression; luciferase reporter assays demonstrate direct transcriptional regulation, and PXN inhibition partially abolishes cell proliferation and migration induced by ETV4 in NSCLC cells.\",\n      \"method\": \"Luciferase reporter assay, microarray, gain/loss-of-function, cell proliferation and migration assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional regulation confirmed by luciferase assay plus functional rescue, single lab\",\n      \"pmids\": [\"31670855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGB1 (integrin β1) regulates PXN expression; siRNA knockdown of ITGB1 downregulates PXN and YWHAZ in primary HCC cells. The ITGB1/PXN/YWHAZ/AKT axis promotes HCC cell cycle progression and aggressive tumor behavior.\",\n      \"method\": \"siRNA knockdown, western blot, immunostaining, cell cycle analysis, xenograft\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathway placement by siRNA + downstream readouts, but mechanistic detail is limited, single lab\",\n      \"pmids\": [\"34977001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-497 directly targets CDC42 and ITGB1, whose knockdown inhibits phosphorylation of FAK and PXN (paxillin) and AKT, establishing CDC42/ITGB1/FAK/PXN/AKT as a signaling cascade controlling focal adhesion and gastric cancer cell migration/invasion. CDC42 restoration counteracts miR-497-mediated suppression of this pathway.\",\n      \"method\": \"miRNA overexpression, siRNA knockdown, phospho-western blotting, migration/invasion assay, in vivo metastasis, CDC42 rescue experiment\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-PXN readout downstream of CDC42/ITGB1 with CDC42 rescue establishing pathway order, single lab, multiple methods\",\n      \"pmids\": [\"34589278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Pxn (paxillin) is specifically expressed in pillar cells of the mouse organ of Corti during embryonic and early postnatal ages, localizing as a focal adhesion scaffold protein in the inner ear.\",\n      \"method\": \"Transcriptional and translational reporter expression analysis, in situ hybridization\",\n      \"journal\": \"Gene expression patterns\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by expression reporter, no functional consequence established, single study\",\n      \"pmids\": [\"22446079\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Paxillin (PXN) is a focal adhesion scaffold protein whose disordered N-terminal domain forms a multi-state fuzzy complex with the FAT domain of FAK to localize FAK to focal adhesions; it is phosphorylated at tyrosine residues by FAK/Src (promoting focal adhesion assembly and cell migration) and at S32/S119 by ULK1/2 (opposing FA assembly by weakening PXN homotypic interactions and liquid-liquid phase separation); its transcription is regulated by STAT3 (which it reciprocally activates via SRC), ETV4, and LSD1; downstream it activates Rac1-YAP, AKT, and STAT3 signaling cascades; and upstream inputs including ITGB1, ANGPTL4/NRP1/ABL1, CXCL5, and mechanical stimuli converge on PXN phosphorylation to control cell migration, mechanotransduction, and tumor progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Paxillin (PXN) is a focal adhesion scaffold protein that couples integrin-based adhesion and mechanical inputs to actin remodeling, cell migration, and tumor progression [#0, #2]. Its disordered N-terminal domain undergoes conformational compaction upon binding the C-terminal FAT domain of FAK, forming a multi-state fuzzy complex that is necessary and sufficient to localize FAK to focal adhesions [#1]. PXN function is gated by competing phosphorylation: FAK/Src phosphorylate tyrosine residues to promote focal adhesion assembly, while ULK1/2 directly phosphorylate S32 and S119 to weaken PXN homotypic interactions and liquid-liquid phase separation, thereby opposing focal adhesion assembly, stress fiber formation, and migration [#0]. At adhesions, substrate stiffness drives FAK/PXN phosphorylation that activates Rac1 and downstream YAP nuclear translocation to specify endothelial tip cells, and PXN sits functionally upstream of focal-adhesion and adherens-junction tension buildup [#2]. In cancer, multiple upstream inputs converge on PXN phosphorylation and expression to drive migration and invasion: ANGPTL4 binding NRP1 triggers ABL1-dependent PXN phosphorylation [#5], CXCL5 activates a PXN/AKT cascade that upregulates PD-L1 for immune evasion [#6], and integrin \\u03b21 feeds a PXN/YWHAZ/AKT axis [#12, #13]. PXN expression is transcriptionally controlled by STAT3, ETV4, and LSD1 and is suppressed by miR-212, while PXN reciprocally activates STAT3 via SRC and stabilizes YB-1 against ubiquitin-mediated degradation, establishing feed-forward loops in tumor cells [#4, #7, #8, #9, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established a tissue-specific expression context for PXN as a focal adhesion scaffold, showing it is selectively present in pillar cells of the developing organ of Corti.\",\n      \"evidence\": \"Reporter expression analysis and in situ hybridization in mouse inner ear\",\n      \"pmids\": [\"22446079\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No functional consequence of pillar-cell expression established\",\n        \"No mechanism linking PXN to inner ear development\",\n        \"Localization-only, single study\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected chromatin-level regulation to PXN, showing the demethylase LSD1 controls PXN transcription and a LSD1\\u2192PXN phosphorylation\\u2192migration axis.\",\n      \"evidence\": \"ChIP-seq, transcriptome, siRNA knockdown and migration assays in prostate cancer cells\",\n      \"pmids\": [\"25285406\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Whether LSD1 acts directly at the PXN locus versus indirectly not fully resolved\",\n        \"Kinase responsible for the downstream PXN phosphorylation not identified\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a post-transcriptional brake on PXN, demonstrating miR-212 directly targets the PXN 3'UTR to suppress invasion.\",\n      \"evidence\": \"Luciferase 3'UTR reporter, miRNA mimic/inhibitor, rescue, in vitro/in vivo invasion in gastric cancer\",\n      \"pmids\": [\"26693054\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Other miR-212 targets contributing to phenotype not excluded\",\n        \"Does not address PXN protein-level activity changes\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped a direct transcriptional input by showing STAT3 binds the PXN promoter to drive PXN-mediated tumor angiogenesis.\",\n      \"evidence\": \"EMSA and ChIP at the PXN promoter, HUVEC angiogenesis assay in ER+ breast cancer cells\",\n      \"pmids\": [\"28468300\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Direction of causality within Src/FAK/STAT3 loop not fully dissected\",\n        \"Pharmacological agent (nobiletin) may have off-target effects\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed PXN within a YAP1-FAK/PXN signaling module governing the switch from collective to mesenchymal invasion.\",\n      \"evidence\": \"IHC correlation, invasion assays, Src-family inhibition in nasopharyngeal carcinoma\",\n      \"pmids\": [\"30504771\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"PXN's specific contribution versus FAK/YAP1 not separated\",\n        \"Direct molecular link between cytoplasmic LIF and PXN unresolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Added a second direct transcriptional activator, showing ETV4 upregulates PXN to drive proliferation and migration.\",\n      \"evidence\": \"Luciferase reporter, microarray, gain/loss-of-function in NSCLC cells\",\n      \"pmids\": [\"31670855\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"ETV4 binding site within PXN regulatory region not mapped precisely\",\n        \"PXN inhibition only partially abolishes ETV4 effects\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the mechanotransduction output of PXN phosphorylation, linking substrate stiffness through FAK/PXN to Rac1 activation and YAP-driven endothelial tip cell specification.\",\n      \"evidence\": \"Tunable hydrogels, phospho-WB, Rac1 GTP-pulldown, YAP imaging, loss-of-function in endothelial cells\",\n      \"pmids\": [\"34466738\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Specific phospho-residues mediating Rac1 activation not defined\",\n        \"How p-PXN loosens intercellular junctions mechanistically unclear\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Embedded PXN in integrin and small-GTPase signaling cascades, placing it downstream of ITGB1 and CDC42/ITGB1 in AKT-coupled migration and cell-cycle pathways.\",\n      \"evidence\": \"siRNA knockdown, phospho-WB, CDC42 rescue, migration/invasion, xenograft in HCC and gastric cancer\",\n      \"pmids\": [\"34977001\", \"34589278\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Direct versus indirect regulation of PXN by ITGB1 not distinguished in HCC study (Low confidence)\",\n        \"Mechanism of YWHAZ involvement in the axis not detailed\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an antagonistic regulatory logic on PXN, showing ULK1/2 directly phosphorylate S32/S119 to weaken PXN phase separation and oppose FAK/Src-driven focal adhesion assembly.\",\n      \"evidence\": \"In vitro kinase assay, S32/S119 mutagenesis, phase separation assay, FA imaging, KO/KD migration phenotypes\",\n      \"pmids\": [\"37846507\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"How the ULK1/2 versus FAK/Src balance is set in cells not defined\",\n        \"Physiological signals controlling ULK1/2 phosphorylation of PXN unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an upstream receptor-kinase route to PXN phosphorylation, showing ANGPTL4/NRP1/ABL1 drives PXN phosphorylation and migration.\",\n      \"evidence\": \"Co-receptor binding, siRNA of NRP1/ABL1, dasatinib, phospho-PXN WB, migration in HNSCC\",\n      \"pmids\": [\"37169211\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"ABL1 phospho-target residues on PXN not mapped\",\n        \"dasatinib inhibits multiple kinases beyond ABL1\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked PXN to immune evasion, showing CXCL5 drives a PXN/AKT cascade that upregulates PD-L1 in a positive feedback loop.\",\n      \"evidence\": \"Gene silencing, p-PXN/p-AKT WB, PD-L1 flow cytometry, xenograft in lung cancer\",\n      \"pmids\": [\"39034411\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Direct biochemical link between p-PXN and AKT activation not shown\",\n        \"Mechanism by which PXN/AKT controls PD-L1 transcription unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the structural basis of FAK recruitment, showing the disordered PXN N-terminus forms a multi-state fuzzy complex with the FAK FAT domain that is necessary and sufficient to localize FAK to adhesions.\",\n      \"evidence\": \"NMR and SAXS ensemble analysis of the PXN\\u2013FAT disordered complex (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.01.630265\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Preprint, not yet peer-reviewed\",\n        \"Functional consequence of individual fuzzy states in cells not tested\",\n        \"How phosphorylation reshapes the fuzzy ensemble not addressed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned PXN upstream of force buildup in early transformation, showing PXN is required for transient FA and adherens-junction tension and the proliferative advantage of Src-activated cells.\",\n      \"evidence\": \"siRNA, FRET tension biosensors at FAs/AJs, FAK inhibition, proliferation assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.05.663275\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Preprint, single lab, not peer-reviewed\",\n        \"Molecular link between PXN and adherens-junction tension not defined\",\n        \"Connection to EGFR-ERK/MRTF-A-SRF axis correlative\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a self-reinforcing transcriptional circuit and a protein-stabilization role, showing STAT3 drives PXN, PXN reactivates STAT3 via SRC, and PXN stabilizes YB-1 against ubiquitin-mediated degradation.\",\n      \"evidence\": \"qRT-PCR, WB, mRNA-seq, knockdown, ubiquitination assay in IDH-wildtype GBM\",\n      \"pmids\": [\"41872167\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Whether PXN regulates YB-1 ubiquitination directly or via an intermediary unknown\",\n        \"Mechanism by which PXN controls SRC transcription unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the competing FAK/Src and ULK1/2 phosphorylation inputs, the fuzzy PXN-FAT ensemble, and PXN phase separation are integrated to set adhesion dynamics in physiological versus tumor contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No unified model coupling phosphorylation state to fuzzy-complex conformation and phase behavior\",\n        \"In vivo physiological role of PXN phase separation untested\",\n        \"Cytoplasmic versus nuclear/transcriptional functions of PXN not mechanistically reconciled\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [0, 1, 2, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 6, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 2, 10]}\n    ],\n    \"complexes\": [\n      \"focal adhesion\"\n    ],\n    \"partners\": [\n      \"FAK\",\n      \"SRC\",\n      \"ABL1\",\n      \"STAT3\",\n      \"YB-1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}