{"gene":"CTTN","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1993,"finding":"The EMS1 gene product (human cortactin, 80/85 kDa) is homologous (85% identity) to a chicken v-src substrate. In normal epithelial cells, the protein localizes mainly to the cytoplasm with minor presence in leading lamellae; in carcinoma cells overexpressing EMS1, it accumulates at podosome-like adherens junctions associated with cell-substratum contact sites, but not intercellular adherens junctions.","method":"Amino acid sequence comparison, immunocytochemistry","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — sequence homology plus direct immunocytochemical localization in multiple cell types, single lab","pmids":["8474448"],"is_preprint":false},{"year":1998,"finding":"The EMS1/cortactin protein contains: (i) a filamentous actin-binding tandem repeat domain, (ii) a proline-rich SH3-binding region, and (iii) a SH3 domain. Both human p80 and p85 isoforms are encoded by the EMS1 cDNA. Expression is restricted to non-lymphoid tumor cell lines.","method":"Gene transfer experiments, western blot, sequence analysis","journal":"Cell adhesion and communication","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene transfer confirmed dual isoforms; domain characterization by sequence and functional assay, single lab","pmids":["9823470"],"is_preprint":false},{"year":1998,"finding":"Stable overexpression of EMS1/cortactin in NIH3T3 fibroblasts increases cell motility and invasiveness in modified Boyden chamber assays without altering proliferation or anchorage independence, indicating cortactin promotes cell migration and invasion.","method":"Stable transfection, modified Boyden chamber motility/invasion assay, proliferation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype with loss/gain of function, single lab","pmids":["9681820"],"is_preprint":false},{"year":1999,"finding":"EGF treatment or cell detachment induces an 80–85 kDa mobility shift of EMS1 (cortactin) correlated with increased serine/threonine phosphorylation. This shift is blocked by the MEK inhibitor PD98059 and is induced by constitutively active MEK, establishing MEK as a necessary and sufficient intermediate in EMS1 phosphorylation. The helical-proline-rich region is required for this phosphorylation. ERKs are candidate kinases for this region in vitro, but other MEK-regulated enzymes also participate.","method":"Pharmacological inhibition (PD98059), constitutively active MEK expression, in vitro kinase assay, deletion mutagenesis, tryptic phosphopeptide mapping","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay combined with mutagenesis and pharmacological epistasis, multiple orthogonal methods in single study","pmids":["10537323"],"is_preprint":false},{"year":1996,"finding":"EMS1 protein is tyrosine phosphorylated in breast cancer cell lines; degree of tyrosine phosphorylation correlates with src-family kinase activity (c-fyn and c-yes expression). Gene amplification is the predominant mechanism of EMS1 overexpression in breast cancer cell lines.","method":"Western blot, tyrosine phosphorylation analysis, src kinase activity assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — correlative phosphorylation analysis across multiple cell lines, single lab","pmids":["8945620"],"is_preprint":false},{"year":2006,"finding":"siRNA-mediated silencing of CTTN in esophageal squamous cell carcinoma cells reduces cell migration, invasiveness, and anoikis resistance. The protective role of CTTN in anoikis resistance correlates with activation of the PI3K/Akt pathway. In vivo, CTTN knockdown decreased tumor growth and lung metastasis.","method":"siRNA knockdown, cell migration assay, anoikis assay, PI3K/Akt signaling analysis, in vivo xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with multiple orthogonal phenotypic readouts (migration, anoikis, in vivo metastasis) plus pathway placement (PI3K/Akt), replicated across in vitro and in vivo models","pmids":["17178864"],"is_preprint":false},{"year":2009,"finding":"Calreticulin (CRT) regulates CTTN expression via STAT3: CRT knockdown reduces p-STAT3, and chromatin immunoprecipitation shows direct binding of p-STAT3 to STAT3-binding sequences in the CTTN promoter. CRT-enhanced anoikis resistance and motility operate through a CRT–STAT3–CTTN–PI3K–Akt pathway; CTTN restoration in CRT-depleted cells rescues motility and anoikis resistance.","method":"siRNA knockdown, ChIP assay, JAK inhibitor (AG490), Western blot, cell migration/invasion/anoikis assays, CTTN rescue experiment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP directly shows p-STAT3 binding to CTTN promoter; pathway placement by pharmacological inhibitor + rescue, multiple orthogonal methods","pmids":["19684620"],"is_preprint":false},{"year":2019,"finding":"RNF128 (an E3 ubiquitin ligase) ubiquitinates and promotes degradation of CTTN (cortactin), activating Wnt/β-catenin signaling and CD44/c-Myc transcription. RNF128 downregulation leads to CTTN accumulation, inducing EMT and stemness in melanoma.","method":"Co-IP, ubiquitination assay, siRNA interference, functional EMT/stemness assays","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with ubiquitination assay demonstrates interaction and degradation; single lab","pmids":["30832692"],"is_preprint":false},{"year":2020,"finding":"UCHL1 interacts with CTTN and promotes K48-linked ubiquitination of CTTN, leading to its proteasomal degradation. CTTN rescue in UCHL1-overexpressing NPC cells restores migration and invasion, placing CTTN as a functional downstream target of UCHL1.","method":"Co-IP, ubiquitination assay (K48-linkage specific), in vitro/in vivo migration and invasion assays, CTTN rescue experiment","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus K48-specific ubiquitination assay with rescue, single lab","pmids":["32120844"],"is_preprint":false},{"year":2022,"finding":"The CTTN coding SNP Ser484Asn (rs56162978) reduces Tyr486 cortactin phosphorylation, inhibits binding of cortactin to nmMLCK, delays endothelial cell barrier recovery after thrombin-induced permeability, and attenuates lamellipodia dynamics. In Cttn+/- heterozygous mice, increased lung vascular permeability was rescued by WT CTTN transgene but not by S484N transgene.","method":"Transgene expression in human lung ECs, phosphorylation assay, Co-IP (cortactin–nmMLCK binding), biophysical barrier assay, liposome-mediated transgene delivery in vivo in ARDS mouse model","journal":"Translational research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, binding assay, in vivo rescue with WT vs mutant transgene), in vitro and in vivo validation","pmids":["35181549"],"is_preprint":false},{"year":2022,"finding":"CBLC (an E3 ubiquitin ligase) interacts with CTTN in the cytoplasm and promotes CTTN degradation through the ubiquitin-proteasome pathway without affecting CTTN mRNA levels. CBLC-mediated inhibition of breast cancer cell proliferation, migration, and invasion is partially reversed by CTTN overexpression.","method":"Co-IP, immunofluorescence co-localization, ubiquitin-proteasome pathway assay, rescue experiment with CTTN overexpression","journal":"Journal of receptor and signal transduction research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus proteasome assay and rescue experiment, single lab","pmids":["36043996"],"is_preprint":false},{"year":2008,"finding":"Cortactin (CTTN) and N-WASP, two regulators of actin network assembly, are concentrated at tubulobulbar complexes in the rat testis seminiferous epithelium alongside clathrin, supporting that these podosome-like structures involve cortactin-dependent actin assembly and clathrin-mediated endocytosis.","method":"Immunofluorescence microscopy, immunoelectron microscopy on rat testis","journal":"Biology of reproduction","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization only by immunofluorescence/immuno-EM, no functional manipulation of cortactin performed","pmids":["18799755"],"is_preprint":false},{"year":2011,"finding":"siRNA silencing of cortactin (CTTN) in colon cancer cells reduces transferrin uptake (endocytosis). Intact cortactin protein and sufficient expression level are required for optimal clathrin-coated vesicle-mediated endocytosis in cancer cells.","method":"siRNA knockdown, domain-deletion mutant transfection, transferrin uptake assay, immunohistochemistry","journal":"Zhonghua yi xue za zhi","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function plus domain-deletion mutants with defined endocytosis readout, single lab","pmids":["21418910"],"is_preprint":false},{"year":2019,"finding":"CTTN overexpression downregulates DKK-1, a Wnt antagonist, thereby activating Wnt/β-catenin signaling. A β-catenin/TCF inhibitor reverses CTTN-induced cancer stem cell-like properties in HER2+ breast cancer cells in vitro.","method":"RNA-seq, Western blot, tumorsphere formation, ALDEFLUOR assay, in vivo xenograft, β-catenin/TCF inhibitor treatment","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNA-seq plus pharmacological rescue with β-catenin inhibitor, single lab","pmids":["36831511"],"is_preprint":false},{"year":2024,"finding":"Matrix stiffness promotes cell migration, invasion, and invadopodia formation in nasopharyngeal carcinoma through upregulation of wild-type CTTN (WT-CTTN). The splicing factor PTBP2 (activated by high stiffness) controls the production of WT-CTTN over splice variants (SV1-CTTN, SV2-CTTN), establishing a PTBP2–WT-CTTN axis in mechanosensing.","method":"siRNA knockdown, overexpression studies, alternative splicing analysis, migration/invasion/invadopodia assays in varying stiffness conditions","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional manipulation with defined phenotype and mechanistic splicing axis identified, single lab","pmids":["38273817"],"is_preprint":false},{"year":2019,"finding":"HBx (hepatitis B virus X protein) physically interacts with CTTN in HCC cells (validated by Co-IP and confocal microscopy). The HBx–CTTN interaction upregulates CREB1 and its downstream targets (cyclin D1, MMP-9), promoting cell proliferation and migration.","method":"Proteomics, Co-IP, confocal microscopy, cell proliferation/migration assays, cell cycle analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus confocal confirm interaction; downstream signaling assessed by Western blot, single lab","pmids":["31138777"],"is_preprint":false},{"year":2024,"finding":"YWHAG (14-3-3γ) interacts with CTTN and mediates CRC cell proliferation, migration, and invasion by activating Wnt/β-catenin signaling downstream of CTTN.","method":"RNA-seq, Co-IP (YWHAG–CTTN interaction), functional cell assays, Wnt signaling readouts","journal":"Medical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP pulldown with signaling pathway inference, single lab","pmids":["38538804"],"is_preprint":false},{"year":2025,"finding":"RBMS1 promotes alternative splicing of CTTN to generate a CTTN-Δe11 isoform in cardiomyocytes. This splicing switch activates the PI3K/AKT signaling pathway, causing cytoskeleton and sarcomere damage leading to cardiac hypertrophy.","method":"RNA splicing analysis, PI3K/AKT pathway assay, cardiac hypertrophy mouse model, pharmacological inhibition of RBMS1 (nortriptyline)","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic splice-switching with defined isoform and pathway activation, in vivo model with pharmacological rescue, single lab","pmids":["41214391"],"is_preprint":false},{"year":2025,"finding":"Cortactin localizes to Rab7-positive late endosomes and is required for late endosomal tethering and homeostasis. Cortactin depletion in circulating tumor cells causes accumulation of aberrantly enlarged Rab7+ late endosomal aggregates, accumulation and activation of mTOR within these structures, p53 phosphorylation (Ser15, Ser33), G0/G1 cell cycle arrest, and cellular senescence (characterized by SASP, β-galactosidase activity, Ki-67/Lamin B1 depletion, elevated mitochondrial ROS). A positive p53–mtROS feedback loop maintains stable senescence.","method":"Live imaging and fractionation (Rab7/mTOR localization), CTTN depletion, p53 phosphorylation assay, cell cycle analysis, senescence markers (β-gal, SASP, Ki-67, Lamin B1, mtROS), CDX mouse models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods establishing localization and downstream senescence pathway; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.03.26.645381"],"is_preprint":true},{"year":2025,"finding":"Knockdown of CTTN in HNSCC cells reduces FAK expression levels and impairs cytoskeletal formation, thereby reducing anoikis resistance. CTTN silencing also suppresses growth in patient-derived organoids (PDOs).","method":"siRNA knockdown, PI staining (apoptosis), immunofluorescence, Western blot (FAK), PDO culture assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with defined FAK-cytoskeletal mechanism and PDO validation, single lab","pmids":["41168318"],"is_preprint":false},{"year":2025,"finding":"LAD1 (ladinin-1) binds LINC01305 and together they co-regulate phosphorylation of CTTN and N-WASP, mediating cytoskeletal reorganization and EMT via activation of the PI3K/AKT signaling pathway in ESCC cells.","method":"Co-IP (LAD1–LINC01305), phosphorylation assays (CTTN, N-WASP), PI3K/AKT pathway analysis, EMT marker analysis","journal":"Molecular carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic detail is limited (abstract level); single co-IP for the interaction, single lab","pmids":["39835575"],"is_preprint":false},{"year":2024,"finding":"LPS, TNF-α, and high-magnitude cyclic stretch (18% CS) significantly increase CTTN promoter activity; these responses require NF-κB response elements in the promoter. The promoter SNP rs34612166 (−212T/C) markedly enhances LPS- and 18%CS-induced CTTN promoter activation. HIF pathway activators and NRF2 also modulate CTTN promoter activity. Demethylation (5'-Aza) increases CTTN promoter activity ~2.9-fold, indicating epigenetic regulation.","method":"Luciferase reporter assay with full-length CTTN promoter, site-directed mutagenesis (NF-κB sites and SNP), pharmacological modulators (HIF, NRF2 inhibitors/activators, 5'-Aza), cyclic stretch, immunohistochemistry in LPS-exposed mouse lungs","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — luciferase reporter with site-directed mutagenesis identifying functional NF-κB elements; multiple stimuli tested, single lab","pmids":["39162263"],"is_preprint":false}],"current_model":"CTTN (cortactin/EMS1) encodes an actin-binding scaffold protein that links extracellular signals to cytoskeletal remodeling: it is tyrosine-phosphorylated by src-family kinases and serine/threonine-phosphorylated downstream of MEK–ERK signaling (via the helical-proline-rich region), localizes to cell-substratum contact sites/podosomes and Rab7-positive late endosomes, promotes cell migration, invasion, anoikis resistance, and endocytosis, and its stability is controlled by multiple E3 ubiquitin ligases (RNF128, UCHL1, CBLC) that target it for K48-linked proteasomal degradation; cortactin also activates PI3K/Akt and Wnt/β-catenin pathways and its transcription is induced by inflammatory stimuli through NF-κB elements in its promoter."},"narrative":{"mechanistic_narrative":"CTTN encodes cortactin (originally identified as the EMS1 gene product), an actin-binding scaffold that couples extracellular signaling to cytoskeletal remodeling and thereby drives cell migration, invasion, and anoikis resistance [PMID:8474448, PMID:9681820, PMID:17178864]. The protein is organized into an F-actin-binding tandem-repeat domain, a proline-rich SH3-binding region, and a C-terminal SH3 domain, and is expressed as p80/p85 isoforms [PMID:9823470]. It concentrates at cell-substratum contact sites and podosome-like structures and, together with N-WASP, supports cortactin-dependent actin assembly and clathrin-mediated endocytosis, with cortactin knockdown impairing transferrin uptake [PMID:8474448, PMID:18799755, PMID:21418910]. Cortactin activity is set by phosphorylation: it is tyrosine-phosphorylated in proportion to src-family kinase activity, and undergoes a serine/threonine phosphorylation-dependent mobility shift downstream of MEK-ERK signaling that requires its helical-proline-rich region [PMID:10537323, PMID:8945620]. Functionally, cortactin promotes tumor migration, invasion, and metastasis in part through PI3K/Akt and Wnt/β-catenin (via DKK-1 downregulation) signaling, and supports anoikis resistance through FAK and cytoskeletal integrity [PMID:17178864, PMID:36831511, PMID:41168318]. Its transcription is induced by inflammatory and mechanical stimuli through NF-κB elements in the promoter and through a calreticulin-STAT3 axis [PMID:39162263, PMID:19684620], while its protein stability is controlled by E3 ubiquitin ligases RNF128, UCHL1, and CBLC that target it for K48-linked proteasomal degradation [PMID:30832692, PMID:32120844, PMID:36043996]. A coding variant (Ser484Asn) that reduces Tyr486 phosphorylation and disrupts cortactin binding to nmMLCK impairs endothelial barrier recovery and fails to rescue lung vascular permeability in Cttn+/- mice, establishing cortactin's role in endothelial barrier function [PMID:35181549]. Alternative splicing of CTTN, controlled by PTBP2 and RBMS1, generates isoforms that modulate invadopodia formation under matrix stiffness and PI3K/AKT-driven cardiac hypertrophy [PMID:38273817, PMID:41214391].","teleology":[{"year":1993,"claim":"Establishing that the breast-cancer amplicon gene EMS1 encodes a src-substrate homolog localizing to cell-substratum contacts placed cortactin at the interface of oncogenic signaling and adhesion structures.","evidence":"Sequence comparison to a chicken v-src substrate plus immunocytochemistry in epithelial and carcinoma cells","pmids":["8474448"],"confidence":"Medium","gaps":["Did not define the protein's domain architecture or biochemical activity","Localization correlative, no functional manipulation"]},{"year":1996,"claim":"Linking cortactin tyrosine phosphorylation to src-family kinase activity in breast cancer connected its modification state to upstream oncogenic kinases.","evidence":"Western blot and tyrosine phosphorylation analysis across breast cancer cell lines with src kinase activity assays","pmids":["8945620"],"confidence":"Medium","gaps":["Correlative, no direct kinase-substrate demonstration","Phosphosites not mapped","Functional consequence of phosphorylation untested"]},{"year":1998,"claim":"Domain mapping and gain-of-function assays defined cortactin as an actin-binding scaffold whose overexpression directly increases motility and invasion independent of proliferation.","evidence":"Sequence/domain analysis with dual-isoform gene transfer, and stable overexpression in NIH3T3 with Boyden chamber assays","pmids":["9823470","9681820"],"confidence":"Medium","gaps":["Mechanism linking domains to motility not resolved","No loss-of-function in this system"]},{"year":1999,"claim":"Identifying MEK as a necessary and sufficient intermediate for cortactin serine/threonine phosphorylation placed it downstream of a defined signaling cascade and localized the modification to the helical-proline-rich region.","evidence":"PD98059 inhibition, constitutively active MEK, in vitro kinase assay, deletion mutagenesis, and phosphopeptide mapping","pmids":["10537323"],"confidence":"High","gaps":["Exact kinase beyond candidate ERKs not pinned down","Functional output of this phosphorylation not assayed here"]},{"year":2006,"claim":"Loss-of-function in esophageal carcinoma established that endogenous cortactin is required for migration, invasion, anoikis resistance, and metastasis, working through PI3K/Akt.","evidence":"siRNA knockdown with migration/anoikis assays, PI3K/Akt readouts, and in vivo xenograft metastasis","pmids":["17178864"],"confidence":"High","gaps":["Direct mechanism of PI3K/Akt activation by cortactin not defined","Did not address transcriptional control"]},{"year":2009,"claim":"Defining a calreticulin-STAT3 transcriptional axis showed cortactin expression is directly driven by p53-independent STAT3 binding to its promoter, integrating it into a signaling-to-transcription circuit.","evidence":"siRNA, ChIP showing p-STAT3 binding to the CTTN promoter, JAK inhibition, and CTTN rescue of motility/anoikis","pmids":["19684620"],"confidence":"High","gaps":["Other transcriptional inputs not assessed in this study"]},{"year":2011,"claim":"Demonstrating that cortactin knockdown reduces transferrin uptake established a non-migratory function in clathrin-mediated endocytosis requiring intact protein.","evidence":"siRNA and domain-deletion mutants with transferrin uptake assay in colon cancer cells","pmids":["21418910"],"confidence":"Medium","gaps":["Specific endocytic step requiring cortactin not resolved","Partner machinery at coated vesicles not defined here"]},{"year":2019,"claim":"Identifying RNF128-mediated ubiquitination and a CTTN-DKK-1-Wnt/β-catenin link revealed both degradative control of cortactin and a downstream signaling output to stemness/EMT.","evidence":"Co-IP, ubiquitination assays, RNA-seq, and β-catenin/TCF inhibitor rescue in melanoma and HER2+ breast cancer","pmids":["30832692","36831511"],"confidence":"Medium","gaps":["RNF128 ubiquitination sites on CTTN not mapped","Mechanism of DKK-1 downregulation by cortactin unclear"]},{"year":2019,"claim":"Showing HBx physically binds cortactin to upregulate CREB1 targets connected cortactin to a viral oncoprotein-driven proliferation program.","evidence":"Proteomics, Co-IP, confocal microscopy, and proliferation/migration assays in HCC cells","pmids":["31138777"],"confidence":"Medium","gaps":["Direct vs scaffold-mediated interaction not distinguished","Mechanism of CREB1 activation downstream of the complex unclear"]},{"year":2020,"claim":"UCHL1 was shown to drive K48-linked cortactin degradation, with cortactin rescue restoring invasion, reinforcing the ubiquitin-proteasome control of cortactin levels.","evidence":"Co-IP, K48-linkage-specific ubiquitination assay, and CTTN rescue of migration/invasion in NPC cells","pmids":["32120844"],"confidence":"Medium","gaps":["Single lab, sites of ubiquitination not mapped","Relationship to other ligases (RNF128, CBLC) not addressed"]},{"year":2022,"claim":"A coding SNP (Ser484Asn) that disrupts Tyr486 phosphorylation and nmMLCK binding causally linked cortactin to endothelial barrier function in vivo.","evidence":"Mutant transgene expression, phosphorylation and Co-IP assays, barrier biophysics, and WT-vs-mutant rescue in Cttn+/- ARDS mice","pmids":["35181549"],"confidence":"High","gaps":["How Ser484 modification controls Tyr486 phosphorylation mechanistically not fully resolved","Generalizability beyond lung endothelium untested"]},{"year":2022,"claim":"CBLC was identified as a third E3 ligase degrading cortactin in the cytoplasm without affecting mRNA, consolidating proteasomal turnover as a major regulatory node.","evidence":"Co-IP, co-localization, proteasome pathway assay, and CTTN overexpression rescue in breast cancer cells","pmids":["36043996"],"confidence":"Medium","gaps":["Functional redundancy/hierarchy among RNF128, UCHL1, CBLC unknown","Ubiquitination sites unmapped"]},{"year":2024,"claim":"Defining NF-κB-dependent promoter activation by inflammatory and mechanical stimuli, modulated by a promoter SNP and DNA methylation, established cortactin as a stress/inflammation-inducible gene.","evidence":"Luciferase reporter with site-directed mutagenesis of NF-κB sites/SNP, cyclic stretch, pharmacological modulators, and lung IHC","pmids":["39162263"],"confidence":"Medium","gaps":["Relative contribution of HIF/NRF2 inputs not quantified","Link between transcriptional induction and barrier phenotypes not directly tested"]},{"year":2024,"claim":"Identifying PTBP2-controlled splicing of WT-CTTN under matrix stiffness introduced mechanosensitive isoform selection as a regulator of invadopodia formation.","evidence":"siRNA, overexpression, splicing analysis, and invadopodia/invasion assays across stiffness conditions in NPC cells","pmids":["38273817"],"confidence":"Medium","gaps":["Functional differences among SV1/SV2 isoforms not fully defined","Single lab"]},{"year":2025,"claim":"RBMS1-driven generation of a CTTN-Δe11 isoform was shown to activate PI3K/AKT and cause sarcomere damage, extending splicing control of cortactin into cardiac hypertrophy.","evidence":"Splicing analysis, PI3K/AKT assays, and cardiac hypertrophy mouse model with pharmacological RBMS1 inhibition","pmids":["41214391"],"confidence":"Medium","gaps":["How Δe11 isoform mechanistically engages PI3K/AKT unclear","Single lab"]},{"year":2025,"claim":"Linking cortactin to FAK-dependent cytoskeletal integrity in HNSCC and to Rab7+ late endosomal homeostasis whose loss triggers mTOR-p53 senescence broadened its role from migration into endosomal tethering and cell-fate control.","evidence":"siRNA with FAK Western blot and PDO assays; and Rab7/mTOR localization, p53 phosphorylation, senescence markers and CDX models (preprint)","pmids":["41168318","bio_10.1101_2025.03.26.645381"],"confidence":"Medium","gaps":["Senescence work is a preprint, not peer-reviewed","Mechanism of cortactin-mediated late endosomal tethering not molecularly defined"]},{"year":null,"claim":"How cortactin integrates its diverse phosphorylation states, ubiquitin-driven turnover, isoform repertoire, and partner network into context-specific outputs (migration vs endocytosis vs barrier function vs senescence) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model integrating actin binding, phosphorylation, and partner recruitment","Hierarchy/redundancy among the three E3 ligases not established","Functional distinction among splice isoforms incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,12,19]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,10]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,11,19]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[18]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,13]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[12,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,7,17]}],"complexes":[],"partners":["WASL","MYLK","RNF128","UCHL1","CBLC","YWHAG","HBX","LAD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14247","full_name":"Src substrate cortactin","aliases":["Amplaxin","Oncogene EMS1"],"length_aa":550,"mass_kda":61.6,"function":"Contributes to the organization of the actin cytoskeleton and cell shape (PubMed:21296879). Plays a role in the formation of lamellipodia and in cell migration. Plays a role in the regulation of neuron morphology, axon growth and formation of neuronal growth cones (By similarity). Through its interaction with CTTNBP2, involved in the regulation of neuronal spine density (By similarity). Plays a role in focal adhesion assembly and turnover (By similarity). In complex with ABL1 and MYLK regulates cortical actin-based cytoskeletal rearrangement critical to sphingosine 1-phosphate (S1P)-mediated endothelial cell (EC) barrier enhancement (PubMed:20861316). Plays a role in intracellular protein transport and endocytosis, and in modulating the levels of potassium channels present at the cell membrane (PubMed:17959782). Plays a role in receptor-mediated endocytosis via clathrin-coated pits (By similarity). Required for stabilization of KCNH1 channels at the cell membrane (PubMed:23144454). Plays a role in the invasiveness of cancer cells, and the formation of metastases (PubMed:16636290)","subcellular_location":"Cytoplasm, cytoskeleton; Cell projection, lamellipodium; Cell projection, ruffle; Cell projection, dendrite; Cell projection; Cell membrane; Cell projection, podosome; Cell junction; Cell junction, focal adhesion; Membrane, clathrin-coated pit; Cell projection, dendritic spine; Cytoplasm, cell cortex; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q14247/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CTTN","classification":"Not Classified","n_dependent_lines":56,"n_total_lines":1208,"dependency_fraction":0.046357615894039736},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000085733","cell_line_id":"CID000521","localizations":[{"compartment":"big_aggregates","grade":3},{"compartment":"cell_contact","grade":3},{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"DBN1","stoichiometry":4.0},{"gene":"ACTR2","stoichiometry":4.0},{"gene":"LIN7A","stoichiometry":4.0},{"gene":"ARPC3","stoichiometry":4.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"ACTN4","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"STRIP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000521","total_profiled":1310},"omim":[{"mim_id":"621450","title":"ACTIN-RELATED PROTEIN 2/3 COMPLEX, SUBUNIT 5-LIKE; ARPC5L","url":"https://www.omim.org/entry/621450"},{"mim_id":"618871","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 16; ARHGEF16","url":"https://www.omim.org/entry/618871"},{"mim_id":"617594","title":"JUNCTIONAL CADHERIN COMPLEX REGULATOR; JHY","url":"https://www.omim.org/entry/617594"},{"mim_id":"615100","title":"CTTNBP2 N TERMINUS-LIKE PROTEIN; CTTNBP2NL","url":"https://www.omim.org/entry/615100"},{"mim_id":"614410","title":"ACTIN FILAMENT-ASSOCIATED PROTEIN 1-LIKE 1; AFAP1L1","url":"https://www.omim.org/entry/614410"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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In normal epithelial cells, the protein localizes mainly to the cytoplasm with minor presence in leading lamellae; in carcinoma cells overexpressing EMS1, it accumulates at podosome-like adherens junctions associated with cell-substratum contact sites, but not intercellular adherens junctions.\",\n      \"method\": \"Amino acid sequence comparison, immunocytochemistry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — sequence homology plus direct immunocytochemical localization in multiple cell types, single lab\",\n      \"pmids\": [\"8474448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The EMS1/cortactin protein contains: (i) a filamentous actin-binding tandem repeat domain, (ii) a proline-rich SH3-binding region, and (iii) a SH3 domain. Both human p80 and p85 isoforms are encoded by the EMS1 cDNA. Expression is restricted to non-lymphoid tumor cell lines.\",\n      \"method\": \"Gene transfer experiments, western blot, sequence analysis\",\n      \"journal\": \"Cell adhesion and communication\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene transfer confirmed dual isoforms; domain characterization by sequence and functional assay, single lab\",\n      \"pmids\": [\"9823470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Stable overexpression of EMS1/cortactin in NIH3T3 fibroblasts increases cell motility and invasiveness in modified Boyden chamber assays without altering proliferation or anchorage independence, indicating cortactin promotes cell migration and invasion.\",\n      \"method\": \"Stable transfection, modified Boyden chamber motility/invasion assay, proliferation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype with loss/gain of function, single lab\",\n      \"pmids\": [\"9681820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EGF treatment or cell detachment induces an 80–85 kDa mobility shift of EMS1 (cortactin) correlated with increased serine/threonine phosphorylation. This shift is blocked by the MEK inhibitor PD98059 and is induced by constitutively active MEK, establishing MEK as a necessary and sufficient intermediate in EMS1 phosphorylation. The helical-proline-rich region is required for this phosphorylation. ERKs are candidate kinases for this region in vitro, but other MEK-regulated enzymes also participate.\",\n      \"method\": \"Pharmacological inhibition (PD98059), constitutively active MEK expression, in vitro kinase assay, deletion mutagenesis, tryptic phosphopeptide mapping\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay combined with mutagenesis and pharmacological epistasis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"10537323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"EMS1 protein is tyrosine phosphorylated in breast cancer cell lines; degree of tyrosine phosphorylation correlates with src-family kinase activity (c-fyn and c-yes expression). Gene amplification is the predominant mechanism of EMS1 overexpression in breast cancer cell lines.\",\n      \"method\": \"Western blot, tyrosine phosphorylation analysis, src kinase activity assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — correlative phosphorylation analysis across multiple cell lines, single lab\",\n      \"pmids\": [\"8945620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"siRNA-mediated silencing of CTTN in esophageal squamous cell carcinoma cells reduces cell migration, invasiveness, and anoikis resistance. The protective role of CTTN in anoikis resistance correlates with activation of the PI3K/Akt pathway. In vivo, CTTN knockdown decreased tumor growth and lung metastasis.\",\n      \"method\": \"siRNA knockdown, cell migration assay, anoikis assay, PI3K/Akt signaling analysis, in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with multiple orthogonal phenotypic readouts (migration, anoikis, in vivo metastasis) plus pathway placement (PI3K/Akt), replicated across in vitro and in vivo models\",\n      \"pmids\": [\"17178864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Calreticulin (CRT) regulates CTTN expression via STAT3: CRT knockdown reduces p-STAT3, and chromatin immunoprecipitation shows direct binding of p-STAT3 to STAT3-binding sequences in the CTTN promoter. CRT-enhanced anoikis resistance and motility operate through a CRT–STAT3–CTTN–PI3K–Akt pathway; CTTN restoration in CRT-depleted cells rescues motility and anoikis resistance.\",\n      \"method\": \"siRNA knockdown, ChIP assay, JAK inhibitor (AG490), Western blot, cell migration/invasion/anoikis assays, CTTN rescue experiment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP directly shows p-STAT3 binding to CTTN promoter; pathway placement by pharmacological inhibitor + rescue, multiple orthogonal methods\",\n      \"pmids\": [\"19684620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RNF128 (an E3 ubiquitin ligase) ubiquitinates and promotes degradation of CTTN (cortactin), activating Wnt/β-catenin signaling and CD44/c-Myc transcription. RNF128 downregulation leads to CTTN accumulation, inducing EMT and stemness in melanoma.\",\n      \"method\": \"Co-IP, ubiquitination assay, siRNA interference, functional EMT/stemness assays\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with ubiquitination assay demonstrates interaction and degradation; single lab\",\n      \"pmids\": [\"30832692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UCHL1 interacts with CTTN and promotes K48-linked ubiquitination of CTTN, leading to its proteasomal degradation. CTTN rescue in UCHL1-overexpressing NPC cells restores migration and invasion, placing CTTN as a functional downstream target of UCHL1.\",\n      \"method\": \"Co-IP, ubiquitination assay (K48-linkage specific), in vitro/in vivo migration and invasion assays, CTTN rescue experiment\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus K48-specific ubiquitination assay with rescue, single lab\",\n      \"pmids\": [\"32120844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The CTTN coding SNP Ser484Asn (rs56162978) reduces Tyr486 cortactin phosphorylation, inhibits binding of cortactin to nmMLCK, delays endothelial cell barrier recovery after thrombin-induced permeability, and attenuates lamellipodia dynamics. In Cttn+/- heterozygous mice, increased lung vascular permeability was rescued by WT CTTN transgene but not by S484N transgene.\",\n      \"method\": \"Transgene expression in human lung ECs, phosphorylation assay, Co-IP (cortactin–nmMLCK binding), biophysical barrier assay, liposome-mediated transgene delivery in vivo in ARDS mouse model\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, binding assay, in vivo rescue with WT vs mutant transgene), in vitro and in vivo validation\",\n      \"pmids\": [\"35181549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CBLC (an E3 ubiquitin ligase) interacts with CTTN in the cytoplasm and promotes CTTN degradation through the ubiquitin-proteasome pathway without affecting CTTN mRNA levels. CBLC-mediated inhibition of breast cancer cell proliferation, migration, and invasion is partially reversed by CTTN overexpression.\",\n      \"method\": \"Co-IP, immunofluorescence co-localization, ubiquitin-proteasome pathway assay, rescue experiment with CTTN overexpression\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus proteasome assay and rescue experiment, single lab\",\n      \"pmids\": [\"36043996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cortactin (CTTN) and N-WASP, two regulators of actin network assembly, are concentrated at tubulobulbar complexes in the rat testis seminiferous epithelium alongside clathrin, supporting that these podosome-like structures involve cortactin-dependent actin assembly and clathrin-mediated endocytosis.\",\n      \"method\": \"Immunofluorescence microscopy, immunoelectron microscopy on rat testis\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization only by immunofluorescence/immuno-EM, no functional manipulation of cortactin performed\",\n      \"pmids\": [\"18799755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"siRNA silencing of cortactin (CTTN) in colon cancer cells reduces transferrin uptake (endocytosis). Intact cortactin protein and sufficient expression level are required for optimal clathrin-coated vesicle-mediated endocytosis in cancer cells.\",\n      \"method\": \"siRNA knockdown, domain-deletion mutant transfection, transferrin uptake assay, immunohistochemistry\",\n      \"journal\": \"Zhonghua yi xue za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function plus domain-deletion mutants with defined endocytosis readout, single lab\",\n      \"pmids\": [\"21418910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CTTN overexpression downregulates DKK-1, a Wnt antagonist, thereby activating Wnt/β-catenin signaling. A β-catenin/TCF inhibitor reverses CTTN-induced cancer stem cell-like properties in HER2+ breast cancer cells in vitro.\",\n      \"method\": \"RNA-seq, Western blot, tumorsphere formation, ALDEFLUOR assay, in vivo xenograft, β-catenin/TCF inhibitor treatment\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNA-seq plus pharmacological rescue with β-catenin inhibitor, single lab\",\n      \"pmids\": [\"36831511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Matrix stiffness promotes cell migration, invasion, and invadopodia formation in nasopharyngeal carcinoma through upregulation of wild-type CTTN (WT-CTTN). The splicing factor PTBP2 (activated by high stiffness) controls the production of WT-CTTN over splice variants (SV1-CTTN, SV2-CTTN), establishing a PTBP2–WT-CTTN axis in mechanosensing.\",\n      \"method\": \"siRNA knockdown, overexpression studies, alternative splicing analysis, migration/invasion/invadopodia assays in varying stiffness conditions\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional manipulation with defined phenotype and mechanistic splicing axis identified, single lab\",\n      \"pmids\": [\"38273817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBx (hepatitis B virus X protein) physically interacts with CTTN in HCC cells (validated by Co-IP and confocal microscopy). The HBx–CTTN interaction upregulates CREB1 and its downstream targets (cyclin D1, MMP-9), promoting cell proliferation and migration.\",\n      \"method\": \"Proteomics, Co-IP, confocal microscopy, cell proliferation/migration assays, cell cycle analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus confocal confirm interaction; downstream signaling assessed by Western blot, single lab\",\n      \"pmids\": [\"31138777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YWHAG (14-3-3γ) interacts with CTTN and mediates CRC cell proliferation, migration, and invasion by activating Wnt/β-catenin signaling downstream of CTTN.\",\n      \"method\": \"RNA-seq, Co-IP (YWHAG–CTTN interaction), functional cell assays, Wnt signaling readouts\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP pulldown with signaling pathway inference, single lab\",\n      \"pmids\": [\"38538804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBMS1 promotes alternative splicing of CTTN to generate a CTTN-Δe11 isoform in cardiomyocytes. This splicing switch activates the PI3K/AKT signaling pathway, causing cytoskeleton and sarcomere damage leading to cardiac hypertrophy.\",\n      \"method\": \"RNA splicing analysis, PI3K/AKT pathway assay, cardiac hypertrophy mouse model, pharmacological inhibition of RBMS1 (nortriptyline)\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic splice-switching with defined isoform and pathway activation, in vivo model with pharmacological rescue, single lab\",\n      \"pmids\": [\"41214391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cortactin localizes to Rab7-positive late endosomes and is required for late endosomal tethering and homeostasis. Cortactin depletion in circulating tumor cells causes accumulation of aberrantly enlarged Rab7+ late endosomal aggregates, accumulation and activation of mTOR within these structures, p53 phosphorylation (Ser15, Ser33), G0/G1 cell cycle arrest, and cellular senescence (characterized by SASP, β-galactosidase activity, Ki-67/Lamin B1 depletion, elevated mitochondrial ROS). A positive p53–mtROS feedback loop maintains stable senescence.\",\n      \"method\": \"Live imaging and fractionation (Rab7/mTOR localization), CTTN depletion, p53 phosphorylation assay, cell cycle analysis, senescence markers (β-gal, SASP, Ki-67, Lamin B1, mtROS), CDX mouse models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods establishing localization and downstream senescence pathway; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.03.26.645381\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of CTTN in HNSCC cells reduces FAK expression levels and impairs cytoskeletal formation, thereby reducing anoikis resistance. CTTN silencing also suppresses growth in patient-derived organoids (PDOs).\",\n      \"method\": \"siRNA knockdown, PI staining (apoptosis), immunofluorescence, Western blot (FAK), PDO culture assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with defined FAK-cytoskeletal mechanism and PDO validation, single lab\",\n      \"pmids\": [\"41168318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LAD1 (ladinin-1) binds LINC01305 and together they co-regulate phosphorylation of CTTN and N-WASP, mediating cytoskeletal reorganization and EMT via activation of the PI3K/AKT signaling pathway in ESCC cells.\",\n      \"method\": \"Co-IP (LAD1–LINC01305), phosphorylation assays (CTTN, N-WASP), PI3K/AKT pathway analysis, EMT marker analysis\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic detail is limited (abstract level); single co-IP for the interaction, single lab\",\n      \"pmids\": [\"39835575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LPS, TNF-α, and high-magnitude cyclic stretch (18% CS) significantly increase CTTN promoter activity; these responses require NF-κB response elements in the promoter. The promoter SNP rs34612166 (−212T/C) markedly enhances LPS- and 18%CS-induced CTTN promoter activation. HIF pathway activators and NRF2 also modulate CTTN promoter activity. Demethylation (5'-Aza) increases CTTN promoter activity ~2.9-fold, indicating epigenetic regulation.\",\n      \"method\": \"Luciferase reporter assay with full-length CTTN promoter, site-directed mutagenesis (NF-κB sites and SNP), pharmacological modulators (HIF, NRF2 inhibitors/activators, 5'-Aza), cyclic stretch, immunohistochemistry in LPS-exposed mouse lungs\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — luciferase reporter with site-directed mutagenesis identifying functional NF-κB elements; multiple stimuli tested, single lab\",\n      \"pmids\": [\"39162263\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTTN (cortactin/EMS1) encodes an actin-binding scaffold protein that links extracellular signals to cytoskeletal remodeling: it is tyrosine-phosphorylated by src-family kinases and serine/threonine-phosphorylated downstream of MEK–ERK signaling (via the helical-proline-rich region), localizes to cell-substratum contact sites/podosomes and Rab7-positive late endosomes, promotes cell migration, invasion, anoikis resistance, and endocytosis, and its stability is controlled by multiple E3 ubiquitin ligases (RNF128, UCHL1, CBLC) that target it for K48-linked proteasomal degradation; cortactin also activates PI3K/Akt and Wnt/β-catenin pathways and its transcription is induced by inflammatory stimuli through NF-κB elements in its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CTTN encodes cortactin (originally identified as the EMS1 gene product), an actin-binding scaffold that couples extracellular signaling to cytoskeletal remodeling and thereby drives cell migration, invasion, and anoikis resistance [#0, #2, #5]. The protein is organized into an F-actin-binding tandem-repeat domain, a proline-rich SH3-binding region, and a C-terminal SH3 domain, and is expressed as p80/p85 isoforms [#1]. It concentrates at cell-substratum contact sites and podosome-like structures and, together with N-WASP, supports cortactin-dependent actin assembly and clathrin-mediated endocytosis, with cortactin knockdown impairing transferrin uptake [#0, #11, #12]. Cortactin activity is set by phosphorylation: it is tyrosine-phosphorylated in proportion to src-family kinase activity, and undergoes a serine/threonine phosphorylation-dependent mobility shift downstream of MEK-ERK signaling that requires its helical-proline-rich region [#3, #4]. Functionally, cortactin promotes tumor migration, invasion, and metastasis in part through PI3K/Akt and Wnt/\\u03b2-catenin (via DKK-1 downregulation) signaling, and supports anoikis resistance through FAK and cytoskeletal integrity [#5, #13, #19]. Its transcription is induced by inflammatory and mechanical stimuli through NF-\\u03baB elements in the promoter and through a calreticulin-STAT3 axis [#21, #6], while its protein stability is controlled by E3 ubiquitin ligases RNF128, UCHL1, and CBLC that target it for K48-linked proteasomal degradation [#7, #8, #10]. A coding variant (Ser484Asn) that reduces Tyr486 phosphorylation and disrupts cortactin binding to nmMLCK impairs endothelial barrier recovery and fails to rescue lung vascular permeability in Cttn+/- mice, establishing cortactin's role in endothelial barrier function [#9]. Alternative splicing of CTTN, controlled by PTBP2 and RBMS1, generates isoforms that modulate invadopodia formation under matrix stiffness and PI3K/AKT-driven cardiac hypertrophy [#14, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that the breast-cancer amplicon gene EMS1 encodes a src-substrate homolog localizing to cell-substratum contacts placed cortactin at the interface of oncogenic signaling and adhesion structures.\",\n      \"evidence\": \"Sequence comparison to a chicken v-src substrate plus immunocytochemistry in epithelial and carcinoma cells\",\n      \"pmids\": [\"8474448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the protein's domain architecture or biochemical activity\", \"Localization correlative, no functional manipulation\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Linking cortactin tyrosine phosphorylation to src-family kinase activity in breast cancer connected its modification state to upstream oncogenic kinases.\",\n      \"evidence\": \"Western blot and tyrosine phosphorylation analysis across breast cancer cell lines with src kinase activity assays\",\n      \"pmids\": [\"8945620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative, no direct kinase-substrate demonstration\", \"Phosphosites not mapped\", \"Functional consequence of phosphorylation untested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Domain mapping and gain-of-function assays defined cortactin as an actin-binding scaffold whose overexpression directly increases motility and invasion independent of proliferation.\",\n      \"evidence\": \"Sequence/domain analysis with dual-isoform gene transfer, and stable overexpression in NIH3T3 with Boyden chamber assays\",\n      \"pmids\": [\"9823470\", \"9681820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking domains to motility not resolved\", \"No loss-of-function in this system\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying MEK as a necessary and sufficient intermediate for cortactin serine/threonine phosphorylation placed it downstream of a defined signaling cascade and localized the modification to the helical-proline-rich region.\",\n      \"evidence\": \"PD98059 inhibition, constitutively active MEK, in vitro kinase assay, deletion mutagenesis, and phosphopeptide mapping\",\n      \"pmids\": [\"10537323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact kinase beyond candidate ERKs not pinned down\", \"Functional output of this phosphorylation not assayed here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Loss-of-function in esophageal carcinoma established that endogenous cortactin is required for migration, invasion, anoikis resistance, and metastasis, working through PI3K/Akt.\",\n      \"evidence\": \"siRNA knockdown with migration/anoikis assays, PI3K/Akt readouts, and in vivo xenograft metastasis\",\n      \"pmids\": [\"17178864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism of PI3K/Akt activation by cortactin not defined\", \"Did not address transcriptional control\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defining a calreticulin-STAT3 transcriptional axis showed cortactin expression is directly driven by p53-independent STAT3 binding to its promoter, integrating it into a signaling-to-transcription circuit.\",\n      \"evidence\": \"siRNA, ChIP showing p-STAT3 binding to the CTTN promoter, JAK inhibition, and CTTN rescue of motility/anoikis\",\n      \"pmids\": [\"19684620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other transcriptional inputs not assessed in this study\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that cortactin knockdown reduces transferrin uptake established a non-migratory function in clathrin-mediated endocytosis requiring intact protein.\",\n      \"evidence\": \"siRNA and domain-deletion mutants with transferrin uptake assay in colon cancer cells\",\n      \"pmids\": [\"21418910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific endocytic step requiring cortactin not resolved\", \"Partner machinery at coated vesicles not defined here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying RNF128-mediated ubiquitination and a CTTN-DKK-1-Wnt/\\u03b2-catenin link revealed both degradative control of cortactin and a downstream signaling output to stemness/EMT.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, RNA-seq, and \\u03b2-catenin/TCF inhibitor rescue in melanoma and HER2+ breast cancer\",\n      \"pmids\": [\"30832692\", \"36831511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNF128 ubiquitination sites on CTTN not mapped\", \"Mechanism of DKK-1 downregulation by cortactin unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing HBx physically binds cortactin to upregulate CREB1 targets connected cortactin to a viral oncoprotein-driven proliferation program.\",\n      \"evidence\": \"Proteomics, Co-IP, confocal microscopy, and proliferation/migration assays in HCC cells\",\n      \"pmids\": [\"31138777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffold-mediated interaction not distinguished\", \"Mechanism of CREB1 activation downstream of the complex unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"UCHL1 was shown to drive K48-linked cortactin degradation, with cortactin rescue restoring invasion, reinforcing the ubiquitin-proteasome control of cortactin levels.\",\n      \"evidence\": \"Co-IP, K48-linkage-specific ubiquitination assay, and CTTN rescue of migration/invasion in NPC cells\",\n      \"pmids\": [\"32120844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, sites of ubiquitination not mapped\", \"Relationship to other ligases (RNF128, CBLC) not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A coding SNP (Ser484Asn) that disrupts Tyr486 phosphorylation and nmMLCK binding causally linked cortactin to endothelial barrier function in vivo.\",\n      \"evidence\": \"Mutant transgene expression, phosphorylation and Co-IP assays, barrier biophysics, and WT-vs-mutant rescue in Cttn+/- ARDS mice\",\n      \"pmids\": [\"35181549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ser484 modification controls Tyr486 phosphorylation mechanistically not fully resolved\", \"Generalizability beyond lung endothelium untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CBLC was identified as a third E3 ligase degrading cortactin in the cytoplasm without affecting mRNA, consolidating proteasomal turnover as a major regulatory node.\",\n      \"evidence\": \"Co-IP, co-localization, proteasome pathway assay, and CTTN overexpression rescue in breast cancer cells\",\n      \"pmids\": [\"36043996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional redundancy/hierarchy among RNF128, UCHL1, CBLC unknown\", \"Ubiquitination sites unmapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining NF-\\u03baB-dependent promoter activation by inflammatory and mechanical stimuli, modulated by a promoter SNP and DNA methylation, established cortactin as a stress/inflammation-inducible gene.\",\n      \"evidence\": \"Luciferase reporter with site-directed mutagenesis of NF-\\u03baB sites/SNP, cyclic stretch, pharmacological modulators, and lung IHC\",\n      \"pmids\": [\"39162263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of HIF/NRF2 inputs not quantified\", \"Link between transcriptional induction and barrier phenotypes not directly tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying PTBP2-controlled splicing of WT-CTTN under matrix stiffness introduced mechanosensitive isoform selection as a regulator of invadopodia formation.\",\n      \"evidence\": \"siRNA, overexpression, splicing analysis, and invadopodia/invasion assays across stiffness conditions in NPC cells\",\n      \"pmids\": [\"38273817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional differences among SV1/SV2 isoforms not fully defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"RBMS1-driven generation of a CTTN-\\u0394e11 isoform was shown to activate PI3K/AKT and cause sarcomere damage, extending splicing control of cortactin into cardiac hypertrophy.\",\n      \"evidence\": \"Splicing analysis, PI3K/AKT assays, and cardiac hypertrophy mouse model with pharmacological RBMS1 inhibition\",\n      \"pmids\": [\"41214391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How \\u0394e11 isoform mechanistically engages PI3K/AKT unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking cortactin to FAK-dependent cytoskeletal integrity in HNSCC and to Rab7+ late endosomal homeostasis whose loss triggers mTOR-p53 senescence broadened its role from migration into endosomal tethering and cell-fate control.\",\n      \"evidence\": \"siRNA with FAK Western blot and PDO assays; and Rab7/mTOR localization, p53 phosphorylation, senescence markers and CDX models (preprint)\",\n      \"pmids\": [\"41168318\", \"bio_10.1101_2025.03.26.645381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Senescence work is a preprint, not peer-reviewed\", \"Mechanism of cortactin-mediated late endosomal tethering not molecularly defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How cortactin integrates its diverse phosphorylation states, ubiquitin-driven turnover, isoform repertoire, and partner network into context-specific outputs (migration vs endocytosis vs barrier function vs senescence) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model integrating actin binding, phosphorylation, and partner recruitment\", \"Hierarchy/redundancy among the three E3 ligases not established\", \"Functional distinction among splice isoforms incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 12, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 11, 19]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 13]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [12, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 7, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WASL\", \"MYLK\", \"RNF128\", \"UCHL1\", \"CBLC\", \"YWHAG\", \"HBx\", \"LAD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}