{"gene":"ITGB5","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2012,"finding":"αvβ5 integrin (expressed by the RPE, requiring ITGB5) is required for the diurnal phagocytic rhythm of the retinal pigment epithelium; loss of ITGB5 abolishes the diurnal peak of phosphatidylserine (PS) exposure at rod outer segment tips, demonstrating that RPE αvβ5 activity—not intrinsic photoreceptor signaling—drives the circadian PS demarcation of rod tips that precedes shedding and phagocytosis.","method":"Itgb5-/- mouse retina live imaging with annexin V and pSIVA biosensor; comparison with Mfge8-/- and wild-type mice; RPE phagocytosis culture assays with PS blockade","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with specific cellular phenotype, multiple orthogonal fluorescent PS-detection methods, replicated across two knockout models (Itgb5-/- and Mfge8-/-) in the same study","pmids":["22566632"],"is_preprint":false},{"year":2019,"finding":"Porcine ITGB5 (integrin αvβ5) acts as a direct receptor for ETEC F4ac fimbriae on intestinal epithelial cells: GST pull-down showed FaeG fimbrial adhesin binds directly to ITGB5, CRISPR/Cas9 knockout of ITGB5 significantly reduced ETEC F4ac adhesion, and ITGB5 overexpression significantly enhanced adhesion.","method":"CRISPR/Cas9 biallelic knockout in IPEC-J2 cells; ITGB5 overexpression; GST pull-down with purified FaeG and ITGB5; bacterial adhesion assay","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro binding (GST pull-down), gain- and loss-of-function experiments with specific adhesion readout, multiple orthogonal methods in one study","pmids":["31921118"],"is_preprint":false},{"year":2023,"finding":"ITGB5 interacts with EPS15 to prevent EGFR lysosomal degradation in HCC cells, thereby activating AKT-mTOR and MAPK signaling and reducing sorafenib sensitivity. Additionally, ITGB5 upregulates CSNK1A1 via the EGFR-AKT-mTOR pathway; CSNK1A1 in turn phosphorylates ITGB5, enhancing the ITGB5–EPS15 interaction and further activating EGFR, forming a positive feedback loop.","method":"Unbiased mass spectrometry with ITGB5 antibodies (Co-IP/MS) identifying EPS15 and CSNK1A1 as binding partners; co-immunoprecipitation; ITGB5 knockdown/overexpression; EGFR degradation assays; signaling pathway analysis","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP/MS plus functional pathway assays in a single lab; multiple orthogonal methods but not independently replicated","pmids":["37149115"],"is_preprint":false},{"year":2024,"finding":"ITGB5 acts as a scaffold that physically interacts with TGFBR2 and SNX17, facilitating SNX17-mediated endosomal recycling of TGFBR2 and preventing its lysosomal degradation, thereby maintaining TGFBR2 surface levels and sustaining TGFβ-driven EMT and gastric cancer metastasis. TGFβ signaling in turn transcriptionally upregulates ITGB5, establishing a positive feedback loop.","method":"Co-immunoprecipitation of ITGB5 with TGFBR2 and SNX17; ITGB5 knockdown in vitro and in vivo; endosomal recycling assay; TGFBR2 surface distribution analysis; ITGB5 knockdown EMT/metastasis assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying scaffold interactions, in vitro and in vivo loss-of-function with defined mechanistic phenotype, single lab","pmids":["38729557"],"is_preprint":false},{"year":2025,"finding":"NAT10-mediated N4-acetylcytidine (ac4C) modification in the CDS region of ITGB5 mRNA promotes its stability, leading to upregulation of ITGB5 protein and activation of the ITGB5–pFAK–pSrc signaling pathway, which enhances perineural invasion in pancreatic ductal adenocarcinoma.","method":"UPLC/MS-MS profiling of ac4C modification; acRIP-seq and ac4C-seq in NAT10-knockdown PDAC cells; RNA-seq; CRISPR-based NAT10 manipulation; dorsal root ganglion co-culture and sciatic nerve injection in vivo models; ITGB5 mRNA stability assays","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ac4C-seq and acRIP-seq identify modification site, CRISPR validation, in vivo model, multiple orthogonal methods in single lab","pmids":["40119353"],"is_preprint":false},{"year":2024,"finding":"ENAH upregulates ITGB5 expression in oral squamous cell carcinoma cells, and ITGB5 in turn activates Src signaling to promote cell migration and growth. ENAH expression itself is driven by the EGFR/PI3K/AKT/GSK3β/β-catenin cascade.","method":"Gene knockdown and ectopic expression in OSCC cells; proliferation, transwell migration, and invasion assays; integrated proteome and transcriptome analysis; PDX model","journal":"Cellular & molecular biology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown/overexpression with pathway phenotype in single lab; no direct binding assay between ENAH and ITGB5 reported in abstract","pmids":["39511483"],"is_preprint":false},{"year":2024,"finding":"ROS enhances ITGB5 expression in tongue squamous cell carcinoma cells, and elevated ITGB5 promotes invasion and migration through the cell adhesion signaling pathway; knockdown of ITGB5 suppressed these phenotypes.","method":"ITGB5 knockdown and overexpression in TSCC cells; ROS manipulation; invasion and migration assays; Western blot","journal":"Journal of cancer research and clinical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown/overexpression with phenotypic readout, single lab, no direct mechanistic binding or pathway reconstitution described","pmids":["39180583"],"is_preprint":false},{"year":2024,"finding":"ITGB5 and ITGB1 recombinant proteins promote PDAC tumor cell proliferation and migration by activating the FAK/PI3K/AKT signaling pathway, and enhance macrophage-fibroblast interactions in the tumor microenvironment.","method":"In vitro macrophage-fibroblast co-culture system with ITGB5/ITGB1 recombinant protein addition or knockdown; Western blot for FAK/PI3K/AKT pathway; in vivo tumor growth assays","journal":"International journal of biological macromolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — recombinant protein addition and knockdown experiments with signaling readout, single lab, limited mechanistic detail in abstract","pmids":["39719238"],"is_preprint":false},{"year":2022,"finding":"ITGB5 promotes radiation resistance in pancreatic adenocarcinoma by facilitating DNA damage repair and activating the MEK/ERK signaling pathway; knockdown of ITGB5 increased radiation sensitivity.","method":"ITGB5 knockdown in PAAD cells; irradiation assays; DNA damage repair assays; MEK/ERK pathway analysis","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-lab knockdown study with signaling and DNA repair readout, limited mechanistic depth reported in abstract","pmids":["36249018"],"is_preprint":false},{"year":2026,"finding":"USP1 deubiquitinase stabilizes ITGB5 protein through deubiquitination; USP1 knockdown reduces ITGB5 expression, and ITGB5 overexpression rescues the inhibitory effect of USP1 knockdown on pancreatic stellate cell activation. ITGB5 promotes PSC activation via the PI3K/AKT pathway.","method":"Immunoprecipitation–LC/MS identifying ITGB5 as USP1 target; USP1 knockdown with lentivirus; ITGB5 overexpression rescue experiments; in vivo cerulein CP model; Western blot for PI3K/AKT","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS identification of USP1-ITGB5 interaction, deubiquitination/stabilization assay, rescue experiments, and in vivo validation in single lab","pmids":["41857463"],"is_preprint":false},{"year":2026,"finding":"STAU1 RNA-binding protein directly binds the 3' UTR of ITGB5 mRNA to stabilize it, increasing ITGB5 protein levels. Elevated ITGB5 increases FOXP3 phosphorylation at serine 418, which enhances FOXP3 binding to the STAU1 promoter and activates STAU1 transcription, forming a STAU1–ITGB5–FOXP3 positive feedback loop driving colorectal cancer metastasis.","method":"RNA immunoprecipitation confirming STAU1 binding to ITGB5 3' UTR; STAU1 knockdown/overexpression; mRNA stability assays; FOXP3 phosphorylation analysis; ChIP assay for FOXP3 binding to STAU1 promoter; in vitro and in vivo metastasis assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirming direct 3' UTR binding, mRNA stability assay, ChIP for downstream transcriptional loop, in vivo validation; single lab with multiple orthogonal methods","pmids":["41796846"],"is_preprint":false},{"year":2013,"finding":"ITGB5 knockdown in porcine intestinal epithelial cells (IPEC-J2) increased ETEC F4ac bacterial adhesion and attenuated ETEC-induced inflammation (reduced pro-inflammatory gene expression), indicating ITGB5 plays a role in defending against ETEC attachment and modulating mucosal immune signaling.","method":"siRNA knockdown of ITGB5 in IPEC-J2 cells; ETEC bacterial adhesion assay; qPCR for pro-inflammatory and mucosal genes","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-method siRNA knockdown with adhesion and gene expression readouts, single lab, no direct binding assay","pmids":["23922972"],"is_preprint":false}],"current_model":"ITGB5 (integrin β5, forming αvβ5 heterodimer) functions as a phagocytic receptor in retinal pigment epithelium required for diurnal rod outer segment phagocytosis, a direct adhesion receptor for bacterial fimbriae (ETEC F4ac FaeG) on intestinal epithelium, and a multifunctional scaffold in cancer cells that interacts with EPS15 to stabilize EGFR and activate AKT-mTOR/MAPK signaling, with TGFBR2/SNX17 to promote TGFβ receptor recycling and EMT, and is itself post-translationally stabilized by USP1-mediated deubiquitination and post-transcriptionally stabilized by NAT10-mediated ac4C modification of its mRNA and STAU1 binding to its 3' UTR; collectively, these mechanisms position ITGB5 as a context-dependent regulator of cell adhesion, receptor trafficking, and downstream FAK/PI3K/AKT/ERK signaling in both normal tissue homeostasis and cancer progression."},"narrative":{"mechanistic_narrative":"ITGB5 (integrin β5) pairs with αv to form the αvβ5 heterodimer, which functions as an adhesion and phagocytic receptor in normal tissue and as a context-dependent driver of receptor trafficking and pro-survival signaling in cancer [PMID:22566632, PMID:37149115]. In the retinal pigment epithelium, αvβ5 activity is required for the diurnal phagocytic rhythm: loss of ITGB5 abolishes the circadian peak of phosphatidylserine exposure at rod outer segment tips that precedes shedding and phagocytosis [PMID:22566632]. On intestinal epithelium, ITGB5 acts as a direct receptor for ETEC F4ac fimbriae, binding the FaeG adhesin and mediating bacterial adhesion [PMID:31921118]. In cancer, ITGB5 operates as a signaling scaffold: it interacts with EPS15 to block EGFR lysosomal degradation and activate AKT-mTOR and MAPK signaling, with a CSNK1A1-dependent phosphorylation feedback loop reinforcing the ITGB5–EPS15 interaction [PMID:37149115], and it binds TGFBR2 and SNX17 to promote endosomal recycling of TGFBR2, sustaining TGFβ-driven EMT [PMID:38729557]. Downstream, ITGB5 engages FAK/Src and PI3K/AKT/ERK signaling to promote invasion and proliferation [PMID:40119353, PMID:41857463]. ITGB5 abundance is itself controlled at multiple levels: USP1-mediated deubiquitination stabilizes the protein [PMID:41857463], NAT10-mediated ac4C modification stabilizes its mRNA [PMID:40119353], and STAU1 binding to its 3' UTR stabilizes the transcript within a STAU1–ITGB5–FOXP3 feedback loop [PMID:41796846].","teleology":[{"year":2012,"claim":"Established that RPE αvβ5 integrin activity, not intrinsic photoreceptor signaling, drives the circadian phosphatidylserine demarcation of rod outer segment tips required for diurnal phagocytosis.","evidence":"Itgb5-/- mouse retina live imaging with annexin V/pSIVA biosensors, compared to Mfge8-/- and wild-type, plus RPE phagocytosis assays with PS blockade","pmids":["22566632"],"confidence":"High","gaps":["Does not resolve how ITGB5 senses or transduces the circadian timing cue","Downstream cytoplasmic signaling effectors in RPE not defined"]},{"year":2013,"claim":"First implicated ITGB5 in intestinal defense against ETEC F4ac, linking it to bacterial adhesion and modulation of mucosal inflammation.","evidence":"siRNA knockdown of ITGB5 in porcine IPEC-J2 cells with bacterial adhesion assay and qPCR of inflammatory genes","pmids":["23922972"],"confidence":"Low","gaps":["Single-method knockdown with no direct binding assay","Knockdown increased adhesion, complicating the receptor interpretation later refined by direct binding work","Mechanism of inflammation modulation undefined"]},{"year":2019,"claim":"Demonstrated that ITGB5 is a direct physical receptor for the ETEC F4ac fimbrial adhesin FaeG, resolving the adhesion mechanism at the molecular level.","evidence":"GST pull-down of purified FaeG with ITGB5, CRISPR/Cas9 knockout and overexpression in IPEC-J2 cells with bacterial adhesion readouts","pmids":["31921118"],"confidence":"High","gaps":["Binding interface residues not mapped","Whether αvβ5 heterodimer or ITGB5 alone mediates binding unaddressed","Reconciliation with earlier knockdown adhesion result not provided"]},{"year":2022,"claim":"Connected ITGB5 to therapy resistance by showing it facilitates DNA damage repair and MEK/ERK activation to confer radiation resistance in pancreatic cancer.","evidence":"ITGB5 knockdown in PAAD cells with irradiation, DNA damage repair, and MEK/ERK pathway assays","pmids":["36249018"],"confidence":"Low","gaps":["Single-lab knockdown with limited mechanistic depth","No direct link between ITGB5 and DNA repair machinery established","How a surface integrin influences nuclear DNA repair unexplained"]},{"year":2023,"claim":"Defined ITGB5 as a scaffold that protects EGFR from degradation via EPS15, establishing a CSNK1A1-reinforced feedback loop driving AKT-mTOR/MAPK signaling and sorafenib resistance.","evidence":"Co-IP/MS identifying EPS15 and CSNK1A1, reciprocal Co-IP, knockdown/overexpression, EGFR degradation and signaling assays in HCC cells","pmids":["37149115"],"confidence":"Medium","gaps":["Not independently replicated","Direct EPS15-ITGB5 binding interface unmapped","CSNK1A1 phosphorylation site on ITGB5 not defined"]},{"year":2024,"claim":"Showed ITGB5 functions as a scaffold linking TGFBR2 to SNX17-mediated endosomal recycling, sustaining TGFβ-driven EMT and metastasis within a TGFβ–ITGB5 feedback loop.","evidence":"Reciprocal Co-IP of ITGB5 with TGFBR2 and SNX17, endosomal recycling and TGFBR2 surface assays, in vitro and in vivo knockdown in gastric cancer","pmids":["38729557"],"confidence":"Medium","gaps":["Single lab, not independently replicated","Direct vs indirect nature of the ternary scaffold not dissected","Stoichiometry and binding domains undefined"]},{"year":2024,"claim":"Extended ITGB5's pro-tumor signaling roles via FAK/Src, PI3K/AKT, and Src in multiple cancers, with upstream regulation by ENAH and ROS.","evidence":"Knockdown/overexpression with migration, invasion, and signaling assays in OSCC, TSCC, and PDAC microenvironment co-cultures; recombinant ITGB5/ITGB1 protein addition","pmids":["39511483","39180583","39719238"],"confidence":"Low","gaps":["No direct binding assay between ENAH and ITGB5","Pathway phenotypes from single labs without reconstitution","Whether effects depend on αvβ5 heterodimer formation untested"]},{"year":2025,"claim":"Identified post-transcriptional control of ITGB5 via NAT10-mediated ac4C modification of its mRNA CDS, stabilizing the transcript to drive ITGB5–pFAK–pSrc signaling and perineural invasion.","evidence":"acRIP-seq/ac4C-seq mapping, NAT10 CRISPR manipulation, mRNA stability assays, DRG co-culture and sciatic nerve in vivo PDAC models","pmids":["40119353"],"confidence":"Medium","gaps":["Single lab","Functional contribution of individual ac4C sites not isolated","Generality of NAT10-ITGB5 axis beyond PDAC unknown"]},{"year":2026,"claim":"Revealed two additional layers of ITGB5 stabilization—USP1 deubiquitination of the protein and STAU1 binding to the 3' UTR of its mRNA—each embedded in feedback loops driving disease progression.","evidence":"IP-MS identifying USP1-ITGB5 with deubiquitination and rescue assays in a pancreatitis model; RIP confirming STAU1 3' UTR binding with mRNA stability, FOXP3 phosphorylation, and ChIP in colorectal cancer","pmids":["41857463","41796846"],"confidence":"Medium","gaps":["Both single-lab studies","USP1 ubiquitination site on ITGB5 not mapped","Mechanism by which ITGB5 promotes FOXP3 S418 phosphorylation undefined"]},{"year":null,"claim":"How the diverse cancer scaffolding and trafficking functions of ITGB5 relate to its canonical αvβ5 adhesion-receptor role, and whether they require heterodimerization with αv, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ITGB5 in its scaffold complexes","Dependence of intracellular signaling roles on αv pairing untested","Integration of multiple feedback loops into one regulatory network not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[1]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]}],"complexes":["αvβ5 integrin"],"partners":["EPS15","CSNK1A1","TGFBR2","SNX17","USP1","STAU1","NAT10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P18084","full_name":"Integrin beta-5","aliases":[],"length_aa":799,"mass_kda":88.1,"function":"Integrin alpha-V/beta-5 (ITGAV:ITGB5) is a receptor for fibronectin. It recognizes the sequence R-G-D in its ligand (Microbial infection) Integrin ITGAV:ITGB5 acts as a receptor for adenovirus type C","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P18084/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGB5","classification":"Not Classified","n_dependent_lines":484,"n_total_lines":1208,"dependency_fraction":0.40066225165562913},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ITGB5","total_profiled":1310},"omim":[{"mim_id":"616309","title":"FERM DOMAIN-CONTAINING PROTEIN 5; FRMD5","url":"https://www.omim.org/entry/616309"},{"mim_id":"615793","title":"ISTHMIN 1; ISM1","url":"https://www.omim.org/entry/615793"},{"mim_id":"611906","title":"FIBRONECTIN TYPE III DOMAIN-CONTAINING PROTEIN 5; FNDC5","url":"https://www.omim.org/entry/611906"},{"mim_id":"608777","title":"PERIOSTIN; POSTN","url":"https://www.omim.org/entry/608777"},{"mim_id":"602713","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 9; ADAM9","url":"https://www.omim.org/entry/602713"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":290.3}],"url":"https://www.proteinatlas.org/search/ITGB5"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P18084","domains":[{"cath_id":"3.30.1680.10","chopping":"23-82","consensus_level":"medium","plddt":76.8428,"start":23,"end":82},{"cath_id":"2.60.40.1510","chopping":"84-133_390-458","consensus_level":"high","plddt":86.645,"start":84,"end":458},{"cath_id":"3.40.50.410","chopping":"137-379","consensus_level":"high","plddt":91.5465,"start":137,"end":379},{"cath_id":"2.10.25.10","chopping":"556-587","consensus_level":"medium","plddt":87.4997,"start":556,"end":587},{"cath_id":"4.10.1240.30","chopping":"632-708","consensus_level":"high","plddt":76.4531,"start":632,"end":708}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P18084","model_url":"https://alphafold.ebi.ac.uk/files/AF-P18084-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P18084-F1-predicted_aligned_error_v6.png","plddt_mean":82.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGB5","jax_strain_url":"https://www.jax.org/strain/search?query=ITGB5"},"sequence":{"accession":"P18084","fasta_url":"https://rest.uniprot.org/uniprotkb/P18084.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P18084/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P18084"}},"corpus_meta":[{"pmid":"22566632","id":"PMC_22566632","title":"Diurnal, localized exposure of phosphatidylserine by rod outer segment tips in wild-type but not Itgb5-/- or Mfge8-/- mouse retina.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22566632","citation_count":134,"is_preprint":false},{"pmid":"34109215","id":"PMC_34109215","title":"Using CRISPRa and CRISPRi Technologies to Study the Biological Functions of ITGB5, TIMP1, and TMEM176B in Prostate Cancer Cells.","date":"2021","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34109215","citation_count":17,"is_preprint":false},{"pmid":"24737953","id":"PMC_24737953","title":"Expression profiling using a cDNA array and immunohistochemistry for the extracellular matrix genes FN-1, ITGA-3, ITGB-5, MMP-2, and MMP-9 in colorectal carcinoma progression and 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crosstalk","date":"2025-11-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.19.689184","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.27.672618","title":"LOX inhibition disrupts a collagen-integrin–MYC axis as a translatable targeting strategy in invasive lobular carcinoma","date":"2025-09-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.27.672618","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13239,"output_tokens":3584,"usd":0.046739,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11160,"output_tokens":3806,"usd":0.075475,"stage2_stop_reason":"end_turn"},"total_usd":0.122214,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"αvβ5 integrin (expressed by the RPE, requiring ITGB5) is required for the diurnal phagocytic rhythm of the retinal pigment epithelium; loss of ITGB5 abolishes the diurnal peak of phosphatidylserine (PS) exposure at rod outer segment tips, demonstrating that RPE αvβ5 activity—not intrinsic photoreceptor signaling—drives the circadian PS demarcation of rod tips that precedes shedding and phagocytosis.\",\n      \"method\": \"Itgb5-/- mouse retina live imaging with annexin V and pSIVA biosensor; comparison with Mfge8-/- and wild-type mice; RPE phagocytosis culture assays with PS blockade\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with specific cellular phenotype, multiple orthogonal fluorescent PS-detection methods, replicated across two knockout models (Itgb5-/- and Mfge8-/-) in the same study\",\n      \"pmids\": [\"22566632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Porcine ITGB5 (integrin αvβ5) acts as a direct receptor for ETEC F4ac fimbriae on intestinal epithelial cells: GST pull-down showed FaeG fimbrial adhesin binds directly to ITGB5, CRISPR/Cas9 knockout of ITGB5 significantly reduced ETEC F4ac adhesion, and ITGB5 overexpression significantly enhanced adhesion.\",\n      \"method\": \"CRISPR/Cas9 biallelic knockout in IPEC-J2 cells; ITGB5 overexpression; GST pull-down with purified FaeG and ITGB5; bacterial adhesion assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro binding (GST pull-down), gain- and loss-of-function experiments with specific adhesion readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31921118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ITGB5 interacts with EPS15 to prevent EGFR lysosomal degradation in HCC cells, thereby activating AKT-mTOR and MAPK signaling and reducing sorafenib sensitivity. Additionally, ITGB5 upregulates CSNK1A1 via the EGFR-AKT-mTOR pathway; CSNK1A1 in turn phosphorylates ITGB5, enhancing the ITGB5–EPS15 interaction and further activating EGFR, forming a positive feedback loop.\",\n      \"method\": \"Unbiased mass spectrometry with ITGB5 antibodies (Co-IP/MS) identifying EPS15 and CSNK1A1 as binding partners; co-immunoprecipitation; ITGB5 knockdown/overexpression; EGFR degradation assays; signaling pathway analysis\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP/MS plus functional pathway assays in a single lab; multiple orthogonal methods but not independently replicated\",\n      \"pmids\": [\"37149115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGB5 acts as a scaffold that physically interacts with TGFBR2 and SNX17, facilitating SNX17-mediated endosomal recycling of TGFBR2 and preventing its lysosomal degradation, thereby maintaining TGFBR2 surface levels and sustaining TGFβ-driven EMT and gastric cancer metastasis. TGFβ signaling in turn transcriptionally upregulates ITGB5, establishing a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation of ITGB5 with TGFBR2 and SNX17; ITGB5 knockdown in vitro and in vivo; endosomal recycling assay; TGFBR2 surface distribution analysis; ITGB5 knockdown EMT/metastasis assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying scaffold interactions, in vitro and in vivo loss-of-function with defined mechanistic phenotype, single lab\",\n      \"pmids\": [\"38729557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NAT10-mediated N4-acetylcytidine (ac4C) modification in the CDS region of ITGB5 mRNA promotes its stability, leading to upregulation of ITGB5 protein and activation of the ITGB5–pFAK–pSrc signaling pathway, which enhances perineural invasion in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"UPLC/MS-MS profiling of ac4C modification; acRIP-seq and ac4C-seq in NAT10-knockdown PDAC cells; RNA-seq; CRISPR-based NAT10 manipulation; dorsal root ganglion co-culture and sciatic nerve injection in vivo models; ITGB5 mRNA stability assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ac4C-seq and acRIP-seq identify modification site, CRISPR validation, in vivo model, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"40119353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ENAH upregulates ITGB5 expression in oral squamous cell carcinoma cells, and ITGB5 in turn activates Src signaling to promote cell migration and growth. ENAH expression itself is driven by the EGFR/PI3K/AKT/GSK3β/β-catenin cascade.\",\n      \"method\": \"Gene knockdown and ectopic expression in OSCC cells; proliferation, transwell migration, and invasion assays; integrated proteome and transcriptome analysis; PDX model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown/overexpression with pathway phenotype in single lab; no direct binding assay between ENAH and ITGB5 reported in abstract\",\n      \"pmids\": [\"39511483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ROS enhances ITGB5 expression in tongue squamous cell carcinoma cells, and elevated ITGB5 promotes invasion and migration through the cell adhesion signaling pathway; knockdown of ITGB5 suppressed these phenotypes.\",\n      \"method\": \"ITGB5 knockdown and overexpression in TSCC cells; ROS manipulation; invasion and migration assays; Western blot\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown/overexpression with phenotypic readout, single lab, no direct mechanistic binding or pathway reconstitution described\",\n      \"pmids\": [\"39180583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGB5 and ITGB1 recombinant proteins promote PDAC tumor cell proliferation and migration by activating the FAK/PI3K/AKT signaling pathway, and enhance macrophage-fibroblast interactions in the tumor microenvironment.\",\n      \"method\": \"In vitro macrophage-fibroblast co-culture system with ITGB5/ITGB1 recombinant protein addition or knockdown; Western blot for FAK/PI3K/AKT pathway; in vivo tumor growth assays\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — recombinant protein addition and knockdown experiments with signaling readout, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"39719238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGB5 promotes radiation resistance in pancreatic adenocarcinoma by facilitating DNA damage repair and activating the MEK/ERK signaling pathway; knockdown of ITGB5 increased radiation sensitivity.\",\n      \"method\": \"ITGB5 knockdown in PAAD cells; irradiation assays; DNA damage repair assays; MEK/ERK pathway analysis\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-lab knockdown study with signaling and DNA repair readout, limited mechanistic depth reported in abstract\",\n      \"pmids\": [\"36249018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP1 deubiquitinase stabilizes ITGB5 protein through deubiquitination; USP1 knockdown reduces ITGB5 expression, and ITGB5 overexpression rescues the inhibitory effect of USP1 knockdown on pancreatic stellate cell activation. ITGB5 promotes PSC activation via the PI3K/AKT pathway.\",\n      \"method\": \"Immunoprecipitation–LC/MS identifying ITGB5 as USP1 target; USP1 knockdown with lentivirus; ITGB5 overexpression rescue experiments; in vivo cerulein CP model; Western blot for PI3K/AKT\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS identification of USP1-ITGB5 interaction, deubiquitination/stabilization assay, rescue experiments, and in vivo validation in single lab\",\n      \"pmids\": [\"41857463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STAU1 RNA-binding protein directly binds the 3' UTR of ITGB5 mRNA to stabilize it, increasing ITGB5 protein levels. Elevated ITGB5 increases FOXP3 phosphorylation at serine 418, which enhances FOXP3 binding to the STAU1 promoter and activates STAU1 transcription, forming a STAU1–ITGB5–FOXP3 positive feedback loop driving colorectal cancer metastasis.\",\n      \"method\": \"RNA immunoprecipitation confirming STAU1 binding to ITGB5 3' UTR; STAU1 knockdown/overexpression; mRNA stability assays; FOXP3 phosphorylation analysis; ChIP assay for FOXP3 binding to STAU1 promoter; in vitro and in vivo metastasis assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirming direct 3' UTR binding, mRNA stability assay, ChIP for downstream transcriptional loop, in vivo validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41796846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ITGB5 knockdown in porcine intestinal epithelial cells (IPEC-J2) increased ETEC F4ac bacterial adhesion and attenuated ETEC-induced inflammation (reduced pro-inflammatory gene expression), indicating ITGB5 plays a role in defending against ETEC attachment and modulating mucosal immune signaling.\",\n      \"method\": \"siRNA knockdown of ITGB5 in IPEC-J2 cells; ETEC bacterial adhesion assay; qPCR for pro-inflammatory and mucosal genes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-method siRNA knockdown with adhesion and gene expression readouts, single lab, no direct binding assay\",\n      \"pmids\": [\"23922972\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGB5 (integrin β5, forming αvβ5 heterodimer) functions as a phagocytic receptor in retinal pigment epithelium required for diurnal rod outer segment phagocytosis, a direct adhesion receptor for bacterial fimbriae (ETEC F4ac FaeG) on intestinal epithelium, and a multifunctional scaffold in cancer cells that interacts with EPS15 to stabilize EGFR and activate AKT-mTOR/MAPK signaling, with TGFBR2/SNX17 to promote TGFβ receptor recycling and EMT, and is itself post-translationally stabilized by USP1-mediated deubiquitination and post-transcriptionally stabilized by NAT10-mediated ac4C modification of its mRNA and STAU1 binding to its 3' UTR; collectively, these mechanisms position ITGB5 as a context-dependent regulator of cell adhesion, receptor trafficking, and downstream FAK/PI3K/AKT/ERK signaling in both normal tissue homeostasis and cancer progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGB5 (integrin \\u03b25) pairs with \\u03b1v to form the \\u03b1v\\u03b25 heterodimer, which functions as an adhesion and phagocytic receptor in normal tissue and as a context-dependent driver of receptor trafficking and pro-survival signaling in cancer [#0, #2]. In the retinal pigment epithelium, \\u03b1v\\u03b25 activity is required for the diurnal phagocytic rhythm: loss of ITGB5 abolishes the circadian peak of phosphatidylserine exposure at rod outer segment tips that precedes shedding and phagocytosis [#0]. On intestinal epithelium, ITGB5 acts as a direct receptor for ETEC F4ac fimbriae, binding the FaeG adhesin and mediating bacterial adhesion [#1]. In cancer, ITGB5 operates as a signaling scaffold: it interacts with EPS15 to block EGFR lysosomal degradation and activate AKT-mTOR and MAPK signaling, with a CSNK1A1-dependent phosphorylation feedback loop reinforcing the ITGB5\\u2013EPS15 interaction [#2], and it binds TGFBR2 and SNX17 to promote endosomal recycling of TGFBR2, sustaining TGF\\u03b2-driven EMT [#3]. Downstream, ITGB5 engages FAK/Src and PI3K/AKT/ERK signaling to promote invasion and proliferation [#4, #9]. ITGB5 abundance is itself controlled at multiple levels: USP1-mediated deubiquitination stabilizes the protein [#9], NAT10-mediated ac4C modification stabilizes its mRNA [#4], and STAU1 binding to its 3' UTR stabilizes the transcript within a STAU1\\u2013ITGB5\\u2013FOXP3 feedback loop [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that RPE \\u03b1v\\u03b25 integrin activity, not intrinsic photoreceptor signaling, drives the circadian phosphatidylserine demarcation of rod outer segment tips required for diurnal phagocytosis.\",\n      \"evidence\": \"Itgb5-/- mouse retina live imaging with annexin V/pSIVA biosensors, compared to Mfge8-/- and wild-type, plus RPE phagocytosis assays with PS blockade\",\n      \"pmids\": [\"22566632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve how ITGB5 senses or transduces the circadian timing cue\", \"Downstream cytoplasmic signaling effectors in RPE not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"First implicated ITGB5 in intestinal defense against ETEC F4ac, linking it to bacterial adhesion and modulation of mucosal inflammation.\",\n      \"evidence\": \"siRNA knockdown of ITGB5 in porcine IPEC-J2 cells with bacterial adhesion assay and qPCR of inflammatory genes\",\n      \"pmids\": [\"23922972\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-method knockdown with no direct binding assay\", \"Knockdown increased adhesion, complicating the receptor interpretation later refined by direct binding work\", \"Mechanism of inflammation modulation undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that ITGB5 is a direct physical receptor for the ETEC F4ac fimbrial adhesin FaeG, resolving the adhesion mechanism at the molecular level.\",\n      \"evidence\": \"GST pull-down of purified FaeG with ITGB5, CRISPR/Cas9 knockout and overexpression in IPEC-J2 cells with bacterial adhesion readouts\",\n      \"pmids\": [\"31921118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface residues not mapped\", \"Whether \\u03b1v\\u03b25 heterodimer or ITGB5 alone mediates binding unaddressed\", \"Reconciliation with earlier knockdown adhesion result not provided\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected ITGB5 to therapy resistance by showing it facilitates DNA damage repair and MEK/ERK activation to confer radiation resistance in pancreatic cancer.\",\n      \"evidence\": \"ITGB5 knockdown in PAAD cells with irradiation, DNA damage repair, and MEK/ERK pathway assays\",\n      \"pmids\": [\"36249018\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab knockdown with limited mechanistic depth\", \"No direct link between ITGB5 and DNA repair machinery established\", \"How a surface integrin influences nuclear DNA repair unexplained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined ITGB5 as a scaffold that protects EGFR from degradation via EPS15, establishing a CSNK1A1-reinforced feedback loop driving AKT-mTOR/MAPK signaling and sorafenib resistance.\",\n      \"evidence\": \"Co-IP/MS identifying EPS15 and CSNK1A1, reciprocal Co-IP, knockdown/overexpression, EGFR degradation and signaling assays in HCC cells\",\n      \"pmids\": [\"37149115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not independently replicated\", \"Direct EPS15-ITGB5 binding interface unmapped\", \"CSNK1A1 phosphorylation site on ITGB5 not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed ITGB5 functions as a scaffold linking TGFBR2 to SNX17-mediated endosomal recycling, sustaining TGF\\u03b2-driven EMT and metastasis within a TGF\\u03b2\\u2013ITGB5 feedback loop.\",\n      \"evidence\": \"Reciprocal Co-IP of ITGB5 with TGFBR2 and SNX17, endosomal recycling and TGFBR2 surface assays, in vitro and in vivo knockdown in gastric cancer\",\n      \"pmids\": [\"38729557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently replicated\", \"Direct vs indirect nature of the ternary scaffold not dissected\", \"Stoichiometry and binding domains undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended ITGB5's pro-tumor signaling roles via FAK/Src, PI3K/AKT, and Src in multiple cancers, with upstream regulation by ENAH and ROS.\",\n      \"evidence\": \"Knockdown/overexpression with migration, invasion, and signaling assays in OSCC, TSCC, and PDAC microenvironment co-cultures; recombinant ITGB5/ITGB1 protein addition\",\n      \"pmids\": [\"39511483\", \"39180583\", \"39719238\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding assay between ENAH and ITGB5\", \"Pathway phenotypes from single labs without reconstitution\", \"Whether effects depend on \\u03b1v\\u03b25 heterodimer formation untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified post-transcriptional control of ITGB5 via NAT10-mediated ac4C modification of its mRNA CDS, stabilizing the transcript to drive ITGB5\\u2013pFAK\\u2013pSrc signaling and perineural invasion.\",\n      \"evidence\": \"acRIP-seq/ac4C-seq mapping, NAT10 CRISPR manipulation, mRNA stability assays, DRG co-culture and sciatic nerve in vivo PDAC models\",\n      \"pmids\": [\"40119353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Functional contribution of individual ac4C sites not isolated\", \"Generality of NAT10-ITGB5 axis beyond PDAC unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed two additional layers of ITGB5 stabilization\\u2014USP1 deubiquitination of the protein and STAU1 binding to the 3' UTR of its mRNA\\u2014each embedded in feedback loops driving disease progression.\",\n      \"evidence\": \"IP-MS identifying USP1-ITGB5 with deubiquitination and rescue assays in a pancreatitis model; RIP confirming STAU1 3' UTR binding with mRNA stability, FOXP3 phosphorylation, and ChIP in colorectal cancer\",\n      \"pmids\": [\"41857463\", \"41796846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both single-lab studies\", \"USP1 ubiquitination site on ITGB5 not mapped\", \"Mechanism by which ITGB5 promotes FOXP3 S418 phosphorylation undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse cancer scaffolding and trafficking functions of ITGB5 relate to its canonical \\u03b1v\\u03b25 adhesion-receptor role, and whether they require heterodimerization with \\u03b1v, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ITGB5 in its scaffold complexes\", \"Dependence of intracellular signaling roles on \\u03b1v pairing untested\", \"Integration of multiple feedback loops into one regulatory network not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"\\u03b1v\\u03b25 integrin\"],\n    \"partners\": [\"EPS15\", \"CSNK1A1\", \"TGFBR2\", \"SNX17\", \"USP1\", \"STAU1\", \"NAT10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}