{"gene":"TRIP6","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1998,"finding":"TRIP6 protein displays a proline-rich N-terminal region linked to three tandemly arrayed C-terminal LIM domains, placing it in the same structural family as zyxin and LPP; it was first identified as a ligand-dependent binding partner for the thyroid hormone receptor.","method":"cDNA cloning, sequence analysis, yeast two-hybrid","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain architecture established by sequencing and yeast two-hybrid, replicated across multiple labs","pmids":["9598321"],"is_preprint":false},{"year":1999,"finding":"TRIP6/ZRP-1 directly interacts with the second PDZ domain of the cytosolic protein tyrosine phosphatase hPTP1E (ZRP-1/TRIP6 LIM domains and intact C-terminus required); interaction demonstrated both in vitro with bacterially expressed proteins and in vivo by co-immunoprecipitation.","method":"Yeast two-hybrid, in vitro binding with bacterially expressed proteins, co-immunoprecipitation, deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution with purified proteins plus co-IP in cells, deletion mapping, replicated by Cuppen et al. 2000","pmids":["10400701"],"is_preprint":false},{"year":1999,"finding":"Full-length Trip6 localizes to focal adhesion plaques; deletion of the N-terminal 115 amino acids allows Trip6 to enter the nucleus. A GAL4 fusion containing the Trip6 LIM domain region activates transcription in yeast and chicken fibroblasts.","method":"Overexpression in chicken embryo fibroblasts, fluorescence microscopy, deletion mutagenesis, GAL4 reporter assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct imaging and reporter assays in two cell systems, single lab","pmids":["10395914"],"is_preprint":false},{"year":1999,"finding":"Trip6 LIM domain sequences act as a coactivator for transcriptional activation by v-Rel: GAL4-Trip6 activates transcription in yeast and chicken cells, Trip6 enables C-terminal v-Rel sequences to activate transcription, and Trip6 enhances v-Rel activation from a κB site reporter.","method":"Yeast two-hybrid, GAL4 reporter assay, NF-κB reporter assay","journal":"Gene expression","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple reporter assays in yeast and chicken cells, single lab","pmids":["10794523"],"is_preprint":false},{"year":2000,"finding":"TRIP6 interacts with the PDZ domain of the adaptor protein RIL (second LIM domain of TRIP6 is sufficient for strong interaction) and with the second PDZ domain of PTP-BL (requiring the third LIM domain and intact C-terminus). TRIP6 co-precipitates with RIL and PTP-BL PDZ polypeptides in transfected epithelial cells and co-localizes with RIL at F-actin structures.","method":"Yeast two-hybrid, co-immunoprecipitation, deletion analysis, co-localization by fluorescence microscopy","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus co-IP in cells plus co-localization, domain mapping by deletion, single lab","pmids":["10826496"],"is_preprint":false},{"year":2001,"finding":"TRIP6 contains a functional nuclear export signal (NES) dependent on CRM1: leptomycin B treatment sequesters TRIP6 in the nucleus; NES mutation also retains TRIP6 in the nucleus; the Trip6 NES redirects the nuclear v-Rel oncoprotein to the cytoplasm. TRIP6 also harbors at least two nuclear targeting sequences and multiple transactivation domains, but does not bind DNA-cellulose.","method":"Leptomycin B treatment, NES mutagenesis, nuclear localization sequence fusion to β-galactosidase, GAL4-reporter assays, DNA-cellulose binding assay","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (drug treatment, mutagenesis, heterologous domain transfer, reporter assays) in single rigorous study","pmids":["11336797"],"is_preprint":false},{"year":2003,"finding":"TRIP6 directly binds to the carboxyl-terminal tail of the LPA2 receptor through its LIM domains; LPA stimulation promotes TRIP6 interaction with the LPA2 receptor, recruits TRIP6 to the plasma membrane and focal adhesions, and induces agonist-dependent association with paxillin, FAK, c-Src, and p130cas. Overexpression of TRIP6 augments LPA-induced cell migration; siRNA-mediated knockdown reduces it. This interaction is specific to LPA2 and not LPA1 or LPA3.","method":"Co-immunoprecipitation, pulldown, siRNA knockdown, cell migration assay, fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, direct binding demonstrated, loss-of-function and gain-of-function with defined migration phenotype, receptor specificity established","pmids":["14688263"],"is_preprint":false},{"year":2004,"finding":"TRIP6 functions as a coactivator for both AP-1 and NF-κB; a nuclear isoform of TRIP6 (nTrip6) is recruited to AP-1/NF-κB target gene promoters as shown by chromatin immunoprecipitation. In the presence of glucocorticoids, GR joins the Trip6 complex at these promoters, mediating GR tethering-based transrepression. RNAi knockdown of Trip6 or dominant-negative mutation abolishing GR interaction eliminates GR transrepression.","method":"Chromatin immunoprecipitation, RNAi knockdown, dominant-negative mutagenesis, reporter assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP evidence of promoter recruitment, loss-of-function by RNAi and dominant-negative, multiple orthogonal methods","pmids":["15489293"],"is_preprint":false},{"year":2004,"finding":"TRIP6/ZRP-1 interacts with the cytoplasmic domain of endoglin through its three C-terminal LIM domains. In the absence of endoglin, ZRP-1 localizes to focal adhesions; in the presence of endoglin, ZRP-1 redistributes along actin stress fibers. Endoglin expression causes dramatic reorganization of the actin cytoskeleton from dense F-actin bundles to stress fibers, and siRNA knockdown of endoglin or ZRP-1 or endoglin clustering leads to F-actin mislocalization.","method":"Yeast two-hybrid (bait: endoglin cytoplasmic domain), co-immunoprecipitation, deletion mapping, siRNA knockdown, fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — protein interaction mapped by deletion, co-IP, siRNA loss-of-function with defined cytoskeletal phenotype, multiple methods","pmids":["15148318"],"is_preprint":false},{"year":2005,"finding":"c-Src phosphorylates TRIP6 at Tyr-55 upon LPA stimulation; this phosphorylation is absent in Src-null fibroblasts. Phosphotyrosine-55 together with Pro-58 creates a docking site for Crk SH2 domain. Y55F mutation abolishes Crk and p130cas association and significantly reduces LPA-induced ERK activation and cell migration without affecting TRIP6 focal adhesion localization.","method":"In vitro kinase assay, phospho-specific antibodies, site-directed mutagenesis (Y55F), co-immunoprecipitation, ERK phosphorylation assay, cell migration assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphorylation, mutagenesis, and multiple downstream functional readouts in single study","pmids":["15988003"],"is_preprint":false},{"year":2005,"finding":"TRIP6 is a RIP2-interacting protein; the LIM domains of TRIP6 mediate binding to RIP2. TRIP6 interacts with RIP2 in a TNF- or IL-1-dependent manner in mammalian cells. Overexpression of TRIP6 potentiates RIP2-mediated NF-κB activation; dominant-negative or siRNA of TRIP6 inhibits NF-κB activation by TNF, IL-1, TLR2, or Nod1. TRIP6 also interacts with TRAF2 and potentiates RIP2- and Nod1-mediated ERK activation.","method":"Yeast two-hybrid, co-immunoprecipitation, NF-κB reporter assay, siRNA, dominant-negative overexpression","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus co-IP in cells, multiple pathway readouts (NF-κB, ERK), loss- and gain-of-function","pmids":["15657077"],"is_preprint":false},{"year":2006,"finding":"Supervillin binds the LIM domains of TRIP6 (and LPP but not zyxin) through a defined sequence (SV342-571). SV and TRIP6 co-localize within large focal adhesions. RNAi reduction of either protein increases cell adhesion to fibronectin. TRIP6 partially rescues SV effects on stress fibers and FAs by mislocalizing SV away from FAs.","method":"Pulldown, co-immunoprecipitation, co-localization by fluorescence microscopy, RNAi knockdown, fibronectin adhesion assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding mapped to defined domains, co-localization, reciprocal loss-of-function phenotypes","pmids":["16880273"],"is_preprint":false},{"year":2006,"finding":"AMPK phosphorylates TRIP6 in vitro at its N-terminus; the catalytic subunit AMPKα2 physically interacts with TRIP6 in mammalian cells. AMPK action enhances the transcriptional co-activator properties of TRIP6.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro phosphorylation assay, transcriptional reporter assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus co-IP plus reporter assay, single lab","pmids":["16624523"],"is_preprint":false},{"year":2007,"finding":"PTPL1/FAP-1 dephosphorylates phosphotyrosine-55 of TRIP6 in vitro and inhibits LPA-induced tyrosine phosphorylation of TRIP6 in cells. PTPL1-mediated dephosphorylation requires direct PTPL1–TRIP6 protein–protein interaction and PTPL1 phosphatase activity. PTPL1 prevents TRIP6 turnover at adhesion sites and inhibits LPA-induced TRIP6–Crk association and cell migration.","method":"In vitro phosphatase assay, co-immunoprecipitation, dominant-negative/phosphatase-dead mutants, cell migration assay, FRAP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro dephosphorylation, catalytic-dead mutant, co-IP, and functional migration readout","pmids":["17591779"],"is_preprint":false},{"year":2007,"finding":"ZRP-1/TRIP6 is essential for stress fiber formation, mature focal adhesion assembly, and correct cell-cell adhesion. ZRP-1 depletion reduces FAK tyrosine phosphorylation and elevates Rac1 activity, causing abnormal actin polymerization and membrane protrusions; RhoA overexpression rescues stress fibers in ZRP-1-depleted cells.","method":"siRNA knockdown, fluorescence microscopy, focal adhesion quantification, FAK phosphorylation immunoblot, Rac1 activity assay, RhoA rescue experiment","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi loss-of-function with multiple orthogonal readouts (FAK phos, Rac1 activity, rescue by RhoA), single rigorous study","pmids":["17652164"],"is_preprint":false},{"year":2008,"finding":"TRIP6 directly interacts with the fifth PDZ domain of MAGI-1b scaffold; this interaction is mediated by the C-terminal PDZ-binding motif of TRIP6. Ectopic TRIP6 expression induces cell invasion in a PI3K- and NF-κB-dependent manner and impairs cell–cell aggregation at least partly by uncoupling adherens junctions from the cytoskeleton. TRIP6Stop473 (lacking PDZ-binding motif) cannot promote invasion or interfere with cell aggregation.","method":"Yeast two-hybrid, co-immunoprecipitation, invasion assay, aggregation assay, PDZ-binding mutant (TRIP6Stop473), PI3K/NF-κB inhibitors","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-specific mutant (Stop473), multiple functional readouts, pharmacological validation","pmids":["19017743"],"is_preprint":false},{"year":2008,"finding":"nTrip6 LIM domains interact selectively with Fos family members (not Jun or ATF2), making nTrip6 a selective coactivator for Fos-containing AP-1 dimers. GR transrepression (via nTrip6 tethering) is restricted to Fos-containing AP-1 dimers; c-Jun:ATF2-driven promoters do not recruit nTrip6 or GR.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays with defined AP-1 dimer composition","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP and co-IP with defined dimer-composition experiments, multiple AP-1 dimers tested, builds on prior lab findings","pmids":["18535250"],"is_preprint":false},{"year":2010,"finding":"TRIP6 interacts with the cytoplasmic juxtamembrane domain of Fas receptor and interferes with FADD recruitment to Fas, thereby antagonizing Fas-induced apoptosis. TRIP6 also physically interacts with NF-κB p65 and promotes NF-κB nuclear translocation upon Fas activation or LPA stimulation. TRIP6 promotes Fas-mediated cell migration in apoptosis-resistant cells via Src-dependent pTyr-55 phosphorylation.","method":"Co-immunoprecipitation, FADD recruitment assay, apoptosis assay, NF-κB reporter/translocation assay, site-directed mutagenesis (Y55F), cell migration assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple binding interactions demonstrated, mutagenesis of Tyr-55, loss-of-function with defined apoptotic and migratory phenotypes","pmids":["20876301"],"is_preprint":false},{"year":2010,"finding":"TRIP6 associates with POT1, TRF2, and TIN2 (components of the shelterin complex) by co-immunoprecipitation and is detected at telomeres by ChIP. TRIP6 depletion by siRNA induces telomere dysfunction-induced foci (TIFs), indicating a role in telomere protection.","method":"Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, TIF assay","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP with shelterin components, ChIP, functional siRNA phenotype, single lab","pmids":["20634563"],"is_preprint":false},{"year":2010,"finding":"c-Src-mediated phosphorylation of TRIP6 at Tyr-55 is required for its localization to the osteoclast sealing zone and for osteoclast bone resorptive capacity. TRIP6 resides in the sealing zone through association with tropomyosin 4. LPA promotes TRIP6 sealing zone association and bone resorption via the LPA2 receptor.","method":"RNAi knockdown, overexpression of phosphomimetic (Y55E) and non-phosphorylatable (Y55A/Y55F) TRIP6 mutants, sealing zone perimeter measurement, bone resorption assay, co-immunoprecipitation (with tropomyosin 4), receptor agonist/antagonist pharmacology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphomimetic and non-phosphorylatable mutants, loss- and gain-of-function with defined resorptive phenotype, receptor pharmacology","pmids":["20547766"],"is_preprint":false},{"year":2010,"finding":"nTrip6 is recruited to GR-bound promoters through direct interaction with GR and increases GR-mediated transcription. nTrip6 is also essential for transrepression of GR by NF-κB and AP-1: the interaction of nTrip6 with NF-κB and AP-1 at a GR-bound promoter is required for repression.","method":"Chromatin immunoprecipitation, co-immunoprecipitation, reporter assays, siRNA","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus co-IP, single lab, builds on prior work from the same group","pmids":["20153803"],"is_preprint":false},{"year":2011,"finding":"TRIP6 and LPP (but not Zyxin) localize to a subset of telomeres by immunofluorescence and are found in complex with shelterin; Zyxin, despite high similarity, is not detected at telomeres or in a complex with shelterin.","method":"Immunofluorescence, co-immunoprecipitation, comparison among LIM protein family members","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunofluorescence and co-IP in cells, family member specificity established, single lab","pmids":["21519191"],"is_preprint":false},{"year":2013,"finding":"TRIP6 promotes tumorigenesis by serving as a bridge to recruit p27KIP1 to AKT in the cytosol, facilitating AKT-mediated phosphorylation of p27KIP1 at T157 and its cytosolic mislocalization. TRIP6 also regulates AKT membrane translocation and activation, and promotes serum-induced reduction of nuclear p27KIP1 via Skp2-dependent and -independent mechanisms.","method":"Co-immunoprecipitation, AKT kinase assay, phospho-specific antibody for p27T157, subcellular fractionation, siRNA knockdown, xenograft tumor model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, in-cell kinase readout with phospho-antibody, subcellular fractionation, in vivo xenograft validation","pmids":["23339869"],"is_preprint":false},{"year":2015,"finding":"Trip6 promotes dendritic morphogenesis in hippocampal neurons through interaction with GRIP1 and myosin VI. Phosphorylation of GRIP1 at T956 by AKT1 inhibits GRIP1–myosin VI interaction but promotes GRIP1 binding to 14-3-3, regulating F-actin organization and dendritic morphogenesis. Trip6 depletion reduces F-actin content and impairs dendritic morphology, phenocopying GRIP1 or myosin VI knockdown.","method":"Co-immunoprecipitation, siRNA knockdown, phospho-mutant analysis, F-actin staining, dendritic morphology quantification in cultured hippocampal neurons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP, multiple siRNA phenotypes, phospho-mutant analysis, single lab","pmids":["25673849"],"is_preprint":false},{"year":2016,"finding":"TRIP6 directly binds TRAF6 and recruits it to the LPA2 receptor upon LPA stimulation. TRIP6 antagonizes recruitment of deubiquitinases A20 and CYLD to TRAF6, sustaining TRAF6 E3 ligase activity and augmenting LPA-induced NF-κB and JNK signaling. TRAF6 in turn facilitates TRIP6 binding to NF-κB p65 and c-Src-mediated TRIP6 phosphorylation. TRIP6 shRNA or Cas9/sgRNA depletion enhances A20/CYLD–TRAF6 association and attenuates NF-κB/JNK/p38 activation.","method":"Co-immunoprecipitation, shRNA, CRISPR/Cas9 knockout, NF-κB/JNK reporter assays, deubiquitinase competition assay","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, shRNA, CRISPR KO, multiple signaling readouts), bidirectional regulation demonstrated","pmids":["27134758"],"is_preprint":false},{"year":2017,"finding":"TRIP6 inhibits Hippo signaling at adherens junctions in response to mechanical tension: vinculin (activated by tension) recruits TRIP6 to adherens junctions, where TRIP6 binds LATS1/2 and competes with MOB1 for LATS1/2 binding, thereby blocking MST1/2-mediated LATS1/2 activation and promoting YAP activity.","method":"siRNA knockdown, co-immunoprecipitation, competitive binding assay (TRIP6 vs MOB1 for LATS1/2), tension manipulation, YAP reporter assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway placement with competitive binding assay, loss-of-function, tension manipulation, multiple readouts","pmids":["29222344"],"is_preprint":false},{"year":2019,"finding":"TTPAL directly binds TRIP6 in the cytoplasm (identified by co-IP/mass spectrometry) and inhibits ubiquitin-mediated degradation of TRIP6. Stabilized TRIP6 displaces β-catenin from MAGI1 via competitive binding, allowing β-catenin nuclear entry and activation of Wnt/β-catenin signaling.","method":"Co-immunoprecipitation followed by mass spectrometry, ubiquitination assay, competitive binding assay, β-catenin localization/reporter assay, siRNA depletion of TRIP6","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-identified interaction, ubiquitination assay, competitive binding, Wnt reporter, TRIP6 loss-of-function rescue","pmids":["31018940"],"is_preprint":false},{"year":2021,"finding":"TRIP6 is required for LIMD1 localization to adherens junctions (but not vice versa), for recruitment of vinculin and VASP to adherens junctions, and for maintenance of apical F-actin and myosin organization. TRIP6 knockdown causes loss of apical actin stress fibers and compensatory increase at basal focal adhesions.","method":"siRNA knockdown, fluorescence microscopy, quantification of LIMD1/vinculin/VASP/myosin/F-actin localization","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — systematic siRNA epistasis, multiple protein localization readouts, single lab","pmids":["33558314"],"is_preprint":false},{"year":2021,"finding":"TRIP6 deletion in mice causes ependymal and choroid plexus epithelial cells to carry fewer and shorter cilia, leading to hydrocephalus. TRIP6 localizes at the pericentriolar material and along the ciliary axoneme (super-resolution microscopy). TRIP6 homodimerization is required for its ciliogenesis function; inhibition of homodimerization in vitro phenocopies Trip6 deletion.","method":"Mouse knockout, super-resolution microscopy, RNAi in choroid plexus epithelial cell line, homodimerization inhibition","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with defined phenotype, super-resolution localization, in vitro RNAi and homodimerization inhibition corroboration","pmids":["34620853"],"is_preprint":false},{"year":2022,"finding":"TRIP6 binds TRAF6 and enhances TRAF6 oligomerization and autoubiquitination in vivo, leading to NF-κB activation and pro-inflammatory cytokine (TNFα, IL-6) expression. TRIP6-knockout mice develop less severe DSS-induced colitis compared to wild-type, confirming in vivo role.","method":"TRIP6-knockout mouse model (DSS colitis), co-immunoprecipitation, TRAF6 oligomerization/autoubiquitination assay, NF-κB signaling assay, cytokine measurement","journal":"Journal of inflammation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model with defined colitis phenotype, TRAF6 biochemical assays (oligomerization, autoubiquitination), consistent with in vitro data","pmids":["34983535"],"is_preprint":false},{"year":2023,"finding":"TRIP6 directly interacts with the PDZ domain-containing polarity protein PARD3 to disrupt tight junctions and activate oncogenic Akt signaling, promoting CRC metastasis. TRIP6-induced pro-metastatic phenotypes and Akt activation depend on PARD3; TRIP6 also inhibits PTEN in this context.","method":"Co-immunoprecipitation, tight junction marker quantification, gut permeability assay, siRNA/shRNA knockdown, in vivo mouse metastasis model, nanoparticle-encapsulated siRNA therapeutic experiment","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP, PARD3 epistasis, in vivo model, single lab","pmids":["37827326"],"is_preprint":false},{"year":2023,"finding":"TRIM55 directly interacts with TRIP6, regulates TRIP6 protein stability by influencing its ubiquitination, and thereby activates Wnt/β-catenin signaling to promote HCC cell proliferation.","method":"Co-immunoprecipitation, cycloheximide chase, ubiquitination assay, Wnt reporter, xenograft model","journal":"Journal of hepatocellular carcinoma","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP, ubiquitination assay, CHX chase for stability, single lab","pmids":["37554583"],"is_preprint":false},{"year":2024,"finding":"The three LIM domains of TRIP6 are necessary and sufficient for tension-dependent localization to adherens junctions. TRIP6 and LIMD1 LIM domains bind strained/tensioned F-actin; point mutations in a conserved residue in each LIM domain that impairs strained F-actin binding abolishes localization to adherens junctions and ability to bind/recruit LATS1. TRIP6 co-localizes with ends of actin fibers at adherens junctions.","method":"Domain deletion analysis, LIM domain point mutagenesis, strained F-actin binding assay, fluorescence microscopy, tension manipulation, co-immunoprecipitation (TRIP6–LATS1)","journal":"Cytoskeleton","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro strained actin binding, mutagenesis of conserved residues in all three LIM domains, localization and binding assays","pmids":["38426816"],"is_preprint":false},{"year":2024,"finding":"The TRIP6/LATS1 complex co-localizes with α-catenin/vinculin at both bicellular and tricellular junctions; this junctional localization requires ROCK1 and α-catenin and is sensitive to cytochalasin B, Y-27632, and blebbistatin, indicating mechanosensitive localization. A BiFC-based α-catenin/vinculin mechanosensor co-localizes with TRIP6/LATS1.","method":"Immunofluorescence, pharmacological perturbation (cytochalasin B, Y-27632, blebbistatin), siRNA knockdown of ROCK1/α-catenin, BiFC mechanosensor","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-localization with pharmacological perturbations and genetic knockdowns, single lab","pmids":["38805800"],"is_preprint":false},{"year":2024,"finding":"TRIP6 recruits protein phosphatase PP1A to dephosphorylate LATS1/2, thereby inducing YAP nuclear localization and activation in postnatal neural stem cells. This TRIP6-YAP axis promotes NSC self-renewal and inhibits differentiation; YAP in turn regulates Gli2 expression to activate Sonic Hedgehog signaling.","method":"Co-immunoprecipitation (TRIP6–PP1A), LATS1/2 phosphorylation assay, YAP reporter/immunofluorescence, siRNA knockdown, Gli2 reporter, conditional YAP knockout in mice","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP, phosphorylation assay, reporter, in vivo conditional KO; PP1A recruitment is a novel mechanistic claim from single lab","pmids":["38411462"],"is_preprint":false},{"year":2025,"finding":"TRIP6 binds to and stabilizes the transcription factor c-Fos (verified by co-IP and silver staining); c-Fos then acts as a transcription factor to upregulate GPX4 expression (verified by dual-luciferase reporter), thereby inhibiting ferroptosis in gastric cancer cells.","method":"Co-immunoprecipitation, silver staining, dual-luciferase reporter assay for GPX4 promoter, ferroptosis inducer/inhibitor rescue experiments","journal":"Journal of gastrointestinal oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP binding, luciferase reporter for GPX4, rescue experiments; single lab, new finding","pmids":["40672107"],"is_preprint":false}],"current_model":"TRIP6 is a multi-domain LIM/zyxin-family adaptor that shuttles between focal adhesions and the nucleus via a CRM1-dependent nuclear export signal; at adhesions it integrates signals from LPA2 receptor, endoglin, Fas, and MAGI-1 scaffolds by recruiting and coordinating kinases (c-Src, AKT), phosphatases (PTPL1, PP1A), and cytoskeletal regulators (paxillin, FAK, p130cas, RhoA/Rac1, tropomyosin-4, GRIP1/myosin VI); in the nucleus its Fos-selective LIM domains act as a molecular platform that co-activates AP-1 and NF-κB and mediates glucocorticoid receptor tethering for transrepression; at adherens junctions, TRIP6 senses mechanical tension by binding strained F-actin through its LIM domains, recruits vinculin, and inhibits Hippo pathway LATS1/2 kinases by competing with MOB1, thereby activating YAP; TRIP6 stability is regulated by ubiquitin-mediated degradation counteracted by TTPAL and TRIM55 binding; and TRIP6 also protects telomeres through association with the shelterin complex and is required for brain ciliogenesis in a homodimerization-dependent manner."},"narrative":{"mechanistic_narrative":"TRIP6 is a multi-domain LIM/zyxin-family adaptor that integrates cell-adhesion and growth-factor signaling at focal adhesions, adherens junctions, and the nucleus, built around a proline-rich N-terminus and three tandem C-terminal LIM domains [PMID:9598321]. Its subcellular partitioning is governed by N-terminal focal-adhesion targeting and a CRM1-dependent nuclear export signal, so that removal of the N-terminus or NES drives nuclear accumulation [PMID:10395914, PMID:11336797]. At the plasma membrane, TRIP6 is recruited by the LPA2 receptor in an agonist-dependent manner, where it nucleates a c-Src/paxillin/FAK/p130cas assembly and drives cell migration [PMID:14688263]; c-Src phosphorylation of Tyr-55 creates a Crk docking site that couples TRIP6 to ERK activation and motility, an event reversed by the phosphatase PTPL1 [PMID:15988003, PMID:17591779]. TRIP6 is essential for stress-fiber formation and mature focal-adhesion assembly, balancing RhoA and Rac1 activity and organizing the actin cytoskeleton in concert with partners including endoglin, supervillin, RIL, and the cytosolic phosphatase hPTP1E [PMID:17652164, PMID:15148318, PMID:16880273, PMID:10400701, PMID:10826496]. A nuclear isoform acts as a Fos-selective coactivator platform for AP-1 and NF-κB and mediates glucocorticoid-receptor tethering for transrepression [PMID:15489293, PMID:18535250, PMID:20153803]. TRIP6 amplifies inflammatory and survival signaling by binding RIP2 and TRAF6, sustaining TRAF6 E3-ligase activity against the deubiquitinases A20/CYLD, and by antagonizing Fas-mediated apoptosis through interference with FADD recruitment [PMID:15657077, PMID:27134758, PMID:20876301, PMID:34983535]. At adherens junctions TRIP6 functions as a tension sensor: its LIM domains bind strained F-actin, vinculin recruits it under load, and it inhibits Hippo signaling by binding LATS1/2 and competing with MOB1, thereby activating YAP [PMID:29222344, PMID:38426816, PMID:38411462]. Beyond the cytoskeleton, TRIP6 promotes tumorigenesis through AKT activation and p27KIP1 mislocalization and through Wnt/β-catenin activation stabilized by TTPAL and TRIM55 [PMID:23339869, PMID:31018940, PMID:37554583], protects telomeres via association with the shelterin complex [PMID:20634563, PMID:21519191], and is required for brain ciliogenesis in a homodimerization-dependent manner, its loss in mice causing hydrocephalus [PMID:34620853].","teleology":[{"year":1998,"claim":"Establishing TRIP6's domain architecture defined it as a zyxin/LPP-family LIM adaptor and first linked it to nuclear receptor signaling.","evidence":"cDNA cloning, sequence analysis, and yeast two-hybrid against thyroid hormone receptor","pmids":["9598321"],"confidence":"Medium","gaps":["No functional role assigned to the LIM domains","Thyroid hormone receptor interaction not followed up mechanistically"]},{"year":1999,"claim":"Mapping localization determinants showed TRIP6 partitions between focal adhesions and the nucleus and that its LIM region carries intrinsic transactivation potential, raising the question of how shuttling is controlled.","evidence":"Overexpression/deletion mutagenesis with imaging and GAL4 reporter assays in fibroblasts; LIM-domain interaction with PDZ phosphatases by yeast two-hybrid and co-IP","pmids":["10395914","10400701"],"confidence":"Medium","gaps":["Mechanism of nuclear import/export not defined","Endogenous nuclear function not established"]},{"year":2001,"claim":"Identifying a CRM1-dependent NES plus nuclear targeting sequences explained how TRIP6 shuttles, resolving the basis of its dual localization.","evidence":"Leptomycin B treatment, NES mutagenesis, heterologous domain transfer, and reporter/DNA-binding assays","pmids":["11336797"],"confidence":"High","gaps":["Signals controlling import/export switching unknown","TRIP6 does not bind DNA directly, leaving its nuclear mechanism as adaptor only"]},{"year":2003,"claim":"Linking TRIP6 to the LPA2 receptor established it as a receptor-proximal adaptor that assembles a migration machinery, defining its physiological signaling input.","evidence":"Reciprocal co-IP, pulldown, receptor-subtype specificity, siRNA and overexpression with migration assays","pmids":["14688263"],"confidence":"High","gaps":["How LPA-induced binding is regulated downstream not fully resolved","Direct kinase events not yet defined at this stage"]},{"year":2005,"claim":"Defining c-Src phosphorylation of Tyr-55 as a Crk/p130cas docking switch provided the molecular event coupling TRIP6 to ERK signaling and motility.","evidence":"In vitro kinase assay, Src-null cells, Y55F mutagenesis, co-IP, ERK and migration readouts; parallel RIP2/TRAF2 interaction by yeast two-hybrid and NF-κB assays","pmids":["15988003","15657077"],"confidence":"High","gaps":["Phosphatase counteracting Tyr-55 not yet identified","Integration of adhesion and NF-κB roles not yet unified"]},{"year":2004,"claim":"Demonstrating that nuclear TRIP6 coactivates AP-1/NF-κB and tethers glucocorticoid receptor for transrepression established its function as a promoter-bound coregulator.","evidence":"Chromatin immunoprecipitation, RNAi, dominant-negative mutagenesis, and reporter assays","pmids":["15489293"],"confidence":"High","gaps":["Specificity of transcription-factor selection not yet defined","Relationship between cytoplasmic and nuclear pools unclear"]},{"year":2008,"claim":"Showing nTrip6 LIM domains bind Fos but not Jun/ATF2 explained the selectivity of its coactivation and GR transrepression, refining the nuclear mechanism.","evidence":"Co-IP and ChIP with defined AP-1 dimer compositions","pmids":["18535250"],"confidence":"High","gaps":["Structural basis of Fos selectivity not determined","Endogenous nuclear isoform regulation incompletely defined"]},{"year":2007,"claim":"Identifying PTPL1 as the Tyr-55 phosphatase and demonstrating TRIP6's requirement for stress fibers and FA maturation established it as a Rho/Rac-balancing cytoskeletal organizer.","evidence":"In vitro phosphatase assay, catalytic-dead mutants, FRAP, and siRNA with FAK/Rac1/RhoA readouts and rescue","pmids":["17591779","17652164"],"confidence":"High","gaps":["Direct effectors linking TRIP6 to RhoA/Rac1 not defined","Quantitative phosphorylation dynamics in cells not resolved"]},{"year":2010,"claim":"Connecting TRIP6 to Fas, NF-κB p65, shelterin, and the osteoclast sealing zone broadened its roles into apoptosis suppression, telomere protection, and bone resorption.","evidence":"Co-IP, FADD recruitment and apoptosis assays, ChIP and TIF assays, phosphomimetic mutants and bone resorption assays","pmids":["20876301","20634563","20547766","20153803"],"confidence":"High","gaps":["Mechanism of telomere recruitment not defined","Integration across these diverse contexts unclear"]},{"year":2013,"claim":"Demonstrating that TRIP6 bridges p27KIP1 to AKT and drives its mislocalization established a direct pro-tumorigenic mechanism.","evidence":"Co-IP, in-cell AKT kinase assay with phospho-p27T157 antibody, fractionation, siRNA, and xenografts","pmids":["23339869"],"confidence":"High","gaps":["How TRIP6 regulates AKT membrane translocation mechanistically not fully resolved","Skp2-independent pathway incompletely defined"]},{"year":2016,"claim":"Showing TRIP6 recruits TRAF6 and blocks A20/CYLD deubiquitinases revealed how it sustains TRAF6-dependent NF-κB/JNK signaling, later confirmed in vivo for inflammation.","evidence":"Co-IP, shRNA, CRISPR KO, deubiquitinase competition, and reporter assays; KO mouse DSS colitis with TRAF6 oligomerization/autoubiquitination assays","pmids":["27134758","34983535"],"confidence":"High","gaps":["Stoichiometry of TRIP6-TRAF6-DUB competition not quantified","Cell-type specificity of inflammatory role not fully mapped"]},{"year":2017,"claim":"Placing TRIP6 as a vinculin-recruited LATS1/2 inhibitor that competes with MOB1 established it as a mechanotransducer linking junctional tension to YAP activation.","evidence":"siRNA, co-IP, competitive binding assay, tension manipulation, and YAP reporter","pmids":["29222344"],"confidence":"High","gaps":["Structural basis of MOB1 competition not resolved","Quantitative tension thresholds not defined"]},{"year":2024,"claim":"Demonstrating that the three LIM domains bind strained F-actin defined the direct molecular sensor coupling actin tension to LATS1 binding and junctional localization.","evidence":"Domain deletion, conserved-residue LIM point mutagenesis, strained F-actin binding assay, and co-localization/tension experiments; pharmacology and BiFC mechanosensor for junctional localization","pmids":["38426816","38805800"],"confidence":"High","gaps":["Structure of LIM-strained-actin interface not solved","How tension sensing is converted into LATS1 inhibition mechanistically incomplete"]},{"year":2021,"claim":"Showing TRIP6 is required for ependymal/choroid plexus ciliogenesis via homodimerization extended its role to organelle biogenesis and a hydrocephalus phenotype.","evidence":"Mouse knockout, super-resolution localization to pericentriolar material/axoneme, RNAi, and homodimerization inhibition","pmids":["34620853"],"confidence":"High","gaps":["Ciliary partners of TRIP6 not identified","Relationship of ciliogenesis role to its adhesion/Hippo functions unclear"]},{"year":2023,"claim":"Identifying TTPAL, TRIM55, PARD3, and c-Fos partners established that TRIP6 stability and downstream Wnt/AKT/ferroptosis outputs are tuned by ubiquitination and adaptor competition in cancer.","evidence":"Co-IP/MS, ubiquitination and cycloheximide-chase assays, competitive binding, Wnt and GPX4 reporters, and xenograft/metastasis models","pmids":["31018940","37554583","37827326","40672107"],"confidence":"Medium","gaps":["E3 ligases mediating TRIP6 degradation not fully defined","Several oncogenic mechanisms rest on single-lab findings"]},{"year":null,"claim":"How TRIP6's many context-specific roles (adhesion, transcription, mechanosensing, ciliogenesis, telomere protection) are coordinated by a single shuttling adaptor, and the structural basis of its LIM-domain partner selectivity, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of LIM-domain partner discrimination","Mechanisms switching TRIP6 between distinct functional pools not defined","In vivo contributions of nuclear vs cytoplasmic pools not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,9,22,24,25]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8,11,14,32]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,7,16,35]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,17,25,24]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,5,7,16]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[8,14,27,32]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[22,26]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,17]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[28]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[28]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,25,34]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,24,29]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,16,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[22,30,31,35]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[17,35]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[28]}],"complexes":["shelterin"],"partners":["LPA2","TRAF6","LATS1","MOB1","VINCULIN","PTPL1","GR","PARD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15654","full_name":"Thyroid receptor-interacting protein 6","aliases":["Opa-interacting protein 1","OIP-1","Zyxin-related protein 1","ZRP-1"],"length_aa":476,"mass_kda":50.3,"function":"Relays signals from the cell surface to the nucleus to weaken adherens junction and promote actin cytoskeleton reorganization and cell invasiveness. Involved in lysophosphatidic acid-induced cell adhesion and migration. Acts as a transcriptional coactivator for NF-kappa-B and JUN, and mediates the transrepression of these transcription factors induced by glucocorticoid receptor","subcellular_location":"Cytoplasm, cytoskeleton; Cell junction, focal adhesion; Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q15654/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIP6","classification":"Not Classified","n_dependent_lines":83,"n_total_lines":1208,"dependency_fraction":0.06870860927152318},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ANKRD10","stoichiometry":0.2},{"gene":"ANKRD27","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRIP6","total_profiled":1310},"omim":[{"mim_id":"607733","title":"SCRIBBLE PLANAR CELL POLARITY PROTEIN; SCRIB","url":"https://www.omim.org/entry/607733"},{"mim_id":"606021","title":"PRAME NUCLEAR RECEPTOR TRANSCRIPTIONAL REGULATOR; PRAME","url":"https://www.omim.org/entry/606021"},{"mim_id":"606020","title":"OPA-INTERACTING PROTEIN 5; OIP5","url":"https://www.omim.org/entry/606020"},{"mim_id":"606019","title":"EXOSOME COMPONENT 8; EXOSC8","url":"https://www.omim.org/entry/606019"},{"mim_id":"602933","title":"THYROID HORMONE RECEPTOR INTERACTOR 6; TRIP6","url":"https://www.omim.org/entry/602933"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/33684622","citation_count":9,"is_preprint":false},{"pmid":"21519191","id":"PMC_21519191","title":"TRIP6 and LPP, but not Zyxin, are present at a subset of telomeres in human cells.","date":"2011","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/21519191","citation_count":8,"is_preprint":false},{"pmid":"32046874","id":"PMC_32046874","title":"TRIP6 promotes tumorigenic capability through regulating FOXC1 in hepatocellular carcinoma.","date":"2020","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/32046874","citation_count":7,"is_preprint":false},{"pmid":"38426816","id":"PMC_38426816","title":"The ability of the LIMD1 and TRIP6 LIM domains to bind strained f-actin is critical for their tension dependent localization to adherens junctions and association with the Hippo pathway kinase LATS1.","date":"2024","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/38426816","citation_count":6,"is_preprint":false},{"pmid":"38411462","id":"PMC_38411462","title":"TRIP6 promotes neural stem cell maintenance through YAP-mediated Sonic Hedgehog activation.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/38411462","citation_count":5,"is_preprint":false},{"pmid":"32104300","id":"PMC_32104300","title":"TRIP6 regulates the proliferation, migration, invasion and apoptosis of osteosarcoma cells by activating the NF-κB signaling pathway.","date":"2020","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32104300","citation_count":5,"is_preprint":false},{"pmid":"32151960","id":"PMC_32151960","title":"TRIP6 accelerates the proliferation and migration of fetal airway smooth muscle cells by enhancing YAP activation.","date":"2020","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32151960","citation_count":5,"is_preprint":false},{"pmid":"37554583","id":"PMC_37554583","title":"TRIM55 Promotes Proliferation of Hepatocellular Carcinoma Through Stabilizing TRIP6 to Activate Wnt/β-Catenin Signaling.","date":"2023","source":"Journal of hepatocellular carcinoma","url":"https://pubmed.ncbi.nlm.nih.gov/37554583","citation_count":5,"is_preprint":false},{"pmid":"18348201","id":"PMC_18348201","title":"Osteoclast inhibitory peptide-1 (OIP-1) inhibits measles virus nucleocapsid protein stimulated osteoclast formation/activity.","date":"2008","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18348201","citation_count":5,"is_preprint":false},{"pmid":"36833223","id":"PMC_36833223","title":"ABCB1 Amplicon Contains Cyclic AMP Response Element-Driven TRIP6 Gene in Taxane-Resistant MCF-7 Breast Cancer Sublines.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36833223","citation_count":1,"is_preprint":false},{"pmid":"38805800","id":"PMC_38805800","title":"The TRIP6/LATS1 complex constitutes the tension sensor of α-catenin/vinculin at both bicellular and tricellular junctions.","date":"2024","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/38805800","citation_count":1,"is_preprint":false},{"pmid":"40672107","id":"PMC_40672107","title":"TRIP6/c-Fos regulating GPX4 modulates gastric cancer growth by inhibiting ferroptosis.","date":"2025","source":"Journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40672107","citation_count":0,"is_preprint":false},{"pmid":"38178663","id":"PMC_38178663","title":"Circ_0079471 Regulates the Proliferation, Migration, Invasion and Apoptosis of Osteosarcoma Cells by Mediating miR-485-3p and TRIP6.","date":"2025","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38178663","citation_count":0,"is_preprint":false},{"pmid":"40552937","id":"PMC_40552937","title":"Lnc056 Enhances Hair Follicle Stem Cells Proliferation by Binding Transcription Factor HNRNPUL1 to Up-Regulate TRIP6 Expression.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40552937","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30291,"output_tokens":9419,"usd":0.116079,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19714,"output_tokens":5406,"usd":0.11686,"stage2_stop_reason":"end_turn"},"total_usd":0.232939,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"TRIP6 protein displays a proline-rich N-terminal region linked to three tandemly arrayed C-terminal LIM domains, placing it in the same structural family as zyxin and LPP; it was first identified as a ligand-dependent binding partner for the thyroid hormone receptor.\",\n      \"method\": \"cDNA cloning, sequence analysis, yeast two-hybrid\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain architecture established by sequencing and yeast two-hybrid, replicated across multiple labs\",\n      \"pmids\": [\"9598321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TRIP6/ZRP-1 directly interacts with the second PDZ domain of the cytosolic protein tyrosine phosphatase hPTP1E (ZRP-1/TRIP6 LIM domains and intact C-terminus required); interaction demonstrated both in vitro with bacterially expressed proteins and in vivo by co-immunoprecipitation.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding with bacterially expressed proteins, co-immunoprecipitation, deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution with purified proteins plus co-IP in cells, deletion mapping, replicated by Cuppen et al. 2000\",\n      \"pmids\": [\"10400701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Full-length Trip6 localizes to focal adhesion plaques; deletion of the N-terminal 115 amino acids allows Trip6 to enter the nucleus. A GAL4 fusion containing the Trip6 LIM domain region activates transcription in yeast and chicken fibroblasts.\",\n      \"method\": \"Overexpression in chicken embryo fibroblasts, fluorescence microscopy, deletion mutagenesis, GAL4 reporter assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct imaging and reporter assays in two cell systems, single lab\",\n      \"pmids\": [\"10395914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Trip6 LIM domain sequences act as a coactivator for transcriptional activation by v-Rel: GAL4-Trip6 activates transcription in yeast and chicken cells, Trip6 enables C-terminal v-Rel sequences to activate transcription, and Trip6 enhances v-Rel activation from a κB site reporter.\",\n      \"method\": \"Yeast two-hybrid, GAL4 reporter assay, NF-κB reporter assay\",\n      \"journal\": \"Gene expression\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple reporter assays in yeast and chicken cells, single lab\",\n      \"pmids\": [\"10794523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TRIP6 interacts with the PDZ domain of the adaptor protein RIL (second LIM domain of TRIP6 is sufficient for strong interaction) and with the second PDZ domain of PTP-BL (requiring the third LIM domain and intact C-terminus). TRIP6 co-precipitates with RIL and PTP-BL PDZ polypeptides in transfected epithelial cells and co-localizes with RIL at F-actin structures.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, deletion analysis, co-localization by fluorescence microscopy\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus co-IP in cells plus co-localization, domain mapping by deletion, single lab\",\n      \"pmids\": [\"10826496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TRIP6 contains a functional nuclear export signal (NES) dependent on CRM1: leptomycin B treatment sequesters TRIP6 in the nucleus; NES mutation also retains TRIP6 in the nucleus; the Trip6 NES redirects the nuclear v-Rel oncoprotein to the cytoplasm. TRIP6 also harbors at least two nuclear targeting sequences and multiple transactivation domains, but does not bind DNA-cellulose.\",\n      \"method\": \"Leptomycin B treatment, NES mutagenesis, nuclear localization sequence fusion to β-galactosidase, GAL4-reporter assays, DNA-cellulose binding assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (drug treatment, mutagenesis, heterologous domain transfer, reporter assays) in single rigorous study\",\n      \"pmids\": [\"11336797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TRIP6 directly binds to the carboxyl-terminal tail of the LPA2 receptor through its LIM domains; LPA stimulation promotes TRIP6 interaction with the LPA2 receptor, recruits TRIP6 to the plasma membrane and focal adhesions, and induces agonist-dependent association with paxillin, FAK, c-Src, and p130cas. Overexpression of TRIP6 augments LPA-induced cell migration; siRNA-mediated knockdown reduces it. This interaction is specific to LPA2 and not LPA1 or LPA3.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, siRNA knockdown, cell migration assay, fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, direct binding demonstrated, loss-of-function and gain-of-function with defined migration phenotype, receptor specificity established\",\n      \"pmids\": [\"14688263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TRIP6 functions as a coactivator for both AP-1 and NF-κB; a nuclear isoform of TRIP6 (nTrip6) is recruited to AP-1/NF-κB target gene promoters as shown by chromatin immunoprecipitation. In the presence of glucocorticoids, GR joins the Trip6 complex at these promoters, mediating GR tethering-based transrepression. RNAi knockdown of Trip6 or dominant-negative mutation abolishing GR interaction eliminates GR transrepression.\",\n      \"method\": \"Chromatin immunoprecipitation, RNAi knockdown, dominant-negative mutagenesis, reporter assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP evidence of promoter recruitment, loss-of-function by RNAi and dominant-negative, multiple orthogonal methods\",\n      \"pmids\": [\"15489293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TRIP6/ZRP-1 interacts with the cytoplasmic domain of endoglin through its three C-terminal LIM domains. In the absence of endoglin, ZRP-1 localizes to focal adhesions; in the presence of endoglin, ZRP-1 redistributes along actin stress fibers. Endoglin expression causes dramatic reorganization of the actin cytoskeleton from dense F-actin bundles to stress fibers, and siRNA knockdown of endoglin or ZRP-1 or endoglin clustering leads to F-actin mislocalization.\",\n      \"method\": \"Yeast two-hybrid (bait: endoglin cytoplasmic domain), co-immunoprecipitation, deletion mapping, siRNA knockdown, fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — protein interaction mapped by deletion, co-IP, siRNA loss-of-function with defined cytoskeletal phenotype, multiple methods\",\n      \"pmids\": [\"15148318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Src phosphorylates TRIP6 at Tyr-55 upon LPA stimulation; this phosphorylation is absent in Src-null fibroblasts. Phosphotyrosine-55 together with Pro-58 creates a docking site for Crk SH2 domain. Y55F mutation abolishes Crk and p130cas association and significantly reduces LPA-induced ERK activation and cell migration without affecting TRIP6 focal adhesion localization.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibodies, site-directed mutagenesis (Y55F), co-immunoprecipitation, ERK phosphorylation assay, cell migration assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphorylation, mutagenesis, and multiple downstream functional readouts in single study\",\n      \"pmids\": [\"15988003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRIP6 is a RIP2-interacting protein; the LIM domains of TRIP6 mediate binding to RIP2. TRIP6 interacts with RIP2 in a TNF- or IL-1-dependent manner in mammalian cells. Overexpression of TRIP6 potentiates RIP2-mediated NF-κB activation; dominant-negative or siRNA of TRIP6 inhibits NF-κB activation by TNF, IL-1, TLR2, or Nod1. TRIP6 also interacts with TRAF2 and potentiates RIP2- and Nod1-mediated ERK activation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, NF-κB reporter assay, siRNA, dominant-negative overexpression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus co-IP in cells, multiple pathway readouts (NF-κB, ERK), loss- and gain-of-function\",\n      \"pmids\": [\"15657077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Supervillin binds the LIM domains of TRIP6 (and LPP but not zyxin) through a defined sequence (SV342-571). SV and TRIP6 co-localize within large focal adhesions. RNAi reduction of either protein increases cell adhesion to fibronectin. TRIP6 partially rescues SV effects on stress fibers and FAs by mislocalizing SV away from FAs.\",\n      \"method\": \"Pulldown, co-immunoprecipitation, co-localization by fluorescence microscopy, RNAi knockdown, fibronectin adhesion assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding mapped to defined domains, co-localization, reciprocal loss-of-function phenotypes\",\n      \"pmids\": [\"16880273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AMPK phosphorylates TRIP6 in vitro at its N-terminus; the catalytic subunit AMPKα2 physically interacts with TRIP6 in mammalian cells. AMPK action enhances the transcriptional co-activator properties of TRIP6.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro phosphorylation assay, transcriptional reporter assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus co-IP plus reporter assay, single lab\",\n      \"pmids\": [\"16624523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPL1/FAP-1 dephosphorylates phosphotyrosine-55 of TRIP6 in vitro and inhibits LPA-induced tyrosine phosphorylation of TRIP6 in cells. PTPL1-mediated dephosphorylation requires direct PTPL1–TRIP6 protein–protein interaction and PTPL1 phosphatase activity. PTPL1 prevents TRIP6 turnover at adhesion sites and inhibits LPA-induced TRIP6–Crk association and cell migration.\",\n      \"method\": \"In vitro phosphatase assay, co-immunoprecipitation, dominant-negative/phosphatase-dead mutants, cell migration assay, FRAP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro dephosphorylation, catalytic-dead mutant, co-IP, and functional migration readout\",\n      \"pmids\": [\"17591779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ZRP-1/TRIP6 is essential for stress fiber formation, mature focal adhesion assembly, and correct cell-cell adhesion. ZRP-1 depletion reduces FAK tyrosine phosphorylation and elevates Rac1 activity, causing abnormal actin polymerization and membrane protrusions; RhoA overexpression rescues stress fibers in ZRP-1-depleted cells.\",\n      \"method\": \"siRNA knockdown, fluorescence microscopy, focal adhesion quantification, FAK phosphorylation immunoblot, Rac1 activity assay, RhoA rescue experiment\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi loss-of-function with multiple orthogonal readouts (FAK phos, Rac1 activity, rescue by RhoA), single rigorous study\",\n      \"pmids\": [\"17652164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIP6 directly interacts with the fifth PDZ domain of MAGI-1b scaffold; this interaction is mediated by the C-terminal PDZ-binding motif of TRIP6. Ectopic TRIP6 expression induces cell invasion in a PI3K- and NF-κB-dependent manner and impairs cell–cell aggregation at least partly by uncoupling adherens junctions from the cytoskeleton. TRIP6Stop473 (lacking PDZ-binding motif) cannot promote invasion or interfere with cell aggregation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, invasion assay, aggregation assay, PDZ-binding mutant (TRIP6Stop473), PI3K/NF-κB inhibitors\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-specific mutant (Stop473), multiple functional readouts, pharmacological validation\",\n      \"pmids\": [\"19017743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"nTrip6 LIM domains interact selectively with Fos family members (not Jun or ATF2), making nTrip6 a selective coactivator for Fos-containing AP-1 dimers. GR transrepression (via nTrip6 tethering) is restricted to Fos-containing AP-1 dimers; c-Jun:ATF2-driven promoters do not recruit nTrip6 or GR.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays with defined AP-1 dimer composition\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP and co-IP with defined dimer-composition experiments, multiple AP-1 dimers tested, builds on prior lab findings\",\n      \"pmids\": [\"18535250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRIP6 interacts with the cytoplasmic juxtamembrane domain of Fas receptor and interferes with FADD recruitment to Fas, thereby antagonizing Fas-induced apoptosis. TRIP6 also physically interacts with NF-κB p65 and promotes NF-κB nuclear translocation upon Fas activation or LPA stimulation. TRIP6 promotes Fas-mediated cell migration in apoptosis-resistant cells via Src-dependent pTyr-55 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, FADD recruitment assay, apoptosis assay, NF-κB reporter/translocation assay, site-directed mutagenesis (Y55F), cell migration assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple binding interactions demonstrated, mutagenesis of Tyr-55, loss-of-function with defined apoptotic and migratory phenotypes\",\n      \"pmids\": [\"20876301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRIP6 associates with POT1, TRF2, and TIN2 (components of the shelterin complex) by co-immunoprecipitation and is detected at telomeres by ChIP. TRIP6 depletion by siRNA induces telomere dysfunction-induced foci (TIFs), indicating a role in telomere protection.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, TIF assay\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP with shelterin components, ChIP, functional siRNA phenotype, single lab\",\n      \"pmids\": [\"20634563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Src-mediated phosphorylation of TRIP6 at Tyr-55 is required for its localization to the osteoclast sealing zone and for osteoclast bone resorptive capacity. TRIP6 resides in the sealing zone through association with tropomyosin 4. LPA promotes TRIP6 sealing zone association and bone resorption via the LPA2 receptor.\",\n      \"method\": \"RNAi knockdown, overexpression of phosphomimetic (Y55E) and non-phosphorylatable (Y55A/Y55F) TRIP6 mutants, sealing zone perimeter measurement, bone resorption assay, co-immunoprecipitation (with tropomyosin 4), receptor agonist/antagonist pharmacology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphomimetic and non-phosphorylatable mutants, loss- and gain-of-function with defined resorptive phenotype, receptor pharmacology\",\n      \"pmids\": [\"20547766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"nTrip6 is recruited to GR-bound promoters through direct interaction with GR and increases GR-mediated transcription. nTrip6 is also essential for transrepression of GR by NF-κB and AP-1: the interaction of nTrip6 with NF-κB and AP-1 at a GR-bound promoter is required for repression.\",\n      \"method\": \"Chromatin immunoprecipitation, co-immunoprecipitation, reporter assays, siRNA\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus co-IP, single lab, builds on prior work from the same group\",\n      \"pmids\": [\"20153803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIP6 and LPP (but not Zyxin) localize to a subset of telomeres by immunofluorescence and are found in complex with shelterin; Zyxin, despite high similarity, is not detected at telomeres or in a complex with shelterin.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation, comparison among LIM protein family members\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunofluorescence and co-IP in cells, family member specificity established, single lab\",\n      \"pmids\": [\"21519191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRIP6 promotes tumorigenesis by serving as a bridge to recruit p27KIP1 to AKT in the cytosol, facilitating AKT-mediated phosphorylation of p27KIP1 at T157 and its cytosolic mislocalization. TRIP6 also regulates AKT membrane translocation and activation, and promotes serum-induced reduction of nuclear p27KIP1 via Skp2-dependent and -independent mechanisms.\",\n      \"method\": \"Co-immunoprecipitation, AKT kinase assay, phospho-specific antibody for p27T157, subcellular fractionation, siRNA knockdown, xenograft tumor model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, in-cell kinase readout with phospho-antibody, subcellular fractionation, in vivo xenograft validation\",\n      \"pmids\": [\"23339869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Trip6 promotes dendritic morphogenesis in hippocampal neurons through interaction with GRIP1 and myosin VI. Phosphorylation of GRIP1 at T956 by AKT1 inhibits GRIP1–myosin VI interaction but promotes GRIP1 binding to 14-3-3, regulating F-actin organization and dendritic morphogenesis. Trip6 depletion reduces F-actin content and impairs dendritic morphology, phenocopying GRIP1 or myosin VI knockdown.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, phospho-mutant analysis, F-actin staining, dendritic morphology quantification in cultured hippocampal neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP, multiple siRNA phenotypes, phospho-mutant analysis, single lab\",\n      \"pmids\": [\"25673849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIP6 directly binds TRAF6 and recruits it to the LPA2 receptor upon LPA stimulation. TRIP6 antagonizes recruitment of deubiquitinases A20 and CYLD to TRAF6, sustaining TRAF6 E3 ligase activity and augmenting LPA-induced NF-κB and JNK signaling. TRAF6 in turn facilitates TRIP6 binding to NF-κB p65 and c-Src-mediated TRIP6 phosphorylation. TRIP6 shRNA or Cas9/sgRNA depletion enhances A20/CYLD–TRAF6 association and attenuates NF-κB/JNK/p38 activation.\",\n      \"method\": \"Co-immunoprecipitation, shRNA, CRISPR/Cas9 knockout, NF-κB/JNK reporter assays, deubiquitinase competition assay\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, shRNA, CRISPR KO, multiple signaling readouts), bidirectional regulation demonstrated\",\n      \"pmids\": [\"27134758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIP6 inhibits Hippo signaling at adherens junctions in response to mechanical tension: vinculin (activated by tension) recruits TRIP6 to adherens junctions, where TRIP6 binds LATS1/2 and competes with MOB1 for LATS1/2 binding, thereby blocking MST1/2-mediated LATS1/2 activation and promoting YAP activity.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, competitive binding assay (TRIP6 vs MOB1 for LATS1/2), tension manipulation, YAP reporter assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway placement with competitive binding assay, loss-of-function, tension manipulation, multiple readouts\",\n      \"pmids\": [\"29222344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TTPAL directly binds TRIP6 in the cytoplasm (identified by co-IP/mass spectrometry) and inhibits ubiquitin-mediated degradation of TRIP6. Stabilized TRIP6 displaces β-catenin from MAGI1 via competitive binding, allowing β-catenin nuclear entry and activation of Wnt/β-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation followed by mass spectrometry, ubiquitination assay, competitive binding assay, β-catenin localization/reporter assay, siRNA depletion of TRIP6\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-identified interaction, ubiquitination assay, competitive binding, Wnt reporter, TRIP6 loss-of-function rescue\",\n      \"pmids\": [\"31018940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIP6 is required for LIMD1 localization to adherens junctions (but not vice versa), for recruitment of vinculin and VASP to adherens junctions, and for maintenance of apical F-actin and myosin organization. TRIP6 knockdown causes loss of apical actin stress fibers and compensatory increase at basal focal adhesions.\",\n      \"method\": \"siRNA knockdown, fluorescence microscopy, quantification of LIMD1/vinculin/VASP/myosin/F-actin localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — systematic siRNA epistasis, multiple protein localization readouts, single lab\",\n      \"pmids\": [\"33558314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIP6 deletion in mice causes ependymal and choroid plexus epithelial cells to carry fewer and shorter cilia, leading to hydrocephalus. TRIP6 localizes at the pericentriolar material and along the ciliary axoneme (super-resolution microscopy). TRIP6 homodimerization is required for its ciliogenesis function; inhibition of homodimerization in vitro phenocopies Trip6 deletion.\",\n      \"method\": \"Mouse knockout, super-resolution microscopy, RNAi in choroid plexus epithelial cell line, homodimerization inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with defined phenotype, super-resolution localization, in vitro RNAi and homodimerization inhibition corroboration\",\n      \"pmids\": [\"34620853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIP6 binds TRAF6 and enhances TRAF6 oligomerization and autoubiquitination in vivo, leading to NF-κB activation and pro-inflammatory cytokine (TNFα, IL-6) expression. TRIP6-knockout mice develop less severe DSS-induced colitis compared to wild-type, confirming in vivo role.\",\n      \"method\": \"TRIP6-knockout mouse model (DSS colitis), co-immunoprecipitation, TRAF6 oligomerization/autoubiquitination assay, NF-κB signaling assay, cytokine measurement\",\n      \"journal\": \"Journal of inflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model with defined colitis phenotype, TRAF6 biochemical assays (oligomerization, autoubiquitination), consistent with in vitro data\",\n      \"pmids\": [\"34983535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIP6 directly interacts with the PDZ domain-containing polarity protein PARD3 to disrupt tight junctions and activate oncogenic Akt signaling, promoting CRC metastasis. TRIP6-induced pro-metastatic phenotypes and Akt activation depend on PARD3; TRIP6 also inhibits PTEN in this context.\",\n      \"method\": \"Co-immunoprecipitation, tight junction marker quantification, gut permeability assay, siRNA/shRNA knockdown, in vivo mouse metastasis model, nanoparticle-encapsulated siRNA therapeutic experiment\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP, PARD3 epistasis, in vivo model, single lab\",\n      \"pmids\": [\"37827326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM55 directly interacts with TRIP6, regulates TRIP6 protein stability by influencing its ubiquitination, and thereby activates Wnt/β-catenin signaling to promote HCC cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide chase, ubiquitination assay, Wnt reporter, xenograft model\",\n      \"journal\": \"Journal of hepatocellular carcinoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP, ubiquitination assay, CHX chase for stability, single lab\",\n      \"pmids\": [\"37554583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The three LIM domains of TRIP6 are necessary and sufficient for tension-dependent localization to adherens junctions. TRIP6 and LIMD1 LIM domains bind strained/tensioned F-actin; point mutations in a conserved residue in each LIM domain that impairs strained F-actin binding abolishes localization to adherens junctions and ability to bind/recruit LATS1. TRIP6 co-localizes with ends of actin fibers at adherens junctions.\",\n      \"method\": \"Domain deletion analysis, LIM domain point mutagenesis, strained F-actin binding assay, fluorescence microscopy, tension manipulation, co-immunoprecipitation (TRIP6–LATS1)\",\n      \"journal\": \"Cytoskeleton\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro strained actin binding, mutagenesis of conserved residues in all three LIM domains, localization and binding assays\",\n      \"pmids\": [\"38426816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The TRIP6/LATS1 complex co-localizes with α-catenin/vinculin at both bicellular and tricellular junctions; this junctional localization requires ROCK1 and α-catenin and is sensitive to cytochalasin B, Y-27632, and blebbistatin, indicating mechanosensitive localization. A BiFC-based α-catenin/vinculin mechanosensor co-localizes with TRIP6/LATS1.\",\n      \"method\": \"Immunofluorescence, pharmacological perturbation (cytochalasin B, Y-27632, blebbistatin), siRNA knockdown of ROCK1/α-catenin, BiFC mechanosensor\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-localization with pharmacological perturbations and genetic knockdowns, single lab\",\n      \"pmids\": [\"38805800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIP6 recruits protein phosphatase PP1A to dephosphorylate LATS1/2, thereby inducing YAP nuclear localization and activation in postnatal neural stem cells. This TRIP6-YAP axis promotes NSC self-renewal and inhibits differentiation; YAP in turn regulates Gli2 expression to activate Sonic Hedgehog signaling.\",\n      \"method\": \"Co-immunoprecipitation (TRIP6–PP1A), LATS1/2 phosphorylation assay, YAP reporter/immunofluorescence, siRNA knockdown, Gli2 reporter, conditional YAP knockout in mice\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP, phosphorylation assay, reporter, in vivo conditional KO; PP1A recruitment is a novel mechanistic claim from single lab\",\n      \"pmids\": [\"38411462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIP6 binds to and stabilizes the transcription factor c-Fos (verified by co-IP and silver staining); c-Fos then acts as a transcription factor to upregulate GPX4 expression (verified by dual-luciferase reporter), thereby inhibiting ferroptosis in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, silver staining, dual-luciferase reporter assay for GPX4 promoter, ferroptosis inducer/inhibitor rescue experiments\",\n      \"journal\": \"Journal of gastrointestinal oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP binding, luciferase reporter for GPX4, rescue experiments; single lab, new finding\",\n      \"pmids\": [\"40672107\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIP6 is a multi-domain LIM/zyxin-family adaptor that shuttles between focal adhesions and the nucleus via a CRM1-dependent nuclear export signal; at adhesions it integrates signals from LPA2 receptor, endoglin, Fas, and MAGI-1 scaffolds by recruiting and coordinating kinases (c-Src, AKT), phosphatases (PTPL1, PP1A), and cytoskeletal regulators (paxillin, FAK, p130cas, RhoA/Rac1, tropomyosin-4, GRIP1/myosin VI); in the nucleus its Fos-selective LIM domains act as a molecular platform that co-activates AP-1 and NF-κB and mediates glucocorticoid receptor tethering for transrepression; at adherens junctions, TRIP6 senses mechanical tension by binding strained F-actin through its LIM domains, recruits vinculin, and inhibits Hippo pathway LATS1/2 kinases by competing with MOB1, thereby activating YAP; TRIP6 stability is regulated by ubiquitin-mediated degradation counteracted by TTPAL and TRIM55 binding; and TRIP6 also protects telomeres through association with the shelterin complex and is required for brain ciliogenesis in a homodimerization-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIP6 is a multi-domain LIM/zyxin-family adaptor that integrates cell-adhesion and growth-factor signaling at focal adhesions, adherens junctions, and the nucleus, built around a proline-rich N-terminus and three tandem C-terminal LIM domains [#0]. Its subcellular partitioning is governed by N-terminal focal-adhesion targeting and a CRM1-dependent nuclear export signal, so that removal of the N-terminus or NES drives nuclear accumulation [#2, #5]. At the plasma membrane, TRIP6 is recruited by the LPA2 receptor in an agonist-dependent manner, where it nucleates a c-Src/paxillin/FAK/p130cas assembly and drives cell migration [#6]; c-Src phosphorylation of Tyr-55 creates a Crk docking site that couples TRIP6 to ERK activation and motility, an event reversed by the phosphatase PTPL1 [#9, #13]. TRIP6 is essential for stress-fiber formation and mature focal-adhesion assembly, balancing RhoA and Rac1 activity and organizing the actin cytoskeleton in concert with partners including endoglin, supervillin, RIL, and the cytosolic phosphatase hPTP1E [#14, #8, #11, #1, #4]. A nuclear isoform acts as a Fos-selective coactivator platform for AP-1 and NF-\\u03baB and mediates glucocorticoid-receptor tethering for transrepression [#7, #16, #20]. TRIP6 amplifies inflammatory and survival signaling by binding RIP2 and TRAF6, sustaining TRAF6 E3-ligase activity against the deubiquitinases A20/CYLD, and by antagonizing Fas-mediated apoptosis through interference with FADD recruitment [#10, #24, #17, #29]. At adherens junctions TRIP6 functions as a tension sensor: its LIM domains bind strained F-actin, vinculin recruits it under load, and it inhibits Hippo signaling by binding LATS1/2 and competing with MOB1, thereby activating YAP [#25, #32, #34]. Beyond the cytoskeleton, TRIP6 promotes tumorigenesis through AKT activation and p27KIP1 mislocalization and through Wnt/\\u03b2-catenin activation stabilized by TTPAL and TRIM55 [#22, #26, #31], protects telomeres via association with the shelterin complex [#18, #21], and is required for brain ciliogenesis in a homodimerization-dependent manner, its loss in mice causing hydrocephalus [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing TRIP6's domain architecture defined it as a zyxin/LPP-family LIM adaptor and first linked it to nuclear receptor signaling.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and yeast two-hybrid against thyroid hormone receptor\",\n      \"pmids\": [\"9598321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional role assigned to the LIM domains\", \"Thyroid hormone receptor interaction not followed up mechanistically\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapping localization determinants showed TRIP6 partitions between focal adhesions and the nucleus and that its LIM region carries intrinsic transactivation potential, raising the question of how shuttling is controlled.\",\n      \"evidence\": \"Overexpression/deletion mutagenesis with imaging and GAL4 reporter assays in fibroblasts; LIM-domain interaction with PDZ phosphatases by yeast two-hybrid and co-IP\",\n      \"pmids\": [\"10395914\", \"10400701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear import/export not defined\", \"Endogenous nuclear function not established\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying a CRM1-dependent NES plus nuclear targeting sequences explained how TRIP6 shuttles, resolving the basis of its dual localization.\",\n      \"evidence\": \"Leptomycin B treatment, NES mutagenesis, heterologous domain transfer, and reporter/DNA-binding assays\",\n      \"pmids\": [\"11336797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling import/export switching unknown\", \"TRIP6 does not bind DNA directly, leaving its nuclear mechanism as adaptor only\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linking TRIP6 to the LPA2 receptor established it as a receptor-proximal adaptor that assembles a migration machinery, defining its physiological signaling input.\",\n      \"evidence\": \"Reciprocal co-IP, pulldown, receptor-subtype specificity, siRNA and overexpression with migration assays\",\n      \"pmids\": [\"14688263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LPA-induced binding is regulated downstream not fully resolved\", \"Direct kinase events not yet defined at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defining c-Src phosphorylation of Tyr-55 as a Crk/p130cas docking switch provided the molecular event coupling TRIP6 to ERK signaling and motility.\",\n      \"evidence\": \"In vitro kinase assay, Src-null cells, Y55F mutagenesis, co-IP, ERK and migration readouts; parallel RIP2/TRAF2 interaction by yeast two-hybrid and NF-\\u03baB assays\",\n      \"pmids\": [\"15988003\", \"15657077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase counteracting Tyr-55 not yet identified\", \"Integration of adhesion and NF-\\u03baB roles not yet unified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that nuclear TRIP6 coactivates AP-1/NF-\\u03baB and tethers glucocorticoid receptor for transrepression established its function as a promoter-bound coregulator.\",\n      \"evidence\": \"Chromatin immunoprecipitation, RNAi, dominant-negative mutagenesis, and reporter assays\",\n      \"pmids\": [\"15489293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specificity of transcription-factor selection not yet defined\", \"Relationship between cytoplasmic and nuclear pools unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing nTrip6 LIM domains bind Fos but not Jun/ATF2 explained the selectivity of its coactivation and GR transrepression, refining the nuclear mechanism.\",\n      \"evidence\": \"Co-IP and ChIP with defined AP-1 dimer compositions\",\n      \"pmids\": [\"18535250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Fos selectivity not determined\", \"Endogenous nuclear isoform regulation incompletely defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying PTPL1 as the Tyr-55 phosphatase and demonstrating TRIP6's requirement for stress fibers and FA maturation established it as a Rho/Rac-balancing cytoskeletal organizer.\",\n      \"evidence\": \"In vitro phosphatase assay, catalytic-dead mutants, FRAP, and siRNA with FAK/Rac1/RhoA readouts and rescue\",\n      \"pmids\": [\"17591779\", \"17652164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct effectors linking TRIP6 to RhoA/Rac1 not defined\", \"Quantitative phosphorylation dynamics in cells not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connecting TRIP6 to Fas, NF-\\u03baB p65, shelterin, and the osteoclast sealing zone broadened its roles into apoptosis suppression, telomere protection, and bone resorption.\",\n      \"evidence\": \"Co-IP, FADD recruitment and apoptosis assays, ChIP and TIF assays, phosphomimetic mutants and bone resorption assays\",\n      \"pmids\": [\"20876301\", \"20634563\", \"20547766\", \"20153803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of telomere recruitment not defined\", \"Integration across these diverse contexts unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that TRIP6 bridges p27KIP1 to AKT and drives its mislocalization established a direct pro-tumorigenic mechanism.\",\n      \"evidence\": \"Co-IP, in-cell AKT kinase assay with phospho-p27T157 antibody, fractionation, siRNA, and xenografts\",\n      \"pmids\": [\"23339869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRIP6 regulates AKT membrane translocation mechanistically not fully resolved\", \"Skp2-independent pathway incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing TRIP6 recruits TRAF6 and blocks A20/CYLD deubiquitinases revealed how it sustains TRAF6-dependent NF-\\u03baB/JNK signaling, later confirmed in vivo for inflammation.\",\n      \"evidence\": \"Co-IP, shRNA, CRISPR KO, deubiquitinase competition, and reporter assays; KO mouse DSS colitis with TRAF6 oligomerization/autoubiquitination assays\",\n      \"pmids\": [\"27134758\", \"34983535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of TRIP6-TRAF6-DUB competition not quantified\", \"Cell-type specificity of inflammatory role not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placing TRIP6 as a vinculin-recruited LATS1/2 inhibitor that competes with MOB1 established it as a mechanotransducer linking junctional tension to YAP activation.\",\n      \"evidence\": \"siRNA, co-IP, competitive binding assay, tension manipulation, and YAP reporter\",\n      \"pmids\": [\"29222344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MOB1 competition not resolved\", \"Quantitative tension thresholds not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that the three LIM domains bind strained F-actin defined the direct molecular sensor coupling actin tension to LATS1 binding and junctional localization.\",\n      \"evidence\": \"Domain deletion, conserved-residue LIM point mutagenesis, strained F-actin binding assay, and co-localization/tension experiments; pharmacology and BiFC mechanosensor for junctional localization\",\n      \"pmids\": [\"38426816\", \"38805800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of LIM-strained-actin interface not solved\", \"How tension sensing is converted into LATS1 inhibition mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing TRIP6 is required for ependymal/choroid plexus ciliogenesis via homodimerization extended its role to organelle biogenesis and a hydrocephalus phenotype.\",\n      \"evidence\": \"Mouse knockout, super-resolution localization to pericentriolar material/axoneme, RNAi, and homodimerization inhibition\",\n      \"pmids\": [\"34620853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ciliary partners of TRIP6 not identified\", \"Relationship of ciliogenesis role to its adhesion/Hippo functions unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying TTPAL, TRIM55, PARD3, and c-Fos partners established that TRIP6 stability and downstream Wnt/AKT/ferroptosis outputs are tuned by ubiquitination and adaptor competition in cancer.\",\n      \"evidence\": \"Co-IP/MS, ubiquitination and cycloheximide-chase assays, competitive binding, Wnt and GPX4 reporters, and xenograft/metastasis models\",\n      \"pmids\": [\"31018940\", \"37554583\", \"37827326\", \"40672107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligases mediating TRIP6 degradation not fully defined\", \"Several oncogenic mechanisms rest on single-lab findings\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIP6's many context-specific roles (adhesion, transcription, mechanosensing, ciliogenesis, telomere protection) are coordinated by a single shuttling adaptor, and the structural basis of its LIM-domain partner selectivity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of LIM-domain partner discrimination\", \"Mechanisms switching TRIP6 between distinct functional pools not defined\", \"In vivo contributions of nuclear vs cytoplasmic pools not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 9, 22, 24, 25]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8, 11, 14, 32]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 7, 16, 35]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 17, 25, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [2, 6, 14, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 5, 7, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [8, 14, 27, 32]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [22, 26]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 17]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [28]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 25, 34]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 24, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 16, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [22, 30, 31, 35]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [17, 35]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"complexes\": [\"shelterin\"],\n    \"partners\": [\"LPA2\", \"TRAF6\", \"LATS1\", \"MOB1\", \"vinculin\", \"PTPL1\", \"GR\", \"PARD3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}