Affinage

TRIP6

Thyroid receptor-interacting protein 6 · UniProt Q15654

Length
476 aa
Mass
50.3 kDa
Annotated
2026-06-10
61 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 Medium

    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

    PMID:9598321

    Open questions at the time
    • No functional role assigned to the LIM domains
    • Thyroid hormone receptor interaction not followed up mechanistically
  2. 1999 Medium

    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

    PMID:10395914 PMID:10400701

    Open questions at the time
    • Mechanism of nuclear import/export not defined
    • Endogenous nuclear function not established
  3. 2001 High

    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

    PMID:11336797

    Open questions at the time
    • Signals controlling import/export switching unknown
    • TRIP6 does not bind DNA directly, leaving its nuclear mechanism as adaptor only
  4. 2003 High

    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

    PMID:14688263

    Open questions at the time
    • How LPA-induced binding is regulated downstream not fully resolved
    • Direct kinase events not yet defined at this stage
  5. 2005 High

    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

    PMID:15657077 PMID:15988003

    Open questions at the time
    • Phosphatase counteracting Tyr-55 not yet identified
    • Integration of adhesion and NF-κB roles not yet unified
  6. 2004 High

    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

    PMID:15489293

    Open questions at the time
    • Specificity of transcription-factor selection not yet defined
    • Relationship between cytoplasmic and nuclear pools unclear
  7. 2008 High

    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

    PMID:18535250

    Open questions at the time
    • Structural basis of Fos selectivity not determined
    • Endogenous nuclear isoform regulation incompletely defined
  8. 2007 High

    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

    PMID:17591779 PMID:17652164

    Open questions at the time
    • Direct effectors linking TRIP6 to RhoA/Rac1 not defined
    • Quantitative phosphorylation dynamics in cells not resolved
  9. 2010 High

    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

    PMID:20153803 PMID:20547766 PMID:20634563 PMID:20876301

    Open questions at the time
    • Mechanism of telomere recruitment not defined
    • Integration across these diverse contexts unclear
  10. 2013 High

    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

    PMID:23339869

    Open questions at the time
    • How TRIP6 regulates AKT membrane translocation mechanistically not fully resolved
    • Skp2-independent pathway incompletely defined
  11. 2016 High

    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

    PMID:27134758 PMID:34983535

    Open questions at the time
    • Stoichiometry of TRIP6-TRAF6-DUB competition not quantified
    • Cell-type specificity of inflammatory role not fully mapped
  12. 2017 High

    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

    PMID:29222344

    Open questions at the time
    • Structural basis of MOB1 competition not resolved
    • Quantitative tension thresholds not defined
  13. 2024 High

    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

    PMID:38426816 PMID:38805800

    Open questions at the time
    • Structure of LIM-strained-actin interface not solved
    • How tension sensing is converted into LATS1 inhibition mechanistically incomplete
  14. 2021 High

    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

    PMID:34620853

    Open questions at the time
    • Ciliary partners of TRIP6 not identified
    • Relationship of ciliogenesis role to its adhesion/Hippo functions unclear
  15. 2023 Medium

    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

    PMID:31018940 PMID:37554583 PMID:37827326 PMID:40672107

    Open questions at the time
    • E3 ligases mediating TRIP6 degradation not fully defined
    • Several oncogenic mechanisms rest on single-lab findings

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0008092 cytoskeletal protein binding 4 GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 4
Localization
GO:0005634 nucleus 4 GO:0005856 cytoskeleton 4 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005815 microtubule organizing center 1 GO:0005929 cilium 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
GRLATS1LPA2MOB1PARD3PTPL1TRAF6VINCULIN
Complex memberships
shelterin

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. cDNA cloning, sequence analysis, yeast two-hybrid Genomics Medium 9598321
1999 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. Yeast two-hybrid, in vitro binding with bacterially expressed proteins, co-immunoprecipitation, deletion analysis The Journal of biological chemistry High 10400701
1999 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. Overexpression in chicken embryo fibroblasts, fluorescence microscopy, deletion mutagenesis, GAL4 reporter assay Gene Medium 10395914
1999 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. Yeast two-hybrid, GAL4 reporter assay, NF-κB reporter assay Gene expression Medium 10794523
2000 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. Yeast two-hybrid, co-immunoprecipitation, deletion analysis, co-localization by fluorescence microscopy European journal of cell biology Medium 10826496
2001 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. Leptomycin B treatment, NES mutagenesis, nuclear localization sequence fusion to β-galactosidase, GAL4-reporter assays, DNA-cellulose binding assay Biochimica et biophysica acta High 11336797
2003 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. Co-immunoprecipitation, pulldown, siRNA knockdown, cell migration assay, fluorescence microscopy The Journal of biological chemistry High 14688263
2004 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. Chromatin immunoprecipitation, RNAi knockdown, dominant-negative mutagenesis, reporter assays Genes & development High 15489293
2004 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. Yeast two-hybrid (bait: endoglin cytoplasmic domain), co-immunoprecipitation, deletion mapping, siRNA knockdown, fluorescence microscopy The Journal of biological chemistry High 15148318
2005 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. In vitro kinase assay, phospho-specific antibodies, site-directed mutagenesis (Y55F), co-immunoprecipitation, ERK phosphorylation assay, cell migration assay Molecular and cellular biology High 15988003
2005 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. Yeast two-hybrid, co-immunoprecipitation, NF-κB reporter assay, siRNA, dominant-negative overexpression Journal of cell science High 15657077
2006 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. Pulldown, co-immunoprecipitation, co-localization by fluorescence microscopy, RNAi knockdown, fibronectin adhesion assay The Journal of cell biology High 16880273
2006 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. Yeast two-hybrid, co-immunoprecipitation, in vitro phosphorylation assay, transcriptional reporter assay Cellular signalling Medium 16624523
2007 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. In vitro phosphatase assay, co-immunoprecipitation, dominant-negative/phosphatase-dead mutants, cell migration assay, FRAP The Journal of biological chemistry High 17591779
2007 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. siRNA knockdown, fluorescence microscopy, focal adhesion quantification, FAK phosphorylation immunoblot, Rac1 activity assay, RhoA rescue experiment Journal of cell science High 17652164
2008 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. Yeast two-hybrid, co-immunoprecipitation, invasion assay, aggregation assay, PDZ-binding mutant (TRIP6Stop473), PI3K/NF-κB inhibitors FASEB journal High 19017743
2008 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. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays with defined AP-1 dimer composition Molecular endocrinology High 18535250
2010 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. Co-immunoprecipitation, FADD recruitment assay, apoptosis assay, NF-κB reporter/translocation assay, site-directed mutagenesis (Y55F), cell migration assay Molecular and cellular biology High 20876301
2010 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. Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, TIF assay Aging Medium 20634563
2010 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. 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 The Journal of biological chemistry High 20547766
2010 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. Chromatin immunoprecipitation, co-immunoprecipitation, reporter assays, siRNA Molecular and cellular endocrinology Medium 20153803
2011 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. Immunofluorescence, co-immunoprecipitation, comparison among LIM protein family members Cell cycle Medium 21519191
2013 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. Co-immunoprecipitation, AKT kinase assay, phospho-specific antibody for p27T157, subcellular fractionation, siRNA knockdown, xenograft tumor model Molecular and cellular biology High 23339869
2015 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. Co-immunoprecipitation, siRNA knockdown, phospho-mutant analysis, F-actin staining, dendritic morphology quantification in cultured hippocampal neurons The Journal of neuroscience Medium 25673849
2016 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. Co-immunoprecipitation, shRNA, CRISPR/Cas9 knockout, NF-κB/JNK reporter assays, deubiquitinase competition assay Cell discovery High 27134758
2017 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. siRNA knockdown, co-immunoprecipitation, competitive binding assay (TRIP6 vs MOB1 for LATS1/2), tension manipulation, YAP reporter assay EMBO reports High 29222344
2019 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. Co-immunoprecipitation followed by mass spectrometry, ubiquitination assay, competitive binding assay, β-catenin localization/reporter assay, siRNA depletion of TRIP6 Cancer research High 31018940
2021 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. siRNA knockdown, fluorescence microscopy, quantification of LIMD1/vinculin/VASP/myosin/F-actin localization Journal of cell science Medium 33558314
2021 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. Mouse knockout, super-resolution microscopy, RNAi in choroid plexus epithelial cell line, homodimerization inhibition Nature communications High 34620853
2022 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. TRIP6-knockout mouse model (DSS colitis), co-immunoprecipitation, TRAF6 oligomerization/autoubiquitination assay, NF-κB signaling assay, cytokine measurement Journal of inflammation High 34983535
2023 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. Co-immunoprecipitation, tight junction marker quantification, gut permeability assay, siRNA/shRNA knockdown, in vivo mouse metastasis model, nanoparticle-encapsulated siRNA therapeutic experiment Cancer letters Medium 37827326
2023 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. Co-immunoprecipitation, cycloheximide chase, ubiquitination assay, Wnt reporter, xenograft model Journal of hepatocellular carcinoma Medium 37554583
2024 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. Domain deletion analysis, LIM domain point mutagenesis, strained F-actin binding assay, fluorescence microscopy, tension manipulation, co-immunoprecipitation (TRIP6–LATS1) Cytoskeleton High 38426816
2024 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. Immunofluorescence, pharmacological perturbation (cytochalasin B, Y-27632, blebbistatin), siRNA knockdown of ROCK1/α-catenin, BiFC mechanosensor European journal of cell biology Medium 38805800
2024 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. Co-immunoprecipitation (TRIP6–PP1A), LATS1/2 phosphorylation assay, YAP reporter/immunofluorescence, siRNA knockdown, Gli2 reporter, conditional YAP knockout in mice FASEB journal Medium 38411462
2025 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. Co-immunoprecipitation, silver staining, dual-luciferase reporter assay for GPX4 promoter, ferroptosis inducer/inhibitor rescue experiments Journal of gastrointestinal oncology Medium 40672107

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Endoglin regulates cytoskeletal organization through binding to ZRP-1, a member of the Lim family of proteins. The Journal of biological chemistry 122 15148318
2004 A nuclear isoform of the focal adhesion LIM-domain protein Trip6 integrates activating and repressing signals at AP-1- and NF-kappaB-regulated promoters. Genes & development 84 15489293
2003 TRIP6 enhances lysophosphatidic acid-induced cell migration by interacting with the lysophosphatidic acid 2 receptor. The Journal of biological chemistry 79 14688263
2001 LIM domain protein Trip6 has a conserved nuclear export signal, nuclear targeting sequences, and multiple transactivation domains. Biochimica et biophysica acta 75 11336797
1998 The human TRIP6 gene encodes a LIM domain protein and maps to chromosome 7q22, a region associated with tumorigenesis. Genomics 72 9598321
2000 The zyxin-related protein TRIP6 interacts with PDZ motifs in the adaptor protein RIL and the protein tyrosine phosphatase PTP-BL. European journal of cell biology 64 10826496
2017 TRIP6 inhibits Hippo signaling in response to tension at adherens junctions. EMBO reports 61 29222344
2008 TRIP6, a novel molecular partner of the MAGI-1 scaffolding molecule, promotes invasiveness. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 57 19017743
2011 TRIP6: an adaptor protein that regulates cell motility, antiapoptotic signaling and transcriptional activity. Cellular signalling 54 21689746
1999 ZRP-1, a zyxin-related protein, interacts with the second PDZ domain of the cytosolic protein tyrosine phosphatase hPTP1E. The Journal of biological chemistry 51 10400701
2005 c-Src-mediated phosphorylation of TRIP6 regulates its function in lysophosphatidic acid-induced cell migration. Molecular and cellular biology 50 15988003
2006 Supervillin modulation of focal adhesions involving TRIP6/ZRP-1. The Journal of cell biology 49 16880273
2008 Restriction to Fos family members of Trip6-dependent coactivation and glucocorticoid receptor-dependent trans-repression of activator protein-1. Molecular endocrinology (Baltimore, Md.) 48 18535250
2005 TRIP6 is a RIP2-associated common signaling component of multiple NF-kappaB activation pathways. Journal of cell science 47 15657077
2019 TTPAL Promotes Colorectal Tumorigenesis by Stabilizing TRIP6 to Activate Wnt/β-Catenin Signaling. Cancer research 40 31018940
2010 The adaptor protein TRIP6 antagonizes Fas-induced apoptosis but promotes its effect on cell migration. Molecular and cellular biology 36 20876301
1999 Characterization of mouse Trip6: a putative intracellular signaling protein. Gene 36 10395914
2011 Defining the role of TRIP6 in cell physiology and cancer. Biology of the cell 35 22054418
1999 LIM domain-containing protein trip6 can act as a coactivator for the v-Rel transcription factor. Gene expression 30 10794523
2007 PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration. The Journal of biological chemistry 27 17591779
2006 TRIP6 transcriptional co-activator is a novel substrate of AMP-activated protein kinase. Cellular signalling 27 16624523
2013 The Zyxin-related protein thyroid receptor interacting protein 6 (TRIP6) is overexpressed in Ewing's sarcoma and promotes migration, invasion and cell growth. Biology of the cell 26 24033704
2007 ZRP-1 controls Rho GTPase-mediated actin reorganization by localizing at cell-matrix and cell-cell adhesions. Journal of cell science 25 17652164
2019 MiR-485-3p modulates neural stem cell differentiation and proliferation via regulating TRIP6 expression. Journal of cellular and molecular medicine 24 31730275
2013 TRIP6 regulates p27 KIP1 to promote tumorigenesis. Molecular and cellular biology 24 23339869
2010 LIM-domain proteins TRIP6 and LPP associate with shelterin to mediate telomere protection. Aging 24 20634563
2010 c-Src-mediated phosphorylation of thyroid hormone receptor-interacting protein 6 (TRIP6) promotes osteoclast sealing zone formation. The Journal of biological chemistry 23 20547766
2017 TRIP6 promotes cell proliferation in hepatocellular carcinoma via suppression of FOXO3a. Biochemical and biophysical research communications 21 29080747
2017 MicroRNA‑138‑5p regulates neural stem cell proliferation and differentiation in vitro by targeting TRIP6 expression. Molecular medicine reports 20 28944841
2020 TRIP6 enhances stemness property of breast cancer cells through activation of Wnt/β-catenin. Cancer cell international 19 32082081
2019 TRIP6, as a target of miR-7, regulates the proliferation and metastasis of colorectal cancer cells. Biochemical and biophysical research communications 19 31029422
2015 Overexpression of TRIP6 promotes tumor proliferation and reverses cell adhesion-mediated drug resistance (CAM-DR) via regulating nuclear p27(Kip1) expression in non-Hodgkin's lymphoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 19 26298725
2010 The nuclear isoform of the LIM domain protein Trip6 integrates activating and repressing signals at the promoter-bound glucocorticoid receptor. Molecular and cellular endocrinology 19 20153803
2007 ODF1 phosphorylation by Cdk5/p35 enhances ODF1-OIP1 interaction. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 19 17762160
2016 TRIP6 antagonizes the recruitment of A20 and CYLD to TRAF6 to promote the LPA2 receptor-mediated TRAF6 activation. Cell discovery 18 27134758
2005 [Down-regulation of TRIP6 expression induces actin cytoskeleton rearrangements in human carcinoma cell lines]. Molekuliarnaia biologiia 18 16240724
2023 TRIP6 disrupts tight junctions to promote metastasis and drug resistance and is a therapeutic target in colorectal cancer. Cancer letters 17 37827326
2003 Novel RING finger protein OIP1 binds to conserved amino acid repeats in sperm tail protein ODF1. Biology of reproduction 16 12533418
2019 TRIP6 functions as a potential oncogene and facilitated proliferation and metastasis of gastric cancer. Biologics : targets & therapy 14 31354238
2021 TRIP6 is required for tension at adherens junctions. Journal of cell science 12 33558314
2021 The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes. International journal of molecular sciences 12 35008510
2015 Trip6 promotes dendritic morphogenesis through dephosphorylated GRIP1-dependent myosin VI and F-actin organization. The Journal of neuroscience : the official journal of the Society for Neuroscience 12 25673849
2013 Characterization of TRIP6-dependent nasopharyngeal cancer cell migration. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 23576104
2021 TRIP6 functions in brain ciliogenesis. Nature communications 11 34620853
2014 TRIP6 regulates neural stem cell maintenance in the postnatal mammalian subventricular zone. Developmental dynamics : an official publication of the American Association of Anatomists 11 25044744
2022 TRIP6 promotes inflammatory damage via the activation of TRAF6 signaling in a murine model of DSS-induced colitis. Journal of inflammation (London, England) 10 34983535
2021 PTPN14 deficiency alleviates podocyte injury through suppressing inflammation and fibrosis by targeting TRIP6 in diabetic nephropathy. Biochemical and biophysical research communications 9 33684622
2020 TRIP6 accelerates the proliferation and invasion of cervical cancer by upregulating oncogenic YAP signaling. Experimental cell research 9 32853630
2011 TRIP6 and LPP, but not Zyxin, are present at a subset of telomeres in human cells. Cell cycle (Georgetown, Tex.) 8 21519191
2020 TRIP6 promotes tumorigenic capability through regulating FOXC1 in hepatocellular carcinoma. Pathology, research and practice 7 32046874
2024 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. Cytoskeleton (Hoboken, N.J.) 6 38426816
2024 TRIP6 promotes neural stem cell maintenance through YAP-mediated Sonic Hedgehog activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 5 38411462
2023 TRIM55 Promotes Proliferation of Hepatocellular Carcinoma Through Stabilizing TRIP6 to Activate Wnt/β-Catenin Signaling. Journal of hepatocellular carcinoma 5 37554583
2020 TRIP6 regulates the proliferation, migration, invasion and apoptosis of osteosarcoma cells by activating the NF-κB signaling pathway. Experimental and therapeutic medicine 5 32104300
2020 TRIP6 accelerates the proliferation and migration of fetal airway smooth muscle cells by enhancing YAP activation. International immunopharmacology 5 32151960
2008 Osteoclast inhibitory peptide-1 (OIP-1) inhibits measles virus nucleocapsid protein stimulated osteoclast formation/activity. Journal of cellular biochemistry 5 18348201
2024 The TRIP6/LATS1 complex constitutes the tension sensor of α-catenin/vinculin at both bicellular and tricellular junctions. European journal of cell biology 1 38805800
2023 ABCB1 Amplicon Contains Cyclic AMP Response Element-Driven TRIP6 Gene in Taxane-Resistant MCF-7 Breast Cancer Sublines. Genes 1 36833223
2025 Circ_0079471 Regulates the Proliferation, Migration, Invasion and Apoptosis of Osteosarcoma Cells by Mediating miR-485-3p and TRIP6. Current medicinal chemistry 0 38178663
2025 Lnc056 Enhances Hair Follicle Stem Cells Proliferation by Binding Transcription Factor HNRNPUL1 to Up-Regulate TRIP6 Expression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 40552937
2025 TRIP6/c-Fos regulating GPX4 modulates gastric cancer growth by inhibiting ferroptosis. Journal of gastrointestinal oncology 0 40672107

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