Affinage

TRIO

Triple functional domain protein · UniProt O75962

Length
3097 aa
Mass
346.9 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 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

TRIO is a multidomain Rho-family guanine nucleotide exchange factor that couples cell-surface receptor signaling to actin cytoskeletal remodeling, governing axon guidance, neuronal migration, synapse formation, and morphogenetic cell movements (PMID:11050238, PMID:18212043). Its two catalytic GEF domains are functionally specialized: the N-terminal GEF1 domain activates Rac1 (and RhoG) to drive membrane ruffling, spreading, and migration, while the C-terminal GEF2 domain activates RhoA, and these activities can be experimentally separated by domain-specific constructs and the GEF1-selective inhibitor ITX3 (PMID:10341202, PMID:19549603, PMID:34914033). GEF1 catalytic output is held in check by an intramolecular autoinhibitory contact in which spectrin repeats 6-9 engage the GEF1 pleckstrin-homology region to reduce Rac1 binding; neurodevelopmental-disorder variants in SR8 and GEF1 relieve this constraint, and the GEF1 mutation D1368V drives pathological glutamatergic synaptogenesis (PMID:35963430, PMID:34353896). TRIO is deployed downstream of multiple receptors through distinct adaptors: it binds the netrin receptor DCC/Frazzled to mediate Rac1-dependent commissural axon guidance and neurite outgrowth (PMID:18212043, PMID:15790972), acts as a major Gαq effector that synergizes with PLCβ to activate RhoA (PMID:17942708), and is recruited by VE-cadherin, CDH11, the TWEAK-Fn14 axis, and VEGF/Flt1 signaling to control endothelial junctions, tumor cell migration, and arterial caliber via local Rac1/RhoG activation (PMID:26116572, PMID:22593800, PMID:22571869, PMID:33087700). TRIO function is tuned by phosphorylation—by FAK at Y2737, by Cdk5, and by ABL at Y2681 downstream of a NOTCH-DAB1-ABL cascade that promotes RhoA-driven cancer invasion (PMID:12551902, PMID:15331630, PMID:25432929). In the nervous system TRIO and its paralog Kalirin act redundantly as the CaMKII targets required for synaptic AMPA receptor upregulation during LTP, and TRIO controls dendritic branching, synapse number, radial migration, and spatial learning, with conditional loss producing reduced forebrain size, spine and LTP deficits, and a PDE4A5-PKA signaling imbalance (PMID:26858404, PMID:26721934, PMID:30840899, PMID:25727174). TRIO additionally scaffolds membrane trafficking through Hsc70 and a Golgi-localized spectrin-repeat interaction with RABIN8 that activates RAB8/RAB10, and engages Myosin X via its SH3 domain to regulate N-cadherin-dependent adhesion during migration (PMID:26323693, PMID:31152060, PMID:34914033). Beyond neurons, GEF1-driven Rac1 activation directs invadopodia disassembly and apical constriction during epithelial morphogenesis (PMID:24859002, PMID:22031541).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 Medium

    Established that Trio's two GEF domains are functionally distinct effectors of cytoskeletal change, with GEF1 driving ruffling/migration/transformation and GEF2 a separate lamellar phenotype.

    Evidence Stable expression of individual GEF domains in NIH 3T3/COS cells with actin staining, haptotaxis, and soft-agar growth assays

    PMID:10341202

    Open questions at the time
    • No in vitro biochemical reconstitution of GEF activity
    • GTPase specificity of each domain not directly defined here
  2. 2000 High

    Defined Trio as essential in vivo, linking it to skeletal muscle formation and neural tissue organization through a loss-of-function embryonic phenotype.

    Evidence Constitutive trio-/- mouse knockout with histology across muscle and brain

    PMID:11050238

    Open questions at the time
    • Did not resolve which GEF domain or GTPase mediates each tissue defect
    • Cell-autonomous vs non-autonomous mechanism unaddressed
  3. 2003 Medium

    Showed Trio is integrated with focal adhesion signaling, binding and reciprocally activating FAK and being phosphorylated at Y2737.

    Evidence Reciprocal Co-IP, immunofluorescence co-localization, in vitro kinase assay and phosphopeptide mapping

    PMID:12551902

    Open questions at the time
    • Functional consequence of Y2737 phosphorylation for GEF activity not established
    • Single-lab in vitro kinase data
  4. 2004 Medium

    Connected Trio to regulated exocytosis, showing Cdk5 phosphorylation gates Trio-dependent Rac activation and secretory granule trafficking.

    Evidence Co-IP with PAM, in vitro Cdk5 kinase assay, Rac activation assay, roscovitine inhibition with ultrastructural readout

    PMID:15331630

    Open questions at the time
    • Cdk5 phosphosites not mapped to functional residues
    • Pharmacological Cdk5 inhibition not isoform-specific
  5. 2005 High

    Placed Trio genetically downstream of Netrin/Frazzled axon guidance and as an ABL phosphorylation target in Drosophila.

    Evidence GST-pulldown, Co-IP, genetic epistasis across allele combinations, S2 cell phosphorylation

    PMID:15790972

    Open questions at the time
    • Which GTPase mediates Frazzled output not resolved in this study
    • ABL phosphosite not mapped here
  6. 2007 High

    Identified the Trio/UNC-73 RhoGEF domain as a major Gαq effector activating RhoA in synergy with PLCβ, defining a parallel Gq output.

    Evidence Forward genetic suppressor screen, double-mutant epistasis, cell-based and biochemical Rho activation assays, Co-IP in C. elegans

    PMID:17942708

    Open questions at the time
    • Direct mammalian Gαq-Trio biochemistry not shown here
    • Structural basis of Gαq-RhoGEF synergy unresolved
  7. 2008 High

    Demonstrated Trio physically links the netrin receptor DCC to Rac1 activation required for commissural axon guidance in mammals.

    Evidence Co-IP from embryonic brain, Trio-/- neurite/explant guidance assays, in vivo axon tract analysis

    PMID:18212043

    Open questions at the time
    • Mechanism of DCC-induced Trio activation not defined
    • Role of GEF2/RhoA in guidance unaddressed
  8. 2009 Medium

    Provided a selective chemical tool (ITX3) confirming a discrete Trio/RhoG/Rac1 pathway controlling neurite outgrowth and myotube differentiation.

    Evidence Inhibitor screen against TrioN/GEF1, Rac1 activation, ruffling, neurite and myotube differentiation assays

    PMID:19549603

    Open questions at the time
    • Off-target profile beyond tested GEFs not exhaustive
    • In vivo efficacy not tested
  9. 2011 Medium

    Established Trio as the RhoA-GEF executing Shroom3-driven apical constriction during epithelial invagination.

    Evidence siRNA, dominant-negative/constitutively active RhoA, Rock inhibition, in vivo lens pit assay

    PMID:22031541

    Open questions at the time
    • How Shroom3 recruits/activates Trio not defined
    • Single-lab knockdown evidence
  10. 2012 Medium

    Extended Trio's Rac1-GEF role to cancer cell migration via CDH11- and TWEAK-Fn14-dependent recruitment and ANKRD26 binding in adipogenesis.

    Evidence Co-IP, yeast two-hybrid, siRNA, Rac1/Cdc42 activation, migration/invasion and adipogenesis assays across studies

    PMID:22571869 PMID:22593800 PMID:22666460

    Open questions at the time
    • ANKRD26 interaction limited to Y2H plus single Co-IP
    • Receptor-to-Trio activation mechanisms not fully reconstituted
  11. 2014 High

    Defined opposing roles for Trio-Rac1 in actin structures—driving invadopodia disassembly—and identified ABL phosphorylation of Y2681 downstream of NOTCH-DAB1 as a switch for RhoA-driven invasion.

    Evidence Rac1 FRET biosensor and photoactivation; phospho-specific antibody, Y2681F mutant rescue, ABL inhibition, invasion assays

    PMID:24859002 PMID:25432929

    Open questions at the time
    • Structural effect of Y2681 phosphorylation on GEF2 unknown
    • Interplay of GEF1 and GEF2 outputs in the same cell not reconciled
  12. 2015 High

    Identified Trio (redundant with Kalirin) as the long-sought CaMKII target driving AMPA receptor upregulation during LTP, while also controlling dendritic branching, synapse number, and spatial learning.

    Evidence LTP electrophysiology with dominant-negative/CA constructs, siRNA in primary neurons, organotypic slice physiology, conditional EMX1-Cre KO behavior

    PMID:25727174 PMID:26721934 PMID:26858404

    Open questions at the time
    • Direct CaMKII phosphosite on Trio not mapped here
    • GTPase identity downstream of CaMKII-Trio for AMPAR insertion not resolved
  13. 2015 Medium

    Showed Trio engages additional partners—VE-cadherin at endothelial junctions and the chaperone Hsc70—to spatially control Rac1 activation in junction formation, axon growth, and neuronal migration.

    Evidence Co-IP, Rac1 FRET biosensor, ATPase-dead Hsc70 D10N, barrier resistance, axon growth and in vivo migration assays

    PMID:26116572 PMID:26323693

    Open questions at the time
    • How Hsc70 ATPase cycle gates GEF1 catalysis mechanistically unclear
    • Single-lab Co-IP evidence for each interaction
  14. 2017 Medium

    Established Trio-RhoG signaling downstream of PDGF/PI3K/Src controls dorsal ruffle dynamics, macropinocytosis, and receptor internalization independently of Rac1.

    Evidence siRNA, GTPase activation, CDR/macropinocytosis live imaging, PI3K/Src inhibitors

    PMID:28468978

    Open questions at the time
    • Direct biochemical link from PDGFR to Trio not shown
    • RhoG vs Rac1 separation incomplete
  15. 2019 High

    Revealed Trio scaffolding of membrane trafficking via Golgi RABIN8-RAB8/RAB10 activation and distinct synaptic interactomes, and clarified its haploinsufficiency phenotype via a PDE4A5-PKA axis.

    Evidence Co-IP, FRAP, RAB8/RAB10 activation and rescue, AP-MS proteomics, conditional KO with behavior, LTP, spine morphometry and pharmacological rescue

    PMID:30840899 PMID:31152060 PMID:31801062

    Open questions at the time
    • How GEF activity and RABIN8 scaffolding are coordinated unclear
    • Mechanism linking Trio to PDE4A5 levels not defined
  16. 2020 Medium

    Defined GEF-domain-specialized roles in tissue morphogenesis: GEF1/Rac1-RhoG in VEGF-driven arterial caliber, and GEF2-RhoA via Dishevelled in neural crest migration.

    Evidence Zebrafish and Xenopus genetics, domain-specific rescue, Co-IP (GEF2-DVL), Rac1 activation, actin/protrusion imaging

    PMID:32366678 PMID:33087700

    Open questions at the time
    • Receptor-proximal activation of each GEF domain not reconstituted
    • Cross-talk between GEF1 and GEF2 in same tissue unresolved
  17. 2021 High

    Mapped a spectrin-repeat/Neuroligin-1 interaction controlling NMDA-receptor synaptic function and showed GEF1 variant D1368V drives pathological synaptogenesis blocked by an SR8 variant disrupting NLGN1 binding.

    Evidence Brain Co-IP, super-resolution spine imaging, voltage-clamp electrophysiology, mutant constructs

    PMID:34353896

    Open questions at the time
    • How NLGN1 binding regulates GEF1 catalytic output mechanistically unclear
    • Selectivity for NMDA over AMPA function not fully explained
  18. 2022 High

    Resolved the autoinhibitory architecture: spectrin repeats 6-9 contact the GEF1 PH region to suppress Rac1 binding, and NDD variants relieve this constraint—providing a unifying mechanism for disease mutations.

    Evidence In vitro and cell-based GEF assays, cross-linking MS, bio-layer interferometry, NDD variant mutagenesis

    PMID:35963430

    Open questions at the time
    • High-resolution structure of the autoinhibited state lacking
    • How upstream receptors physically relieve autoinhibition unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct upstream receptors selectively relieve GEF1 autoinhibition and choose between GEF1/Rac1 and GEF2/RhoA outputs within a single cell remains unresolved.
  • No structural model of receptor-triggered de-repression
  • Coordination of GEF1 vs GEF2 activity in shared contexts undefined
  • Direct in vivo requirement of each phosphosite (Y2737, Y2681, Cdk5 sites) not dissected together

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0016740 transferase activity 1
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2
Partners
DCCDVLFAKHSC70MYO10NLGN1RABIN8VE-CADHERIN

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Trio is essential for late embryonic development in mice; trio(-/-) embryos die between E15.5 and birth and display defects in secondary myogenesis (secondary myofibers absent, primary myofibers become aberrantly spherical) and aberrant organization in hippocampal and olfactory bulb regions, establishing Trio's roles in skeletal muscle formation and neural tissue organization. Mouse knockout (trio-/-), histology, genotype analysis Proceedings of the National Academy of Sciences of the United States of America High 11050238
1999 The amino-terminal GEF domain of Trio (GEF1) induces membrane ruffling, rapid cell spreading, haptotactic migration, and anchorage-independent growth when stably expressed in NIH 3T3 cells; the carboxy-terminal GEF domain produces a distinct lamellar/mini-ruffle phenotype. Full-length Trio also alters actin cytoskeleton organization and focal contact distribution in COS cells. Stable cell line expression of individual GEF domains, actin staining, haptotaxis assay, soft-agar anchorage-independent growth assay Journal of cell science Medium 10341202
2008 Trio mediates netrin-1-induced Rac1 activation via its interaction with the netrin-1 receptor DCC. Trio co-immunoprecipitates with DCC in mouse embryonic brains; Trio(-/-) cortical neurons fail to extend neurites in response to netrin-1; commissural axon guidance toward the floor plate is disrupted; anterior commissure is absent and netrin-1/DCC-dependent corpus callosum and internal capsule projections are defective in Trio-null embryos. Co-immunoprecipitation from embryonic brain, Trio(-/-) cortical neuron neurite outgrowth assay, spinal cord explant axon guidance assay, in vivo axon tract analysis Molecular and cellular biology High 18212043
2005 Drosophila Trio physically interacts with the Netrin receptor Frazzled (Fra) in GST-pulldown and co-immunoprecipitation assays. Mutations in trio dominantly enhance fra and Netrin mutant CNS commissure phenotypes; fra;trio double mutants show dramatic loss of commissural axons. Tyrosine phosphorylation of Trio is elevated when Abl kinase levels are increased in S2 cells. Heterozygosity for trio reduces ectopic midline crossing in Robo-Fra chimeric receptor embryos, placing Trio as an effector of Fra/Netrin signaling. GST-pulldown, co-immunoprecipitation, genetic epistasis (double mutants, dominant enhancement), S2 cell phosphorylation assay Development (Cambridge, England) High 15790972
2007 The Rho-specific GEF domain of C. elegans UNC-73 (Trio ortholog) is a major Gαq effector. Forward genetic suppressor screens of hyperactive Gαq identified four mutations in the UNC-73 RhoGEF domain. UNC-73 RhoGEF loss phenocopies EGL-8 (PLCβ) loss (sluggish locomotion); double null of both genes phenocopies Gαq null (near-complete paralysis). Cell-based and biochemical assays show activated Gαq synergizes with Trio RhoGEF to activate RhoA, and activated Gαq co-immunoprecipitates with Trio RhoGEF. Forward genetic suppressor screen, double-mutant epistasis, cell-based Rho activation assay, co-immunoprecipitation, biochemical GEF assay Genes & development High 17942708
2009 ITX3, identified by screening for inhibitors of Trio's N-terminal GEF domain (TrioN/GEF1), selectively blocks TrioN-mediated Rac1 activation and dorsal membrane ruffling in mammalian cells without affecting GEF337-, Tiam1-, or Vav2-mediated GTPase activation. ITX3 inhibits endogenous TrioN activity and blocks NGF-stimulated neurite outgrowth in PC12 cells and C2C12 myotube differentiation, defining a Trio/RhoG/Rac1 signaling pathway. Chemical inhibitor screen, Rac1 activation assay, cell morphology/ruffling assay, neurite outgrowth assay, myotube differentiation assay Chemistry & biology Medium 19549603
2003 Trio binds focal adhesion kinase (FAK) via its SH3 domain (to FAK N-terminal domain) and kinase domain (to FAK kinase domain). Trio is constitutively tyrosine-phosphorylated; co-expression with FAK increases Trio in the detergent-insoluble fraction and causes co-localization at the cell periphery. FAK phosphorylates Trio at Y2737 in the kinase domain subdomain I. Trio reciprocally enhances FAK kinase activity in vitro and in vivo. Co-precipitation/co-immunoprecipitation, immunofluorescence co-localization, in vitro kinase assay, co-transfection, site identification by phosphopeptide mapping The Journal of biological chemistry Medium 12551902
2011 A Trio-RhoA-Shroom3 pathway is required for apical constriction during lens pit invagination. Rock activity and RhoA activity are required for Shroom3-induced apical constriction; Trio was identified as the RhoA-GEF required for Shroom3-dependent apical constriction in both MDCK cells and the lens pit in vivo. Dominant-negative/constitutively active RhoA constructs, siRNA knockdown, lens-specific in vivo studies, Rock inhibitor treatment, epistasis Development (Cambridge, England) Medium 22031541
2014 A Trio-Rac1-Pak1 signaling axis drives invadopodia disassembly. A genetically encoded single-chain Rac1 FRET biosensor showed Rac1 activity exclusion from invadopodia cores and activation at invadopodia disappearance; photoactivation of Rac1 at invadopodia confirmed its disassembly role. Trio (TrioGEF) activates Rac1, which activates Pak1, leading to cortactin phosphorylation and invadopodia dissolution. FRET biosensor (live-cell imaging), Rac1 photoactivation, siRNA knockdown, cortactin phosphorylation assay Nature cell biology High 24859002
2014 TRIO is phosphorylated at Y2681 by ABL tyrosine kinase downstream of a NOTCH-DAB1-ABL signaling cascade in colorectal cancer cells. pY2681 causes RHO activation; the unphosphorylatable TRIO Y2681F mutation reduces RHOGEF activity and inhibits invasion of colorectal cancer cells, establishing Trio as a downstream ABL substrate that transduces NOTCH signaling to RhoA-mediated invasion. Genetic depletion (knockout mice), phospho-specific antibody detection, unphosphorylatable mutant (Y2681F) functional assay, ABL inhibitor treatment, invasion assay Cancer discovery High 25432929
2015 Suppression of endogenous TRIO in dissociated rat hippocampal neurons enhances dendritic formation, and decreasing TRIO in organotypic hippocampal slices increases synaptic strength by increasing functional synapse number, demonstrating a direct role for Trio in dendritic branching and synapse development. siRNA knockdown in primary neurons, morphometric dendritic analysis, whole-cell electrophysiology in organotypic slices Human molecular genetics Medium 26721934
2015 Trio and Kalirin play critical and redundant roles in excitatory synapse structure and function. CaMKII phosphorylation of Kalirin is sufficient to enhance synaptic AMPA receptor expression; preventing CaMKII signaling through Kalirin and Trio prevents LTP induction, placing Trio/Kalirin as the elusive CaMKII targets responsible for AMPA receptor upregulation during LTP. Molecular biology (dominant-negative/constitutively active constructs), electrophysiology (LTP recordings), imaging, biochemical phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 26858404
2015 Trio interacts with VE-cadherin at endothelial adherens junctions and locally activates Rac1 during nascent junction formation. The Rac-GEF domain of Trio remodels junctional actin from radial to cortical bundles, promoting linear adherens junction formation and increasing endothelial monolayer resistance. Co-immunoprecipitation, FRET-based Rac1 biosensor, siRNA knockdown, electrical resistance measurement, actin imaging Journal of cell science Medium 26116572
2004 Trio interacts with peptidylglycine alpha-amidating monooxygenase (PAM), a secretory granule membrane protein. Cdk5-mediated phosphorylation of Trio (at consensus Cdk5 sites) is required for Trio-dependent Rac activation; roscovitine (Cdk5 inhibitor) inhibits Trio-mediated Rac activation, reorganizes cortical actin, and limits secretory granule approach to the plasma membrane, impairing hormone exocytosis. Protein interaction (co-IP with PAM), in vitro Cdk5 phosphorylation assay, Rac activation assay, roscovitine pharmacological inhibition, ultrastructural analysis Journal of cell science Medium 15331630
2011 Trio mediates HOXC8-dependent CDH11 (cadherin 11)-stimulated breast cancer cell migration by activating Rac1. CDH11 physically interacts with Trio and recruits Trio to the plasma membrane where Trio activates Rac, enabling actin ruffle formation and migration; CDH11 knockdown prevents plasma membrane localization of Trio. Co-immunoprecipitation, siRNA knockdown, Rac1 activation assay, actin staining, migration assay, immunofluorescence localization Genes & cancer Medium 22593800
2012 Trio acts as the Rac1-activating GEF downstream of the TWEAK-Fn14 signaling axis in glioblastoma cells. Trio depletion inhibits TWEAK-induced Rac1 activation but not Cdc42 activation, and abrogates TWEAK-Fn14-directed glioma cell migration and invasion, while Ect2 depletion blocks both Cdc42 and Rac1 activation. siRNA knockdown, Rac1/Cdc42 activation assays, migration/invasion assays (Boyden chamber), in vivo RCAS gene transfer model Molecular cancer research : MCR Medium 22571869
2015 Hsc70 (heat shock cognate protein 70) dynamically associates with the N-terminal region and Rac1 GEF domain of Trio, supporting Trio-dependent Rac1 activation. ATPase-deficient Hsc70 (D10N) abrogates Trio Rac1 GEF activity and netrin-1-induced Rac1 activation. Hsc70 is required for netrin-1-mediated axon growth and attraction in vitro and supports callosal projections and radial neuronal migration in the embryonic neocortex. Co-immunoprecipitation, dominant-negative Hsc70 (D10N) expression, Rac1 activation assay, in vitro axon growth assay, in vivo neuronal migration assay The Journal of cell biology Medium 26323693
2017 RhoG and its exchange factor Trio regulate circular dorsal ruffle (CDR) dynamics, macropinocytosis, receptor internalization, and cell migration. RhoG is activated by Trio downstream of PDGF in a PI3K- and Src-dependent manner. Silencing RhoG decreases CDR number and area independently of Rac1. siRNA knockdown, GTPase activation assay, CDR live-cell imaging, macropinocytosis assay, pharmacological inhibitors (PI3K, Src) Molecular biology of the cell Medium 28468978
2019 TRIO localizes to the Golgi in mouse cerebellar granule neurons and regulates directional membrane trafficking by controlling RAB8- and RAB10-positive vesicle maintenance. The spectrin repeats of Golgi-resident TRIO interact with and activate the RAB GEF RABIN8, thereby activating RAB8 and RAB10. Constitutively active RAB8 or RAB10 partially restores neurite outgrowth in TRIO-deficient neurons. Co-localization (immunofluorescence), live-cell imaging, FRAP, co-immunoprecipitation, RAB8/RAB10 activation assay, TRIO knockout neuronal rescue experiment The Journal of biological chemistry Medium 31152060
2019 Trio haploinsufficiency in excitatory neurons causes increased anxiety, impaired social preference, reduced forebrain size, reduced dendritic arborization, increased dendritic spine density, and failure of LTP. PDE4A5 levels are reduced and PKA signaling is increased when TRIO is reduced; elevation of PDE4A5 or attenuation of PKA signaling rescues dendritic spine defects, placing Trio upstream of a PDE4A5-PKA pathway. Conditional neuron-specific Trio knockout (Cre-lox), behavioral tests, spine morphometry, electrophysiology (LTP), Western blot, pharmacological rescue Cell reports High 30840899
2021 ASD/ID-related Trio mutation D1368V (in GEF1 domain) produces pathological increase in glutamatergic synaptogenesis; Trio N1080I (in spectrin repeat 8) inhibits Trio's interaction with Neuroligin 1 (NLGN1) and prevents Trio D1368V-mediated synaptogenesis. Trio interacts with NLGN1 in the brain, and this interaction is required for NLGN1-mediated NMDA receptor (but not AMPA receptor) synaptic function. Co-immunoprecipitation from brain, super-resolution spine imaging, whole-cell voltage-clamp electrophysiology in hippocampal slices, molecular biology (mutant constructs) The Journal of neuroscience : the official journal of the Society for Neuroscience High 34353896
2019 Synaptic proteomics revealed that Trio interacts with axon guidance and presynaptic complexes (distinct from Kalirin-7 which associates more with synaptic adhesion molecules). These differential interactomes were established by unbiased AP-MS proteomics. Unbiased affinity purification mass spectrometry (AP-MS) proteomics Cell reports Medium 31801062
2020 The GEF1 domain of Trio and activation of Rac1 and RhoG in the cell periphery are required for VEGF-signaling-dependent enlargement of arterial endothelial cells, driving large-caliber artery formation in zebrafish and cell models. This involves F-actin remodeling, myosin-based tension at junctions, and focal adhesions. Vegf signaling strength is titrated by soluble Flt1 to control Trio activity. Zebrafish embryo genetics (morpholino/mutant), GEF1-domain-specific Trio constructs, endothelial cell models, actin imaging, focal adhesion analysis Nature communications Medium 33087700
2021 Trio conditional knockout in excitatory cortical/hippocampal neurons causes aberrant polarity and halted migration of late-born pyramidal neurons. The Trio N-terminal SH3 domain interacts with Myosin X, mediating adherence of migrating neurons to radial glial fibers by regulating N-cadherin membrane localization. Independent or synergistic overexpression of RAC1 and RHOA produces different phenotypic recoveries, demonstrating distinct roles of GEF1 (RAC1) and GEF2 (RHOA) domains in radial migration. Conditional knockout, in utero electroporation, immunofluorescence, Co-IP (SH3-Myosin X), N-cadherin membrane localization assay, rescue with constitutively active RAC1/RHOA Neuroscience bulletin Medium 34914033
2022 Spectrin repeats (SRs) 6-9 of Trio interact intramolecularly with the GEF1 domain to autoinhibit its catalytic activity both in vitro and in cells. NDD-associated variants in SR8 and GEF1 domain relieve this autoinhibitory constraint. Chemical cross-linking and bio-layer interferometry indicate SRs primarily contact the pleckstrin homology region of GEF1, reducing GEF1 binding to Rac1. In vitro GEF activity assay, cell-based Rac1 activation assay, chemical cross-linking mass spectrometry, bio-layer interferometry, NDD variant mutagenesis The Journal of biological chemistry High 35963430
2012 TRIO is amplified and overexpressed in urinary bladder cancer and soft tissue sarcomas; TRIO amplification strongly associates with invasive tumor phenotype, high tumor grade, and rapid cell proliferation (Ki67). However, these are correlative findings — no direct mechanistic experiment was performed in this paper. FISH on tissue microarray, RNA in situ hybridization The American journal of pathology Low 15215162
2020 ALKBH5, an m6A RNA demethylase, is downregulated during myocardial ischemia/reperfusion injury (MIRI). MeRIP-seq and RNA-seq in ALKBH5-overexpressed HL-1 cells identified Trio mRNA as a target whose m6A modification level is increased when ALKBH5 is lost, leading to decreased Trio expression. Overexpression of ALKBH5 is protective against MIRI-related cell injury and apoptosis. MeRIP-seq, RNA-seq, MeRIP-qPCR, siRNA/overexpression, cell viability/apoptosis assays Annals of translational medicine Low 35530959
2020 Trio interacts with ANKRD26 protein (identified by yeast two-hybrid and immunoprecipitation). Selective knockdown of Trio increases adipogenesis in 3T3-L1 cells, establishing Trio as a regulator of adipogenesis. Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, adipogenesis assay PloS one Low 22666460
2018 Trio is expressed in glomerular podocytes and activates basal Rac1 activity. Reduced Trio expression in cultured human podocytes decreases basal Rac1 activity, cell size, laminin attachment, and motility. TGFβ1 increases Rac1 activity in control cells but decreases it in Trio-knockdown cells (attributed to simultaneous CdGAP activation). siRNA knockdown, Rac1 activation assay, cell size/adhesion/motility assays, RNA-seq expression profiling International journal of molecular sciences Low 29415466
2015 Trio gene deletion in EMX1-Cre mice (brain cortex and hippocampus) results in smaller brains, abnormal hippocampal structure, and disordered granule cells in DG and CA regions. EMX1-Trio(-/-) mice show impaired hippocampal-dependent spatial learning, establishing Trio's role in adult hippocampal-dependent learning. Conditional knockout (EMX1-Cre), brain morphology analysis, behavioral tests (spatial learning/Morris water maze) Brain research Medium 25727174
2020 Trio is required for Xenopus cranial neural crest cell migration and cartilage formation. Trio cell-autonomously controls protrusion formation; Trio GEF2 domain is sufficient to rescue protrusion and migration defects. The Trio GEF2 domain interacts with the DEP/C-terminus of Dishevelled (DVL), and DVL rescues Rac1 activity and protrusion formation in Trio morphant embryos, defining a Trio-DVL-Rac1 pathway in neural crest migration. Morpholino knockdown in Xenopus, rescue with domain-specific constructs, Co-IP (Trio GEF2 - DVL), Rac1 activation assay, live-cell imaging of protrusions Development (Cambridge, England) Medium 32366678

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. The Lancet. Oncology 1536 25524798
2018 A TRP channel trio mediates acute noxious heat sensing. Nature 365 29539642
2021 Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial. Lancet (London, England) 331 34010611
2011 A trio of microRNAs that control Toll-like receptor signalling. International immunology 252 21652514
2008 CXCR7, CXCR4 and CXCL12: an eccentric trio? Journal of neuroimmunology 199 18533280
2008 The PPAR trio: regulators of myocardial energy metabolism in health and disease. Journal of molecular and cellular cardiology 195 18462747
2020 Intestinal barrier damage, systemic inflammatory response syndrome, and acute lung injury: A troublesome trio for acute pancreatitis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 183 33011613
2012 Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12. Cytokine & growth factor reviews 165 22989616
2009 A molecular trio in relapse and remission in multiple sclerosis. Nature reviews. Immunology 159 19444308
2000 Skeletal muscle deformity and neuronal disorder in Trio exchange factor-deficient mouse embryos. Proceedings of the National Academy of Sciences of the United States of America 146 11050238
2014 A Trio-Rac1-Pak1 signalling axis drives invadopodia disassembly. Nature cell biology 136 24859002
2008 Trio mediates netrin-1-induced Rac1 activation in axon outgrowth and guidance. Molecular and cellular biology 118 18212043
2020 The native ORAI channel trio underlies the diversity of Ca2+ signaling events. Nature communications 115 32415068
2012 Insights into mitochondrial dysfunction: aging, amyloid-β, and tau-A deleterious trio. Antioxidants & redox signaling 109 22117646
2011 A Trio-RhoA-Shroom3 pathway is required for apical constriction and epithelial invagination. Development (Cambridge, England) 99 22031541
2005 The Abelson tyrosine kinase, the Trio GEF and Enabled interact with the Netrin receptor Frazzled in Drosophila. Development (Cambridge, England) 98 15790972
2007 S100A1 and S100B, transcriptional targets of SOX trio, inhibit terminal differentiation of chondrocytes. EMBO reports 94 17396138
2014 Promotion of colorectal cancer invasion and metastasis through activation of NOTCH-DAB1-ABL-RHOGEF protein TRIO. Cancer discovery 89 25432929
2015 TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function. Human molecular genetics 88 26721934
2012 An infernal trio: the chemokine CXCL12 and its receptors CXCR4 and CXCR7 in tumor biology. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft 87 23279723
2009 A cell active chemical GEF inhibitor selectively targets the Trio/RhoG/Rac1 signaling pathway. Chemistry & biology 87 19549603
2022 A receptor-channel trio conducts Ca2+ signalling for pollen tube reception. Nature 86 35794475
2016 Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP. Proceedings of the National Academy of Sciences of the United States of America 85 26858404
2014 Function and regulation of the Rho guanine nucleotide exchange factor Trio. Small GTPases 78 24987837
2012 Cdc42 and the guanine nucleotide exchange factors Ect2 and trio mediate Fn14-induced migration and invasion of glioblastoma cells. Molecular cancer research : MCR 75 22571869
2007 Trio's Rho-specific GEF domain is the missing Galpha q effector in C. elegans. Genes & development 72 17942708
2001 The Trio family of guanine-nucleotide-exchange factors: regulators of axon guidance. Journal of cell science 70 11493634
2018 The Deiodinase Trio and Thyroid Hormone Signaling. Methods in molecular biology (Clifton, N.J.) 67 29892818
2014 Quantifiler® Trio Kit and forensic samples management: a matter of degradation. Forensic science international. Genetics 64 25544252
1999 Trio amino-terminal guanine nucleotide exchange factor domain expression promotes actin cytoskeleton reorganization, cell migration and anchorage-independent cell growth. Journal of cell science 63 10341202
2015 A local VE-cadherin and Trio-based signaling complex stabilizes endothelial junctions through Rac1. Journal of cell science 62 26116572
2003 Signaling between focal adhesion kinase and trio. The Journal of biological chemistry 60 12551902
2016 The bacterial DnaA-trio replication origin element specifies single-stranded DNA initiator binding. Nature 59 27281207
2004 TRIO amplification and abundant mRNA expression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer. The American journal of pathology 55 15215162
2020 Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07). Nature communications 54 33203854
2012 The many faces of the guanine-nucleotide exchange factor trio. Cell adhesion & migration 51 23076143
2005 Multiple novel isoforms of Trio are expressed in the developing rat brain. Gene 51 15715966
2004 Cdk5 and Trio modulate endocrine cell exocytosis. Journal of cell science 46 15331630
2021 Trio exome sequencing is highly relevant in prenatal diagnostics. Prenatal diagnosis 44 34958143
2006 Frequent amplifications and abundant expression of TRIO, NKD2, and IRX2 in soft tissue sarcomas. Genes, chromosomes & cancer 44 16752383
2019 Trio Haploinsufficiency Causes Neurodevelopmental Disease-Associated Deficits. Cell reports 43 30840899
2009 Mitochondria, cholesterol and amyloid beta peptide: a dangerous trio in Alzheimer disease. Journal of bioenergetics and biomembranes 43 19784764
2020 Activation of the SOX-5, SOX-6, and SOX-9 Trio of Transcription Factors Using a Gene-Activated Scaffold Stimulates Mesenchymal Stromal Cell Chondrogenesis and Inhibits Endochondral Ossification. Advanced healthcare materials 42 32329217
2009 Master regulation of bile acid and xenobiotic metabolism via the FXR, PXR and CAR trio. Frontiers in bioscience (Landmark edition) 42 19273385
2014 Osteochondral tissue regeneration through polymeric delivery of DNA encoding for the SOX trio and RUNX2. Acta biomaterialia 40 24854956
2012 Matrix metalloproteinase-2 and -9 in glioblastoma: a trio of old drugs-captopril, disulfiram and nelfinavir-are inhibitors with potential as adjunctive treatments in glioblastoma. Archives of medical research 40 22564423
2016 Recurrent TRIO Fusion in Nontranslocation-Related Sarcomas. Clinical cancer research : an official journal of the American Association for Cancer Research 39 27528700
2022 HIF1, HSF1, and NRF2: Oxidant-Responsive Trio Raising Cellular Defenses and Engaging Immune System. Chemical research in toxicology 38 35948068
2020 Hyaluronic acid wreathed, trio-stimuli receptive and on-demand triggerable nanoconstruct for anchored combinatorial cancer therapy. Carbohydrate polymers 38 32933663
2022 Nonparametric single-cell multiomic characterization of trio relationships between transcription factors, target genes, and cis-regulatory regions. Cell systems 37 36055233
2015 Trio gene is required for mouse learning ability. Brain research 37 25727174
2020 The GEF Trio controls endothelial cell size and arterial remodeling downstream of Vegf signaling in both zebrafish and cell models. Nature communications 36 33087700
2011 HOXC8-Dependent Cadherin 11 Expression Facilitates Breast Cancer Cell Migration through Trio and Rac. Genes & cancer 36 22593800
1994 Cytosolic Ca2+, Na+/H+ antiport, protein kinase C trio in essential hypertension. American journal of hypertension 36 8179856
2020 Angiotensin II, Hypercholesterolemia, and Vascular Smooth Muscle Cells: A Perfect Trio for Vascular Pathology. International journal of molecular sciences 35 32630530
2011 SOX trio decrease in the articular cartilage with the advancement of osteoarthritis. Connective tissue research 34 21728837
2021 Direct and Indirect Effects of Maternal, Paternal, and Offspring Genotypes: Trio-GCTA. Behavior genetics 33 33387132
2017 Regulation of circular dorsal ruffles, macropinocytosis, and cell migration by RhoG and its exchange factor, Trio. Molecular biology of the cell 33 28468978
2017 Identification of de novo germline mutations and causal genes for sporadic diseases using trio-based whole-exome/genome sequencing. Biological reviews of the Cambridge Philosophical Society 32 29154454
2021 Autism Spectrum Disorder/Intellectual Disability-Associated Mutations in Trio Disrupt Neuroligin 1-Mediated Synaptogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 34353896
2019 Trio-whole-exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations. Human mutation 31 31680349
2022 Circ-TRIO promotes TNBC progression by regulating the miR-432-5p/CCDC58 axis. Cell death & disease 30 36075896
2012 ANKRD26 and its interacting partners TRIO, GPS2, HMMR and DIPA regulate adipogenesis in 3T3-L1 cells. PloS one 30 22666460
2005 Engulfment: ingestion and migration with Rac, Rho and TRIO. Current biology : CB 30 15649349
2022 High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases. Brain : a journal of neurology 29 34791078
2021 Trio family proteins as regulators of cell migration and morphogenesis in development and disease - mechanisms and cellular contexts. Journal of cell science 29 33568469
2011 Electroporation-mediated gene transfer of SOX trio to enhance chondrogenesis in adipose stem cells. Osteoarthritis and cartilage 29 21251990
2015 Hsc70 chaperone activity underlies Trio GEF function in axon growth and guidance induced by netrin-1. The Journal of cell biology 27 26323693
2019 Synaptic Kalirin-7 and Trio Interactomes Reveal a GEF Protein-Dependent Neuroligin-1 Mechanism of Action. Cell reports 26 31801062
2009 Combining case-control and case-trio data from the same population in genetic association analyses: overview of approaches and illustration with a candidate gene study. American journal of epidemiology 26 19635737
2005 Expression of Trio, a member of the Dbl family of Rho GEFs in the developing rat brain. The Journal of comparative neurology 26 15669055
2019 Identification of Hürthle cell cancers: solving a clinical challenge with genomic sequencing and a trio of machine learning algorithms. BMC systems biology 25 30952205
2021 Diagnostic yield of chromosomal microarray and trio whole exome sequencing in cryptogenic cerebral palsy. Journal of medical genetics 24 34321325
2019 Golgi-resident TRIO regulates membrane trafficking during neurite outgrowth. The Journal of biological chemistry 23 31152060
2018 A Methyltransferase Trio Essential for Phosphatidylcholine Biosynthesis and Growth. Plant physiology 23 30518673
2011 Natural killer cells, dendritic cells, and the alarmin high-mobility group box 1 protein: a dangerous trio in HIV-1 infection? Current opinion in HIV and AIDS 20 21825870
2022 Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood. HGG advances 19 35586607
2018 Trio, a novel high fecundity allele: I. Transcriptome analysis of granulosa cells from carriers and noncarriers of a major gene for bovine ovulation rate. Biology of reproduction 19 29088317
2018 Trio sequencing in pediatric cancer and clinical implications. EMBO molecular medicine 19 29507082
2023 A de novo missense mutation in MPP2 confers an increased risk of Vogt-Koyanagi-Harada disease as shown by trio-based whole-exome sequencing. Cellular & molecular immunology 18 37828081
2020 Defeating the trypanosomatid trio: proteomics of the protozoan parasites causing neglected tropical diseases. RSC medicinal chemistry 18 33479664
2015 Molecular evolution and expression of the CRAL_TRIO protein family in insects. Insect biochemistry and molecular biology 18 25684408
2017 Association of IMMP2L deletions with autism spectrum disorder: A trio family study and meta-analysis. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 17 29152845
2017 Knockdown of Trio by CRISPR/Cas9 suppresses migration and invasion of cervical cancer cells. Oncology reports 17 29207149
2024 Gamma-Mobile-Trio systems are mobile elements rich in bacterial defensive and offensive tools. Nature microbiology 16 39443754
2023 The cytokine trio - visfatin, placental growth factor and fractalkine - and their role in myocardial infarction with non-obstructive coronary arteries (MINOCA). Cytokine & growth factor reviews 16 37679252
2015 Upregulated TRIO expression correlates with a malignant phenotype in human hepatocellular carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 16 25851347
2023 Trio RNA sequencing in a cohort of medically complex children. American journal of human genetics 15 36990084
2022 Downregulated ALKBH5 contributes to myocardial ischemia/reperfusion injury by increasing m6A modification of Trio mRNA. Annals of translational medicine 15 35530959
2018 Emerging roles of TRIO and F-actin-binding protein in human diseases. Cell communication and signaling : CCS 15 29890989
2023 Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate. HGG advances 14 37719664
2022 Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants. The Journal of biological chemistry 14 35963430
2021 The RhoGEF Trio: A Protein with a Wide Range of Functions in the Vascular Endothelium. International journal of molecular sciences 14 34576329
2021 RhoGEF Trio Regulates Radial Migration of Projection Neurons via Its Distinct Domains. Neuroscience bulletin 14 34914033
2020 The Rho guanine nucleotide exchange factor Trio is required for neural crest cell migration and interacts with Dishevelled. Development (Cambridge, England) 14 32366678
2018 The Role of Trio, a Rho Guanine Nucleotide Exchange Factor, in Glomerular Podocytes. International journal of molecular sciences 14 29415466
2012 Control of dendritic morphogenesis by Trio in Drosophila melanogaster. PloS one 14 22438988
2025 Diagnostic Utility of Trio-Exome Sequencing for Children With Neurodevelopmental Disorders. JAMA network open 13 40131272
2019 Spindle cell liposarcoma with a TRIO-TERT fusion transcript. Virchows Archiv : an international journal of pathology 13 30793229
2022 Trio and Kalirin as unique enactors of Rho/Rac spatiotemporal precision. Cellular signalling 12 35872089

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