{"gene":"TTC3","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2009,"finding":"TTC3 is an E3 ubiquitin ligase that binds specifically to phosphorylated (activated) Akt via its RING finger motif and tetratricopeptide motifs, facilitates K48-linked ubiquitination of phospho-Akt, and promotes its proteasomal degradation within the nucleus, thereby terminating Akt signaling.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, proteasome inhibitor rescue, nuclear fractionation, siRNA knockdown with phospho-Akt measurement","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination assay combined with Co-IP, subcellular fractionation, and genetic rescue experiments; replicated conceptually in multiple subsequent studies","pmids":["20059950","20059946"],"is_preprint":false},{"year":2007,"finding":"TTC3 physically interacts with Citron kinase (CIT-K) and Citron N (CIT-N), two RhoA effectors, and inhibits NGF-induced neuronal differentiation (neurite extension in PC12 cells) through a CIT-K-dependent mechanism; RhoA but not ROCK is required for this TTC3 activity.","method":"Co-immunoprecipitation, RNAi knockdown of CIT-K, TTC3 overexpression/knockdown with neurite extension assays, dominant-negative Rho constructs","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying binding partners, epistasis via CIT-K RNAi rescuing TTC3 overexpression phenotype, multiple orthogonal methods in one study","pmids":["17488780"],"is_preprint":false},{"year":2014,"finding":"TTC3 promotes actin polymerization through a signaling pathway involving RhoA, ROCK, CIT-N, and non-muscle myosin IIa (PIIa), inhibiting neurite extension and disrupting Golgi compactness in differentiating primary neurons; the functional relationships between these molecules differ between neurite extension and Golgi organization contexts.","method":"TTC3 overexpression/knockdown in primary neurons, pharmacological inhibition of ROCK, RNAi of CIT-N and PIIa, F-actin staining, Golgi morphology assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined pathway epistasis with multiple nodes tested; single lab, multiple orthogonal methods","pmids":["24695496"],"is_preprint":false},{"year":2019,"finding":"TTC3, acting as an E3 ubiquitin ligase, directly binds SMURF2 and promotes its ubiquitylation and proteasomal degradation; this inhibits SMURF2-mediated suppression of SMAD2/3, thereby positively regulating TGF-β1-induced epithelial-mesenchymal transition (EMT) and myofibroblast differentiation. TGF-β1-induced TTC3 expression is itself dependent on SMAD2/3, forming a positive feedback loop.","method":"Co-immunoprecipitation, in-cell and in vitro ubiquitylation assays, TTC3 knockdown/overexpression in human bronchial epithelial cells and lung fibroblasts, SMAD2/3 knockdown, bleomycin mouse model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitylation assay plus Co-IP plus genetic knockdown with defined EMT phenotypic readout; multiple orthogonal methods in single lab","pmids":["30696809"],"is_preprint":false},{"year":2023,"finding":"In neurons with LTN1 (RQC E3 ligase) knockout, TTC3 protein abnormally overaccumulates and causes dendritic abnormalities and reduced surface GABAA receptor levels during neuronal development; TTC3 knockdown in medial prefrontal cortex rescues a subset of cognitive behavioral deficits in Ltn1 KO mice, placing TTC3 downstream of the RQC pathway.","method":"Ltn1 KO mouse model, TTC3 knockdown in vivo (medial prefrontal cortex), dendritic morphology analysis, surface GABAA receptor quantification, behavioral cognitive assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in KO mice, in vivo TTC3 knockdown rescue of behavioral phenotype, multiple orthogonal cellular readouts","pmids":["36917672"],"is_preprint":false},{"year":2024,"finding":"KIF18A directly binds TTC3 and enhances the physical interaction between TTC3 and phospho-Akt, thereby promoting TTC3-mediated ubiquitination and proteasomal degradation of p-Akt and suppressing the AKT/mTOR pathway in hepatic stellate cells.","method":"Co-immunoprecipitation (KIF18A–TTC3 and TTC3–p-Akt), KIF18A knockdown/overexpression, CCl4-induced liver fibrosis mouse model, ubiquitination assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP establishing direct binding plus in vivo genetic manipulation with functional readout; single lab","pmids":["38372748"],"is_preprint":false},{"year":2018,"finding":"Overexpressed TTC3 protein is cleaved into multiple N- and C-terminal fragments; the N-terminal sub-fragments (residues 1–650 contain nuclear localization signals) preferentially form insoluble nuclear aggregates, whereas full-length TTC3 also forms aggregates that are increased by proteasome inhibition with MG132; N-terminal fragments show greater cytotoxicity and cell-proliferation inhibition than full-length TTC3.","method":"Fluorescent protein fusion constructs (N- and C-terminal tagging), Western blotting, proteasome inhibitor (MG132) treatment, solubility fractionation, cell viability assays","journal":"Neuromolecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — multiple imaging and biochemical methods but single lab; no orthogonal in vivo validation","pmids":["30203323"],"is_preprint":false},{"year":2023,"finding":"The AD-risk missense variant TTC3 p.S1038C reduces TTC3 expression levels in iPSC-derived cortical neurons, alters PI3K-Akt pathway gene expression, disrupts actin cytoskeleton organization (reversed by Cytochalasin D), increases neurite length and branching, alters synaptic protein expression, and increases migration of neuronal progenitor cells.","method":"CRISPR/Cas9 isogenic iPSC lines, cortical neuron differentiation, transcriptome analysis, neurite morphology quantification, pharmacological rescue with actin-targeting small molecules","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic CRISPR lines with pharmacological rescue and transcriptomic analysis; single lab, multiple cellular readouts","pmids":["37677864","37292815"],"is_preprint":false},{"year":2026,"finding":"TTC3 directly binds DDX3X and promotes its K48-linked ubiquitination and proteasomal degradation; the membrane protein TMEM92 competitively associates with DDX3X to block TTC3 binding, thereby protecting DDX3X from TTC3-mediated degradation in triple-negative breast cancer cells.","method":"Co-immunoprecipitation, ubiquitination assays (K48-linkage specificity), TMEM92 knockdown/rescue experiments, xenograft tumor models","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus ubiquitination assay plus competitive binding model and in vivo xenograft; single lab","pmids":["42138474"],"is_preprint":false},{"year":2026,"finding":"TTC3 ubiquitinates and promotes degradation of APPL1 (adapter protein containing PH domain), thereby inhibiting nuclear export of LKB1 and suppressing AMPKα activation; this TTC3–APPL1–LKB1–AMPKα axis drives EMT and fibroblast-to-myofibroblast transition contributing to airway remodeling.","method":"Ubiquitination assays, TTC3 overexpression in OVA-induced mice, APPL1 overexpression rescue, LKB1 nuclear export tracking, RNA-seq","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ubiquitination assay plus in vivo mouse model rescue; single lab, multiple pathway nodes tested","pmids":["41520735"],"is_preprint":false},{"year":2026,"finding":"Ttc3 knockout mice develop severe pulmonary developmental defects after birth; in a bleomycin-induced pulmonary fibrosis model, Ttc3 activates the PI3K/Akt signaling pathway, and siRNA-mediated Ttc3 silencing in vivo inhibits PI3K/Akt activation and alleviates fibrosis.","method":"Ttc3 knockout mice (lung phenotype), siRNA nanoparticle delivery in bleomycin fibrosis model, PI3K/Akt pathway protein analysis, histological fibrosis scoring","journal":"Journal of controlled release","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO phenotype plus in vivo siRNA rescue with defined pathway readout; single lab","pmids":["41796874"],"is_preprint":false}],"current_model":"TTC3 is a RING-domain E3 ubiquitin ligase that selectively recognizes phosphorylated substrates—most notably phospho-Akt—and targets them for K48-linked ubiquitination and proteasomal degradation in the nucleus; it also ubiquitinates SMURF2, APPL1, and DDX3X to modulate TGF-β/SMAD, LKB1-AMPK, and other signaling axes, while in neurons it additionally interacts with RhoA effectors CIT-K and CIT-N to regulate actin polymerization, neurite outgrowth, and Golgi organization, with its overaccumulation downstream of defective ribosome-associated quality control causing synaptic and cognitive deficits."},"narrative":{"mechanistic_narrative":"TTC3 is a RING-domain E3 ubiquitin ligase that uses its tetratricopeptide repeats to selectively recognize phosphorylated substrates and direct them for K48-linked ubiquitination and proteasomal degradation, thereby terminating their signaling [PMID:20059950, PMID:20059946]. Its prototypical substrate is activated (phospho-)Akt, which TTC3 binds and degrades within the nucleus to shut down Akt signaling [PMID:20059950, PMID:20059946]; this recognition is enhanced when KIF18A binds TTC3 and strengthens the TTC3–phospho-Akt interaction [PMID:38372748]. Through analogous degradative control of additional substrates—SMURF2, APPL1, and DDX3X—TTC3 tunes multiple signaling axes: it stabilizes SMAD2/3 signaling by degrading SMURF2 and operates in a TGF-β1-driven positive feedback loop to promote epithelial-mesenchymal transition and myofibroblast differentiation [PMID:30696809], suppresses LKB1-AMPKα activation by degrading APPL1 to drive airway remodeling [PMID:41520735], and controls DDX3X levels in a manner antagonized by the competing binder TMEM92 [PMID:42138474]. Independently of its ligase activity, TTC3 acts in neurons by binding the RhoA effectors Citron kinase (CIT-K) and Citron-N (CIT-N) to promote actin polymerization, inhibit NGF-induced neurite extension, and regulate Golgi compactness [PMID:17488780, PMID:24695496]. Consistent with these dual roles, TTC3 overaccumulates downstream of defective ribosome-associated quality control when the RQC ligase LTN1 is lost, producing dendritic abnormalities, reduced surface GABAA receptors, and cognitive deficits that are partially rescued by TTC3 knockdown [PMID:36917672], and an Alzheimer's-risk variant (p.S1038C) reduces TTC3 expression and perturbs PI3K-Akt signaling and actin-dependent neuronal morphology [PMID:37677864, PMID:37292815].","teleology":[{"year":2007,"claim":"Established TTC3 as a regulator of neuronal differentiation by identifying its physical partners, addressing what cellular process TTC3 participates in.","evidence":"Reciprocal Co-IP and CIT-K RNAi epistasis with neurite extension assays in PC12 cells","pmids":["17488780"],"confidence":"High","gaps":["Did not define whether ligase activity is required for the CIT-K-dependent effect","Molecular link between TTC3 and RhoA upstream not resolved"]},{"year":2009,"claim":"Defined TTC3's core biochemical activity—answering how it acts at the molecular level—by showing it is an E3 ligase that recognizes phospho-Akt and degrades it to terminate signaling.","evidence":"In vitro ubiquitination assay, Co-IP, nuclear fractionation, and siRNA knockdown with phospho-Akt measurement","pmids":["20059950","20059946"],"confidence":"High","gaps":["Structural basis of phospho-substrate recognition not determined","Generality of phospho-substrate preference beyond Akt unaddressed at the time"]},{"year":2014,"claim":"Resolved the downstream effector pathway of TTC3 in neurons, clarifying how it controls cell shape via cytoskeletal and organelle organization.","evidence":"TTC3 gain/loss-of-function in primary neurons with ROCK inhibition, CIT-N/myosin IIa RNAi, F-actin and Golgi morphology readouts","pmids":["24695496"],"confidence":"Medium","gaps":["Context-dependent wiring between neurite vs Golgi pathways left mechanistically undefined","Single lab"]},{"year":2019,"claim":"Extended TTC3's substrate repertoire beyond Akt, showing it degrades SMURF2 to amplify TGF-β/SMAD signaling, establishing a role in EMT and fibrosis.","evidence":"In vitro and in-cell ubiquitylation assays, Co-IP, knockdown in epithelial/fibroblast cells, bleomycin mouse model","pmids":["30696809"],"confidence":"High","gaps":["Whether phosphorylation gates SMURF2 recognition unknown","Direct test of feedback loop kinetics absent"]},{"year":2018,"claim":"Addressed how TTC3 protein itself is handled, showing proteolytic fragments form cytotoxic nuclear aggregates regulated by the proteasome.","evidence":"Tagged fusion constructs, MG132 treatment, solubility fractionation, viability assays","pmids":["30203323"],"confidence":"Medium","gaps":["Physiological relevance of fragmentation in vivo not shown","Protease responsible for cleavage not identified"]},{"year":2023,"claim":"Placed TTC3 downstream of ribosome-associated quality control, explaining how its dysregulated accumulation causes neurodevelopmental and cognitive deficits.","evidence":"Ltn1 KO mice, in vivo TTC3 knockdown rescue, dendritic and surface GABAA receptor readouts, behavioral assays","pmids":["36917672"],"confidence":"High","gaps":["Substrate(s) of TTC3 mediating dendritic/receptor phenotype unidentified","Whether ligase activity drives the phenotype untested"]},{"year":2023,"claim":"Connected a disease-risk TTC3 variant to neuronal phenotypes, linking reduced TTC3 levels to PI3K-Akt and actin dysregulation in human cortical neurons.","evidence":"CRISPR isogenic iPSC lines, cortical neuron differentiation, transcriptomics, neurite morphometry, actin-targeting pharmacological rescue","pmids":["37677864","37292815"],"confidence":"Medium","gaps":["Causal mechanism linking variant to expression change unknown","Single lab; in vivo confirmation absent"]},{"year":2024,"claim":"Identified a positive regulator of TTC3 ligase function, showing KIF18A enhances TTC3–phospho-Akt binding to suppress AKT/mTOR in fibrosis.","evidence":"Co-IP of KIF18A–TTC3 and TTC3–p-Akt, KIF18A manipulation, CCl4 liver fibrosis model, ubiquitination assays","pmids":["38372748"],"confidence":"Medium","gaps":["Mechanism by which KIF18A strengthens the interaction unresolved","Single lab"]},{"year":2026,"claim":"Broadened the TTC3 substrate set further (APPL1, DDX3X) and identified a competitive binder, refining how TTC3 modulates LKB1-AMPK signaling and how its degradation of substrates can be blocked.","evidence":"Ubiquitination assays, competitive binding (TMEM92), in vivo OVA and xenograft models, LKB1 nuclear export tracking, RNA-seq","pmids":["41520735","42138474"],"confidence":"Medium","gaps":["Whether these substrates share the phospho-recognition logic of Akt unknown","Single lab per substrate; reciprocal validation limited"]},{"year":2026,"claim":"Demonstrated an organismal requirement for TTC3, showing knockout causes pulmonary developmental defects and that TTC3 activates PI3K/Akt in fibrosis.","evidence":"Ttc3 KO mice lung phenotype, in vivo siRNA nanoparticle rescue in bleomycin fibrosis, PI3K/Akt readouts, histology","pmids":["41796874"],"confidence":"Medium","gaps":["Apparent activation of PI3K/Akt contrasts with TTC3-mediated phospho-Akt degradation; reconciliation not provided","Tissue-specific substrate dependence undefined"]},{"year":null,"claim":"How TTC3's RING/TPR architecture achieves selective recognition of phosphorylated substrates, and whether its diverse substrates (Akt, SMURF2, APPL1, DDX3X) share a common recognition determinant, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition","Determinants distinguishing degradative substrates from non-catalytic CIT-K/CIT-N partners undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,3,8,9]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,8,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,5,9]}],"complexes":[],"partners":["AKT1","CIT","SMURF2","KIF18A","DDX3X","APPL1","TMEM92"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P53804","full_name":"E3 ubiquitin-protein ligase TTC3","aliases":["Protein DCRR1","RING finger protein 105","RING-type E3 ubiquitin transferase TTC3","TPR repeat protein D","Tetratricopeptide repeat protein 3","TPR repeat protein 3"],"length_aa":2025,"mass_kda":229.9,"function":"E3 ubiquitin-protein ligase which catalyzes the formation of 'Lys-48'-polyubiquitin chains (PubMed:20059950, PubMed:30696809). Mediates the ubiquitination and subsequent degradation of phosphorylated Akt (AKT1, AKT2 and AKT3) in the nucleus (PubMed:20059950). Acts as a terminal regulator of Akt signaling after activation; its phosphorylation by Akt, which is a prerequisite for ubiquitin ligase activity, suggests the existence of a regulation mechanism required to control Akt levels after activation (PubMed:20059950). Positively regulates TGFB1-induced epithelial-mesenchymal transition and myofibroblast differentiation by mediating the ubiquitination and subsequent degradation of SMURF2 (PubMed:30696809). Regulates neuronal differentiation by regulating actin remodeling and Golgi organization via a signaling cascade involving RHOA, CIT and ROCK (PubMed:17488780, PubMed:24695496). Inhibits cell proliferation (PubMed:30203323)","subcellular_location":"Nucleus; Cytoplasm; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/P53804/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TTC3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TTC3","total_profiled":1310},"omim":[{"mim_id":"608672","title":"DAZ-INTERACTING ZINC FINGER PROTEIN 3; DZIP3","url":"https://www.omim.org/entry/608672"},{"mim_id":"602259","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 3; TTC3","url":"https://www.omim.org/entry/602259"},{"mim_id":"180640","title":"tRNA GLUTAMIC ACID (ANTICODON TTC) 3-1; TRE-TTC3-1","url":"https://www.omim.org/entry/180640"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TTC3"},"hgnc":{"alias_symbol":["TPRD","TPRDI","DCRR1","TPRDII","TPRDIII","RNF105"],"prev_symbol":[]},"alphafold":{"accession":"P53804","domains":[{"cath_id":"-","chopping":"34-223","consensus_level":"medium","plddt":69.8895,"start":34,"end":223},{"cath_id":"1.25.40.10","chopping":"475-645","consensus_level":"medium","plddt":85.7945,"start":475,"end":645},{"cath_id":"-","chopping":"820-1004","consensus_level":"medium","plddt":83.3479,"start":820,"end":1004},{"cath_id":"-","chopping":"1104-1167","consensus_level":"medium","plddt":80.2297,"start":1104,"end":1167}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P53804","model_url":"https://alphafold.ebi.ac.uk/files/AF-P53804-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P53804-F1-predicted_aligned_error_v6.png","plddt_mean":62.09},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TTC3","jax_strain_url":"https://www.jax.org/strain/search?query=TTC3"},"sequence":{"accession":"P53804","fasta_url":"https://rest.uniprot.org/uniprotkb/P53804.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P53804/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P53804"}},"corpus_meta":[{"pmid":"20059950","id":"PMC_20059950","title":"The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt.","date":"2009","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/20059950","citation_count":131,"is_preprint":false},{"pmid":"30876857","id":"PMC_30876857","title":"Circular RNA Ttc3 regulates cardiac function after myocardial infarction by sponging miR-15b.","date":"2019","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/30876857","citation_count":123,"is_preprint":false},{"pmid":"38372748","id":"PMC_38372748","title":"KIF18A inactivates hepatic stellate cells and alleviates liver fibrosis through the TTC3/Akt/mTOR pathway.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/38372748","citation_count":77,"is_preprint":false},{"pmid":"33579365","id":"PMC_33579365","title":"Circular RNA TTC3 regulates cerebral ischemia-reperfusion injury and neural stem cells by miR-372-3p/TLR4 axis in cerebral infarction.","date":"2021","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33579365","citation_count":54,"is_preprint":false},{"pmid":"17488780","id":"PMC_17488780","title":"The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17488780","citation_count":50,"is_preprint":false},{"pmid":"33600863","id":"PMC_33600863","title":"Effects of circular RNA Ttc3/miR-148a/Rcan2 axis on inflammation and oxidative stress in rats with acute kidney injury induced by sepsis.","date":"2021","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33600863","citation_count":41,"is_preprint":false},{"pmid":"30696809","id":"PMC_30696809","title":"TTC3 contributes to TGF-β1-induced epithelial-mesenchymal transition and myofibroblast differentiation, potentially through SMURF2 ubiquitylation and degradation.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30696809","citation_count":40,"is_preprint":false},{"pmid":"27066578","id":"PMC_27066578","title":"Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease.","date":"2016","source":"Neurology. 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iPSC-derived forebrain neurons.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37292815","citation_count":0,"is_preprint":false},{"pmid":"41859106","id":"PMC_41859106","title":"Treponema pallidum TprD and TprK are adhesins and their surface expression promotes spirochetal opsonophagocytosis.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41859106","citation_count":0,"is_preprint":false},{"pmid":"41456226","id":"PMC_41456226","title":"circ-Ttc3 alleviates LPS-induced neuronal injury via stabilizing RBFOX1 to inhibit inflammation and oxidative stress.","date":"2025","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/41456226","citation_count":0,"is_preprint":false},{"pmid":"41796874","id":"PMC_41796874","title":"Lipid nanocomposites for precisely triggered Ttc3 gene silencing in pulmonary fibrosis treatment.","date":"2026","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/41796874","citation_count":0,"is_preprint":false},{"pmid":"42138474","id":"PMC_42138474","title":"TMEM92 shields DDX3X from TTC3-mediated degradation to confer chemoresistance in triple-negative breast cancer.","date":"2026","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42138474","citation_count":0,"is_preprint":false},{"pmid":"41520735","id":"PMC_41520735","title":"TTC3-mediated ubiquitination of APPL1 is suppression involved in the anti-asthmatic effects of the substance P receptor antagonist WIN62577.","date":"2026","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41520735","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16315,"output_tokens":3027,"usd":0.047175,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10489,"output_tokens":3568,"usd":0.070822,"stage2_stop_reason":"end_turn"},"total_usd":0.117997,"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\": 2009,\n      \"finding\": \"TTC3 is an E3 ubiquitin ligase that binds specifically to phosphorylated (activated) Akt via its RING finger motif and tetratricopeptide motifs, facilitates K48-linked ubiquitination of phospho-Akt, and promotes its proteasomal degradation within the nucleus, thereby terminating Akt signaling.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, proteasome inhibitor rescue, nuclear fractionation, siRNA knockdown with phospho-Akt measurement\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination assay combined with Co-IP, subcellular fractionation, and genetic rescue experiments; replicated conceptually in multiple subsequent studies\",\n      \"pmids\": [\"20059950\", \"20059946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TTC3 physically interacts with Citron kinase (CIT-K) and Citron N (CIT-N), two RhoA effectors, and inhibits NGF-induced neuronal differentiation (neurite extension in PC12 cells) through a CIT-K-dependent mechanism; RhoA but not ROCK is required for this TTC3 activity.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown of CIT-K, TTC3 overexpression/knockdown with neurite extension assays, dominant-negative Rho constructs\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying binding partners, epistasis via CIT-K RNAi rescuing TTC3 overexpression phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17488780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TTC3 promotes actin polymerization through a signaling pathway involving RhoA, ROCK, CIT-N, and non-muscle myosin IIa (PIIa), inhibiting neurite extension and disrupting Golgi compactness in differentiating primary neurons; the functional relationships between these molecules differ between neurite extension and Golgi organization contexts.\",\n      \"method\": \"TTC3 overexpression/knockdown in primary neurons, pharmacological inhibition of ROCK, RNAi of CIT-N and PIIa, F-actin staining, Golgi morphology assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined pathway epistasis with multiple nodes tested; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24695496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TTC3, acting as an E3 ubiquitin ligase, directly binds SMURF2 and promotes its ubiquitylation and proteasomal degradation; this inhibits SMURF2-mediated suppression of SMAD2/3, thereby positively regulating TGF-β1-induced epithelial-mesenchymal transition (EMT) and myofibroblast differentiation. TGF-β1-induced TTC3 expression is itself dependent on SMAD2/3, forming a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, in-cell and in vitro ubiquitylation assays, TTC3 knockdown/overexpression in human bronchial epithelial cells and lung fibroblasts, SMAD2/3 knockdown, bleomycin mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitylation assay plus Co-IP plus genetic knockdown with defined EMT phenotypic readout; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"30696809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In neurons with LTN1 (RQC E3 ligase) knockout, TTC3 protein abnormally overaccumulates and causes dendritic abnormalities and reduced surface GABAA receptor levels during neuronal development; TTC3 knockdown in medial prefrontal cortex rescues a subset of cognitive behavioral deficits in Ltn1 KO mice, placing TTC3 downstream of the RQC pathway.\",\n      \"method\": \"Ltn1 KO mouse model, TTC3 knockdown in vivo (medial prefrontal cortex), dendritic morphology analysis, surface GABAA receptor quantification, behavioral cognitive assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in KO mice, in vivo TTC3 knockdown rescue of behavioral phenotype, multiple orthogonal cellular readouts\",\n      \"pmids\": [\"36917672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIF18A directly binds TTC3 and enhances the physical interaction between TTC3 and phospho-Akt, thereby promoting TTC3-mediated ubiquitination and proteasomal degradation of p-Akt and suppressing the AKT/mTOR pathway in hepatic stellate cells.\",\n      \"method\": \"Co-immunoprecipitation (KIF18A–TTC3 and TTC3–p-Akt), KIF18A knockdown/overexpression, CCl4-induced liver fibrosis mouse model, ubiquitination assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP establishing direct binding plus in vivo genetic manipulation with functional readout; single lab\",\n      \"pmids\": [\"38372748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Overexpressed TTC3 protein is cleaved into multiple N- and C-terminal fragments; the N-terminal sub-fragments (residues 1–650 contain nuclear localization signals) preferentially form insoluble nuclear aggregates, whereas full-length TTC3 also forms aggregates that are increased by proteasome inhibition with MG132; N-terminal fragments show greater cytotoxicity and cell-proliferation inhibition than full-length TTC3.\",\n      \"method\": \"Fluorescent protein fusion constructs (N- and C-terminal tagging), Western blotting, proteasome inhibitor (MG132) treatment, solubility fractionation, cell viability assays\",\n      \"journal\": \"Neuromolecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — multiple imaging and biochemical methods but single lab; no orthogonal in vivo validation\",\n      \"pmids\": [\"30203323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The AD-risk missense variant TTC3 p.S1038C reduces TTC3 expression levels in iPSC-derived cortical neurons, alters PI3K-Akt pathway gene expression, disrupts actin cytoskeleton organization (reversed by Cytochalasin D), increases neurite length and branching, alters synaptic protein expression, and increases migration of neuronal progenitor cells.\",\n      \"method\": \"CRISPR/Cas9 isogenic iPSC lines, cortical neuron differentiation, transcriptome analysis, neurite morphology quantification, pharmacological rescue with actin-targeting small molecules\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic CRISPR lines with pharmacological rescue and transcriptomic analysis; single lab, multiple cellular readouts\",\n      \"pmids\": [\"37677864\", \"37292815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TTC3 directly binds DDX3X and promotes its K48-linked ubiquitination and proteasomal degradation; the membrane protein TMEM92 competitively associates with DDX3X to block TTC3 binding, thereby protecting DDX3X from TTC3-mediated degradation in triple-negative breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K48-linkage specificity), TMEM92 knockdown/rescue experiments, xenograft tumor models\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus ubiquitination assay plus competitive binding model and in vivo xenograft; single lab\",\n      \"pmids\": [\"42138474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TTC3 ubiquitinates and promotes degradation of APPL1 (adapter protein containing PH domain), thereby inhibiting nuclear export of LKB1 and suppressing AMPKα activation; this TTC3–APPL1–LKB1–AMPKα axis drives EMT and fibroblast-to-myofibroblast transition contributing to airway remodeling.\",\n      \"method\": \"Ubiquitination assays, TTC3 overexpression in OVA-induced mice, APPL1 overexpression rescue, LKB1 nuclear export tracking, RNA-seq\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ubiquitination assay plus in vivo mouse model rescue; single lab, multiple pathway nodes tested\",\n      \"pmids\": [\"41520735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Ttc3 knockout mice develop severe pulmonary developmental defects after birth; in a bleomycin-induced pulmonary fibrosis model, Ttc3 activates the PI3K/Akt signaling pathway, and siRNA-mediated Ttc3 silencing in vivo inhibits PI3K/Akt activation and alleviates fibrosis.\",\n      \"method\": \"Ttc3 knockout mice (lung phenotype), siRNA nanoparticle delivery in bleomycin fibrosis model, PI3K/Akt pathway protein analysis, histological fibrosis scoring\",\n      \"journal\": \"Journal of controlled release\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO phenotype plus in vivo siRNA rescue with defined pathway readout; single lab\",\n      \"pmids\": [\"41796874\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TTC3 is a RING-domain E3 ubiquitin ligase that selectively recognizes phosphorylated substrates—most notably phospho-Akt—and targets them for K48-linked ubiquitination and proteasomal degradation in the nucleus; it also ubiquitinates SMURF2, APPL1, and DDX3X to modulate TGF-β/SMAD, LKB1-AMPK, and other signaling axes, while in neurons it additionally interacts with RhoA effectors CIT-K and CIT-N to regulate actin polymerization, neurite outgrowth, and Golgi organization, with its overaccumulation downstream of defective ribosome-associated quality control causing synaptic and cognitive deficits.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TTC3 is a RING-domain E3 ubiquitin ligase that uses its tetratricopeptide repeats to selectively recognize phosphorylated substrates and direct them for K48-linked ubiquitination and proteasomal degradation, thereby terminating their signaling [#0]. Its prototypical substrate is activated (phospho-)Akt, which TTC3 binds and degrades within the nucleus to shut down Akt signaling [#0]; this recognition is enhanced when KIF18A binds TTC3 and strengthens the TTC3\\u2013phospho-Akt interaction [#5]. Through analogous degradative control of additional substrates\\u2014SMURF2, APPL1, and DDX3X\\u2014TTC3 tunes multiple signaling axes: it stabilizes SMAD2/3 signaling by degrading SMURF2 and operates in a TGF-\\u03b21-driven positive feedback loop to promote epithelial-mesenchymal transition and myofibroblast differentiation [#3], suppresses LKB1-AMPK\\u03b1 activation by degrading APPL1 to drive airway remodeling [#9], and controls DDX3X levels in a manner antagonized by the competing binder TMEM92 [#8]. Independently of its ligase activity, TTC3 acts in neurons by binding the RhoA effectors Citron kinase (CIT-K) and Citron-N (CIT-N) to promote actin polymerization, inhibit NGF-induced neurite extension, and regulate Golgi compactness [#1, #2]. Consistent with these dual roles, TTC3 overaccumulates downstream of defective ribosome-associated quality control when the RQC ligase LTN1 is lost, producing dendritic abnormalities, reduced surface GABAA receptors, and cognitive deficits that are partially rescued by TTC3 knockdown [#4], and an Alzheimer's-risk variant (p.S1038C) reduces TTC3 expression and perturbs PI3K-Akt signaling and actin-dependent neuronal morphology [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established TTC3 as a regulator of neuronal differentiation by identifying its physical partners, addressing what cellular process TTC3 participates in.\",\n      \"evidence\": \"Reciprocal Co-IP and CIT-K RNAi epistasis with neurite extension assays in PC12 cells\",\n      \"pmids\": [\"17488780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define whether ligase activity is required for the CIT-K-dependent effect\", \"Molecular link between TTC3 and RhoA upstream not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined TTC3's core biochemical activity\\u2014answering how it acts at the molecular level\\u2014by showing it is an E3 ligase that recognizes phospho-Akt and degrades it to terminate signaling.\",\n      \"evidence\": \"In vitro ubiquitination assay, Co-IP, nuclear fractionation, and siRNA knockdown with phospho-Akt measurement\",\n      \"pmids\": [\"20059950\", \"20059946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of phospho-substrate recognition not determined\", \"Generality of phospho-substrate preference beyond Akt unaddressed at the time\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the downstream effector pathway of TTC3 in neurons, clarifying how it controls cell shape via cytoskeletal and organelle organization.\",\n      \"evidence\": \"TTC3 gain/loss-of-function in primary neurons with ROCK inhibition, CIT-N/myosin IIa RNAi, F-actin and Golgi morphology readouts\",\n      \"pmids\": [\"24695496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent wiring between neurite vs Golgi pathways left mechanistically undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended TTC3's substrate repertoire beyond Akt, showing it degrades SMURF2 to amplify TGF-\\u03b2/SMAD signaling, establishing a role in EMT and fibrosis.\",\n      \"evidence\": \"In vitro and in-cell ubiquitylation assays, Co-IP, knockdown in epithelial/fibroblast cells, bleomycin mouse model\",\n      \"pmids\": [\"30696809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phosphorylation gates SMURF2 recognition unknown\", \"Direct test of feedback loop kinetics absent\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Addressed how TTC3 protein itself is handled, showing proteolytic fragments form cytotoxic nuclear aggregates regulated by the proteasome.\",\n      \"evidence\": \"Tagged fusion constructs, MG132 treatment, solubility fractionation, viability assays\",\n      \"pmids\": [\"30203323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of fragmentation in vivo not shown\", \"Protease responsible for cleavage not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed TTC3 downstream of ribosome-associated quality control, explaining how its dysregulated accumulation causes neurodevelopmental and cognitive deficits.\",\n      \"evidence\": \"Ltn1 KO mice, in vivo TTC3 knockdown rescue, dendritic and surface GABAA receptor readouts, behavioral assays\",\n      \"pmids\": [\"36917672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate(s) of TTC3 mediating dendritic/receptor phenotype unidentified\", \"Whether ligase activity drives the phenotype untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected a disease-risk TTC3 variant to neuronal phenotypes, linking reduced TTC3 levels to PI3K-Akt and actin dysregulation in human cortical neurons.\",\n      \"evidence\": \"CRISPR isogenic iPSC lines, cortical neuron differentiation, transcriptomics, neurite morphometry, actin-targeting pharmacological rescue\",\n      \"pmids\": [\"37677864\", \"37292815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mechanism linking variant to expression change unknown\", \"Single lab; in vivo confirmation absent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a positive regulator of TTC3 ligase function, showing KIF18A enhances TTC3\\u2013phospho-Akt binding to suppress AKT/mTOR in fibrosis.\",\n      \"evidence\": \"Co-IP of KIF18A\\u2013TTC3 and TTC3\\u2013p-Akt, KIF18A manipulation, CCl4 liver fibrosis model, ubiquitination assays\",\n      \"pmids\": [\"38372748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which KIF18A strengthens the interaction unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Broadened the TTC3 substrate set further (APPL1, DDX3X) and identified a competitive binder, refining how TTC3 modulates LKB1-AMPK signaling and how its degradation of substrates can be blocked.\",\n      \"evidence\": \"Ubiquitination assays, competitive binding (TMEM92), in vivo OVA and xenograft models, LKB1 nuclear export tracking, RNA-seq\",\n      \"pmids\": [\"41520735\", \"42138474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these substrates share the phospho-recognition logic of Akt unknown\", \"Single lab per substrate; reciprocal validation limited\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated an organismal requirement for TTC3, showing knockout causes pulmonary developmental defects and that TTC3 activates PI3K/Akt in fibrosis.\",\n      \"evidence\": \"Ttc3 KO mice lung phenotype, in vivo siRNA nanoparticle rescue in bleomycin fibrosis, PI3K/Akt readouts, histology\",\n      \"pmids\": [\"41796874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent activation of PI3K/Akt contrasts with TTC3-mediated phospho-Akt degradation; reconciliation not provided\", \"Tissue-specific substrate dependence undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TTC3's RING/TPR architecture achieves selective recognition of phosphorylated substrates, and whether its diverse substrates (Akt, SMURF2, APPL1, DDX3X) share a common recognition determinant, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"Determinants distinguishing degradative substrates from non-catalytic CIT-K/CIT-N partners undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 3, 8, 9]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 8, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 5, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AKT1\", \"CIT\", \"SMURF2\", \"KIF18A\", \"DDX3X\", \"APPL1\", \"TMEM92\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}