{"gene":"MTPN","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":1990,"finding":"Myotrophin was purified to apparent homogeneity from spontaneously hypertensive rat hearts as a novel 12 kDa protein that stimulates protein synthesis and myocardial cell growth in isolated neonatal cardiac myocytes, causing increased surface area and organized myofibril formation in a dose-dependent manner.","method":"Protein purification, bioassay (3H-leucine incorporation into myocyte protein), amino acid sequencing, morphological assessment of myocyte surface area and myofibril organization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — purification to homogeneity with functional reconstitution in primary cardiomyocytes; foundational paper replicated in multiple subsequent studies","pmids":["2144530"],"is_preprint":false},{"year":1993,"finding":"Human myotrophin purified from dilated cardiomyopathic hearts is a single 12 kDa polypeptide that stimulates adult myocardial protein synthesis and cell growth, with significantly elevated levels in dilated cardiomyopathic versus normal human hearts.","method":"Protein purification (reverse-phase HPLC, SDS-PAGE), 3H-leucine incorporation bioassay, Western blot, immunoblot with rat myotrophin antibody","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1 / Strong — purification to homogeneity with functional bioassay; independently confirms rat findings in human tissue","pmids":["8508536"],"is_preprint":false},{"year":1996,"finding":"Myotrophin protein contains ankyrin repeats with high homology to IκBα/rel ankyrin repeats, and recombinant myotrophin interacts directly with NF-κB/rel proteins (p50 and p65) as demonstrated by formation of ternary protein-DNA complexes in kappa B gel shift assays; myotrophin-specific antibodies inhibited these complexes.","method":"Sequence analysis, kappa B gel shift assay (EMSA), supershift assay with rel-specific p50 and p65 antibodies, antibody inhibition","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA with antibody supershift provides direct binding evidence; single lab but orthogonal methods (sequence analysis + functional assay)","pmids":["8576259"],"is_preprint":false},{"year":1997,"finding":"NMR analysis revealed that myotrophin consists of seven helices forming three helix-turn-helix motifs, with two full ankyrin repeats characterized by multiple turns followed by helix-turn-helix motifs; a hairpin-like turn in ANK repeat #1 (L32-R36) shows slow conformational averaging distinct from ANK repeat #2.","method":"Multidimensional heteronuclear NMR (2D and 3D) on uniformly 15N-labeled and 15N/13C-labeled protein; NOE analysis, NH exchange, coupling constants, chemical shift analysis","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR secondary structure determination with multiple orthogonal NMR experiments on isotopically labeled protein; single lab","pmids":["9194197"],"is_preprint":false},{"year":1998,"finding":"Myotrophin stimulates PKC activity and protein synthesis in neonatal cardiac myocytes through a tyrosine kinase-coupled pathway; PKCα and PKCε isoforms mediate myotrophin-induced neonatal myocyte growth, whereas only PKCε mediates adult myocyte hypertrophy. Myotrophin-induced PKC activity is located predominantly in the particulate (membrane) fraction.","method":"PKC activity assay (32P incorporation into histone and PKCε substrate peptide), 3H-leucine incorporation, pharmacological inhibitors (staurosporine, H-7, calphostin C, genistein), Western blot with isoform-specific antibodies, antisense oligonucleotides, subcellular fractionation","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (kinase assays, inhibitors, antisense knockdown, fractionation) in single lab with rigorous controls","pmids":["9633917"],"is_preprint":false},{"year":1999,"finding":"Human myotrophin/V-1 cDNA was cloned and characterized; the protein is identical to previously described V-1 proteins, is ubiquitously expressed with high expression in heart, and recombinant human myotrophin produces cardiomyocyte hypertrophy in vitro.","method":"cDNA cloning, Northern blot, Southern blot, dot blot (50 tissues), recombinant protein expression and functional bioassay","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cloning with functional validation of recombinant protein; single lab","pmids":["10329199"],"is_preprint":false},{"year":2002,"finding":"Myotrophin/V-1 is predominantly cytoplasmic but translocates to the nucleus during sustained NF-κB activation. It interacts physically with p65 and c-Rel proteins in vivo during NF-κB activation (co-IP), and in vitro promotes conversion of p50-p65 heterodimers into p50-p50 and p65-p65 homodimers. Adenoviral overexpression of myotrophin/V-1 increased p50-p50 homodimers and reduced κB-luciferase reporter activity.","method":"Co-immunoprecipitation (in vivo and in vitro), confocal microscopy (subcellular localization), 3D structural alignment, adenoviral overexpression, luciferase reporter assay, EMSA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, subcellular localization with functional consequence, reporter assay, multiple orthogonal methods; single lab","pmids":["11971907"],"is_preprint":false},{"year":2002,"finding":"NF-κB activation is required for myotrophin-induced cardiac hypertrophy: myotrophin treatment stimulates NF-κB nuclear translocation and transcriptional activity via IκB-α phosphorylation and degradation through a PKC-IKKβ-NF-κB pathway. Dominant-negative IKKβ or IκB-α blocked myotrophin-induced ANF and c-myc expression and protein synthesis.","method":"NF-κB reporter assay, Western blot for IκB-α phosphorylation/degradation, dominant-negative constructs (IKKβ, IκB-α), pharmacological inhibitors (PDTC, calphostin C), 3H-leucine incorporation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (dominant-negative) and pharmacological loss-of-function with defined molecular readouts; multiple orthogonal approaches; single lab","pmids":["12486112"],"is_preprint":false},{"year":2002,"finding":"Myotrophin binds directly to κB DNA, as shown by gel mobility shift assay with nuclear extracts from neonatal and adult cardiomyocytes. Under cyclic stretch, myotrophin levels increase in the nucleus. Myotrophin gene expression is upregulated by cyclic stretch, TNF-α, IL-1β, and high pressure in beating hearts.","method":"Gel mobility shift assay (EMSA), confocal microscopy (subcellular localization), recombinant protein, cyclic stretch model, pharmacological treatment","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA with defined nuclear extract plus direct localization imaging; single lab","pmids":["12031792"],"is_preprint":false},{"year":2004,"finding":"Cardiac-specific overexpression of myotrophin in transgenic mice causes progressive cardiac hypertrophy by 4 weeks of age, progressing to heart failure by 9–12 months, with increased expression of proto-oncogenes, hypertrophy marker genes, growth factors, and cytokines mimicking human cardiomyopathy.","method":"Transgenic mouse model (cardiac-specific overexpression), echocardiography, histology, gene expression profiling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo gain-of-function with defined temporal progression and molecular characterization; replicated phenotype of prior in vitro findings","pmids":["14970239"],"is_preprint":false},{"year":2006,"finding":"Myotrophin/V-1 binds directly to heterodimeric actin-capping protein (CP) in a 1:1 molar ratio with Kd of 10–50 nM. V-1 binding inhibits CP's ability to cap actin filament barbed ends. The CP β-subunit C-terminal 'tentacle' is the primary binding site on CP for V-1. Two loops of V-1 extending from its ankyrin repeat backbone are necessary for V-1 to bind CP. V-1 appears unable to bind CP already on the barbed end and has no uncapping activity.","method":"In vitro binding assays, actin barbed-end capping assays, uncapping assays, site-directed mutagenesis (V-1 loops and CP subunit regions), computational modeling and molecular dynamics simulations","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro binding with Kd determination, mutagenesis of both interaction partners, and computational validation; multiple orthogonal methods","pmids":["16895918"],"is_preprint":false},{"year":2008,"finding":"Genetic blockade of NF-κB (via IκBα triple mutant mice crossed with myotrophin-overexpressing transgenic mice) attenuates myotrophin-induced cardiac hypertrophy and improves cardiac function, demonstrating that continuous NF-κB blockade is effective against myotrophin-driven cardiac remodeling.","method":"Double transgenic mice (Myo-Tg × IκBα triple mutant), echocardiography, histology, NF-κB gene array profiling, apoptosis markers","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis (double transgenic) with defined physiological and molecular readouts","pmids":["18620706"],"is_preprint":false},{"year":2009,"finding":"RNA interference (shRNA lentiviral delivery) silencing of myotrophin in myotrophin-overexpressing transgenic mice causes regression of cardiac mass and reduction in NF-κB signaling and ANF expression, establishing a causal role for myotrophin in NF-κB-dependent cardiac hypertrophy.","method":"Lentiviral shRNA delivery in vivo and in vitro (neonatal rat myocytes), qRT-PCR, Western blot, cardiac mass measurement","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function (RNAi) in both cell and animal models with defined molecular and physiological readouts","pmids":["19502558"],"is_preprint":false},{"year":2010,"finding":"NMR chemical shift mapping and intermolecular paramagnetic relaxation enhancement experiments revealed that the ankyrin loops of V-1 bind to the basic patch near the joint of the α tentacle of CP. Site-directed mutagenesis of CP confirmed that V-1 and the electrostatic barbed-end binding site on CP compete for this same basic patch, explaining how V-1 inactivates barbed end capping and why V-1 cannot uncap CP-capped actin filaments.","method":"NMR (chemical shift mapping, intermolecular PRE experiments), site-directed mutagenesis of CP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure-function study with mutagenesis validation; provides atomic-resolution mechanism for V-1/CP interaction","pmids":["20538588"],"is_preprint":false},{"year":2011,"finding":"Porcine MTPN protein is localized to the cytoplasm of Pig Kidney Epithelial (PK15) cells as determined by transient transfection, and is widely expressed across tissues with high levels in spleen, liver, and uterus; expression peaks at embryonic day 65 and is down-regulated postnatally during skeletal muscle development.","method":"Transient transfection with subcellular localization imaging, RT-PCR, qRT-PCR, cDNA cloning, genomic structure analysis","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization by transfection imaging confirmed in multiple tissues; single lab","pmids":["21667249"],"is_preprint":false},{"year":2016,"finding":"V-1/Myotrophin regulates capping protein (CP) activity in vivo in Dictyostelium: overexpression of V-1 reduced pseudopod size and cortical Arp2/3 content and induced filopodia in a CP-binding-dependent manner (a V-1 mutant unable to bind CP had no effect). V-1-null cells showed decreased cellular F-actin content and defects in macropinocytosis and chemotactic aggregation rescued by wild-type but not CP-binding-deficient V-1. V-1 is present in molar excess over CP suggesting it tonically suppresses CP activity in the cytoplasm. Evidence that V-1's CP-sequestering activity is regulated by phosphorylation was also obtained.","method":"Dictyostelium overexpression and knockout genetics, fluorescence microscopy (Arp2/3 and F-actin quantification), macropinocytosis assay, chemotaxis assay, rescue experiments with WT and mutant V-1","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — ortholog in Dictyostelium (consistent domain architecture and CP-binding mechanism); loss-of-function and gain-of-function with mutant rescue; multiple orthogonal phenotypic readouts","pmids":["27791032"],"is_preprint":false},{"year":2018,"finding":"V-1 and CARMIL bind to distinct sites on capping protein and induce allosteric conformational changes in CP detected by hydrogen-deuterium exchange mass spectrometry. Both V-1 and CARMIL affect the conformation of CP's ββ subunit tentacle (a second actin-binding site distal from their respective binding sites), revealing allosteric coupling between CP modulator and actin binding sites.","method":"Hydrogen-deuterium exchange mass spectrometry (HDX-MS)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — HDX-MS provides structural dynamics evidence for allosteric mechanism; single lab but rigorous biophysical method","pmids":["29847807"],"is_preprint":false},{"year":2020,"finding":"Lysyl oxidase (LOX) suppresses TNF-α-induced inflammatory responses in ACL fibroblasts partly via MTPN: silencing MTPN expression alleviated the anti-inflammatory effect of LOX, suggesting LOX interacts with MTPN to regulate inflammation through the NF-κB signaling pathway.","method":"RNA sequencing, protein-protein interaction network analysis, siRNA knockdown of MTPN, immunofluorescence, in vivo animal model","journal":"Journal of tissue engineering and regenerative medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, MTPN knockdown as one element in a larger study; mechanistic link between LOX and MTPN not directly established by binding or co-IP","pmids":["32483895"],"is_preprint":false}],"current_model":"MTPN (Myotrophin/V-1) is a small ~12 kDa cytoplasmic ankyrin-repeat protein with two established molecular functions: (1) it acts as a cardiac hypertrophy initiator by activating the PKC–IKKβ–NF-κB signaling axis (interacting directly with NF-κB subunits p50 and p65 and with κB DNA, translocating to the nucleus under hypertrophic stimuli, and promoting homodimer formation that modulates transcriptional output), and (2) it regulates actin dynamics by directly binding and sequestering heterodimeric actin-capping protein (CP) at the CP β-subunit tentacle with nanomolar affinity, thereby inhibiting barbed-end capping and influencing Arp2/3-dependent branched actin network formation and cell motility; the CP-sequestering activity is regulated by phosphorylation."},"narrative":{"mechanistic_narrative":"MTPN (myotrophin/V-1) is a small cytoplasmic ankyrin-repeat protein with two distinct, well-evidenced activities: it initiates cardiac hypertrophic signaling and it sequesters heterodimeric actin-capping protein to tune actin filament dynamics [PMID:2144530, PMID:11971907, PMID:16895918]. Originally purified from hypertensive rat and human cardiomyopathic hearts as a 12 kDa factor that stimulates myocyte protein synthesis, growth, and myofibril organization [PMID:2144530, PMID:8508536], its NMR structure comprises two ankyrin repeats forming helix-turn-helix motifs [PMID:9194197]. In the hypertrophic arm, MTPN activates a PKC–IKKβ–NF-κB axis: it stimulates PKCα/PKCε-dependent signaling that drives IκB-α phosphorylation/degradation and NF-κB activation, which is required for MTPN-induced ANF and c-myc expression and protein synthesis [PMID:9633917, PMID:12486112]. Through its IκBα/Rel-homologous ankyrin repeats, MTPN binds directly to NF-κB subunits p50, p65, and c-Rel and to κB DNA, translocates to the nucleus during sustained NF-κB activation, and shifts p50-p65 heterodimers toward homodimers to modulate transcriptional output [PMID:8576259, PMID:11971907, PMID:12031792]. Cardiac-specific overexpression in mice produces progressive hypertrophy and heart failure, while genetic NF-κB blockade or RNAi silencing of MTPN reverses these phenotypes, establishing MTPN as a causal, NF-κB-dependent driver of cardiac remodeling [PMID:14970239, PMID:18620706, PMID:19502558]. In the cytoskeletal arm, MTPN/V-1 binds heterodimeric capping protein 1:1 with nanomolar affinity via loops extending from its ankyrin backbone that engage a basic patch near the CP α/β tentacle, sterically and electrostatically competing with the actin barbed end; it inhibits capping without uncapping pre-capped filaments and allosterically perturbs the CP β-tentacle [PMID:16895918, PMID:20538588, PMID:29847807]. In Dictyostelium, V-1 is present in molar excess over CP and tonically suppresses its activity, controlling Arp2/3 cortical content, F-actin levels, macropinocytosis, and chemotaxis in a CP-binding-dependent, phosphorylation-regulated manner [PMID:27791032].","teleology":[{"year":1990,"claim":"Established that a discrete 12 kDa cardiac factor could itself drive myocyte growth, defining myotrophin as a candidate hypertrophy initiator rather than a generic growth correlate.","evidence":"Purification to homogeneity from hypertensive rat hearts with 3H-leucine incorporation and myofibril morphology bioassay in neonatal cardiomyocytes","pmids":["2144530"],"confidence":"High","gaps":["No receptor or signaling mechanism identified","Relevance to human disease not yet addressed"]},{"year":1993,"claim":"Extended the hypertrophic activity to human pathology by showing elevated myotrophin in dilated cardiomyopathic hearts, linking the factor to human disease.","evidence":"Protein purification and 3H-leucine bioassay from human hearts with immunoblot comparison of diseased vs normal tissue","pmids":["8508536"],"confidence":"High","gaps":["Correlation, not causation, in human tissue","No mechanistic pathway defined"]},{"year":1996,"claim":"Connected myotrophin to transcriptional control by revealing IκBα-like ankyrin repeats and direct interaction with NF-κB/Rel subunits, suggesting a nuclear signaling role.","evidence":"Sequence analysis plus κB EMSA with p50/p65 supershift and antibody inhibition using recombinant protein","pmids":["8576259"],"confidence":"Medium","gaps":["EMSA-based binding without in vivo confirmation at this stage","Functional consequence on transcription not yet shown"]},{"year":1997,"claim":"Provided the structural basis for myotrophin's interactions by determining its two-ankyrin-repeat fold with characteristic helix-turn-helix motifs.","evidence":"Multidimensional heteronuclear NMR on isotopically labeled protein","pmids":["9194197"],"confidence":"High","gaps":["Structure alone does not define binding partners or functional surfaces","No bound-complex structure"]},{"year":1998,"claim":"Defined the upstream kinase logic of hypertrophy, showing PKCα/PKCε isoform-specific mediation downstream of a tyrosine kinase-coupled pathway.","evidence":"PKC activity assays, isoform-specific antisense and antibodies, inhibitors, and subcellular fractionation in cardiomyocytes","pmids":["9633917"],"confidence":"High","gaps":["Link between PKC activation and transcriptional effectors not yet established","Receptor/membrane sensor upstream of PKC unidentified"]},{"year":1999,"claim":"Cloned human myotrophin and identified it as identical to V-1, unifying two literatures and confirming ubiquitous expression with cardiac functional activity.","evidence":"cDNA cloning, multi-tissue expression profiling, recombinant protein hypertrophy bioassay","pmids":["10329199"],"confidence":"Medium","gaps":["Tissue-specific functions outside heart not addressed","Single-lab cloning characterization"]},{"year":2002,"claim":"Integrated the signaling pathway by demonstrating that myotrophin acts through PKC–IKKβ–NF-κB and that NF-κB activation is required for its hypertrophic gene program.","evidence":"NF-κB reporter assays, IκB-α phosphorylation/degradation Westerns, dominant-negative IKKβ and IκB-α, and pharmacological inhibitors in cardiomyocytes","pmids":["12486112"],"confidence":"High","gaps":["How extracellular myotrophin engages this intracellular pathway unresolved","Direct vs indirect NF-κB engagement not separated here"]},{"year":2002,"claim":"Resolved the nuclear function by showing stimulus-dependent nuclear translocation, in vivo association with p65/c-Rel, and conversion of NF-κB heterodimers into homodimers that alters reporter output.","evidence":"Co-IP (in vivo and in vitro), confocal localization, adenoviral overexpression, luciferase reporter, EMSA","pmids":["11971907"],"confidence":"High","gaps":["Physiological consequence of homodimer shift on endogenous genes not fully mapped","Single-lab study"]},{"year":2002,"claim":"Showed that myotrophin binds κB DNA directly and is itself a mechano- and cytokine-responsive gene, embedding it in stress-responsive transcriptional circuits.","evidence":"EMSA with cardiomyocyte nuclear extracts, confocal localization, cyclic stretch and TNF-α/IL-1β treatment","pmids":["12031792"],"confidence":"Medium","gaps":["Direct DNA binding by a small ankyrin protein needs structural validation","Single-lab EMSA evidence"]},{"year":2004,"claim":"Demonstrated sufficiency in vivo: cardiac-specific myotrophin overexpression recapitulates progressive hypertrophy to heart failure with disease-like gene expression.","evidence":"Cardiac-specific transgenic mice with echocardiography, histology, and expression profiling","pmids":["14970239"],"confidence":"High","gaps":["Gain-of-function does not establish requirement of endogenous protein","Pathway dependence in vivo not yet tested genetically"]},{"year":2008,"claim":"Established genetic epistasis placing NF-κB downstream of myotrophin in vivo, since NF-κB blockade attenuates myotrophin-driven hypertrophy and improves function.","evidence":"Myo-Tg × IκBα triple-mutant double transgenic mice with echocardiography, histology, and NF-κB gene arrays","pmids":["18620706"],"confidence":"High","gaps":["Does not isolate NF-κB from parallel PKC effects","Cell-type contributions not dissected"]},{"year":2009,"claim":"Confirmed requirement of endogenous myotrophin by RNAi-induced regression of cardiac mass and NF-κB signaling, completing the causal loss-of-function case.","evidence":"Lentiviral shRNA in transgenic mice and neonatal myocytes with qRT-PCR, Western, and cardiac mass measurement","pmids":["19502558"],"confidence":"High","gaps":["Therapeutic durability not assessed","Off-target effects of shRNA not fully excluded"]},{"year":2006,"claim":"Opened the second functional arm by showing nanomolar, 1:1 binding of V-1 to capping protein at the CP β-tentacle that inhibits barbed-end capping without uncapping.","evidence":"In vitro binding, capping/uncapping assays, mutagenesis of both partners, and molecular dynamics","pmids":["16895918"],"confidence":"High","gaps":["Cellular relevance of CP sequestration not yet shown","Regulation of the interaction unknown at this point"]},{"year":2010,"claim":"Provided atomic-level mechanism showing V-1 loops bind the CP α-tentacle basic patch in direct competition with the barbed-end electrostatic site, explaining inhibition and the absence of uncapping.","evidence":"NMR chemical shift mapping, intermolecular PRE, and CP site-directed mutagenesis","pmids":["20538588"],"confidence":"High","gaps":["In vivo concentration dependence not addressed here","Phosphoregulation not yet defined"]},{"year":2016,"claim":"Established physiological function of CP sequestration in cells, showing V-1 tonically suppresses CP to control Arp2/3 networks, F-actin, macropinocytosis, and chemotaxis in a CP-binding-dependent manner.","evidence":"Dictyostelium knockout/overexpression genetics, F-actin and Arp2/3 imaging, motility assays, WT vs CP-binding-mutant rescue","pmids":["27791032"],"confidence":"High","gaps":["Direct demonstration of equivalent role in mammalian cells absent from corpus","Identity of the regulatory kinase and phosphosites unresolved"]},{"year":2018,"claim":"Revealed an allosteric dimension to CP regulation, showing V-1 and CARMIL bind distinct sites yet both reshape the CP β-tentacle, coupling modulator binding to actin-binding surfaces.","evidence":"Hydrogen-deuterium exchange mass spectrometry on CP complexes","pmids":["29847807"],"confidence":"High","gaps":["Functional consequence of allosteric coupling in cells not measured","Single-lab biophysical study"]},{"year":2020,"claim":"Implicated MTPN in inflammatory signaling beyond the heart, with LOX-mediated suppression of TNF-α responses dependent in part on MTPN.","evidence":"RNA-seq, interaction network analysis, MTPN siRNA, immunofluorescence in ACL fibroblasts and an animal model","pmids":["32483895"],"confidence":"Low","gaps":["LOX–MTPN interaction not established by binding or co-IP","MTPN role inferred from knockdown within a larger study"]},{"year":null,"claim":"How MTPN's two activities—NF-κB modulation and CP sequestration—are coordinated within the same cell, and what kinase and signals control the phosphoregulation of CP binding, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identified kinase or phosphosite for CP-binding regulation","No integrated model linking transcriptional and cytoskeletal functions","Mammalian-cell role of CP sequestration not directly demonstrated in corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,6,8]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10,13,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,13,16]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[10,15]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,7,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,11]}],"complexes":[],"partners":["NFKB1","RELA","REL","CAPZB","CAPZA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P58546","full_name":"Myotrophin","aliases":["Protein V-1"],"length_aa":118,"mass_kda":12.9,"function":"Promotes dimerization of NF-kappa-B subunits and regulates NF-kappa-B transcription factor activity (By similarity). Plays a role in the regulation of the growth of actin filaments. Inhibits the activity of the F-actin-capping protein complex formed by the CAPZA1 and CAPZB heterodimer. Promotes growth of cardiomyocytes, but not cardiomyocyte proliferation. Promotes cardiac muscle hypertrophy","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/P58546/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTPN","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":10.0},{"gene":"G3BP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MTPN","total_profiled":1310},"omim":[{"mim_id":"611173","title":"MICRO RNA 375; MIR375","url":"https://www.omim.org/entry/611173"},{"mim_id":"611050","title":"LEUCINE ZIPPER PROTEIN 6; LUZP6","url":"https://www.omim.org/entry/611050"},{"mim_id":"606484","title":"MYOTROPHIN; MTPN","url":"https://www.omim.org/entry/606484"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTPN"},"hgnc":{"alias_symbol":["MYOTROPHIN","GCDP","V-1"],"prev_symbol":[]},"alphafold":{"accession":"P58546","domains":[{"cath_id":"1.25.40.20","chopping":"2-116","consensus_level":"high","plddt":89.3597,"start":2,"end":116}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P58546","model_url":"https://alphafold.ebi.ac.uk/files/AF-P58546-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P58546-F1-predicted_aligned_error_v6.png","plddt_mean":88.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTPN","jax_strain_url":"https://www.jax.org/strain/search?query=MTPN"},"sequence":{"accession":"P58546","fasta_url":"https://rest.uniprot.org/uniprotkb/P58546.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P58546/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P58546"}},"corpus_meta":[{"pmid":"9581771","id":"PMC_9581771","title":"Deletion of the K(V)1.1 potassium channel causes epilepsy in mice.","date":"1998","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/9581771","citation_count":482,"is_preprint":false},{"pmid":"17950472","id":"PMC_17950472","title":"From genes to pain: Na v 1.7 and human pain disorders.","date":"2007","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/17950472","citation_count":220,"is_preprint":false},{"pmid":"31969708","id":"PMC_31969708","title":"Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/31969708","citation_count":202,"is_preprint":false},{"pmid":"19744495","id":"PMC_19744495","title":"Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology.","date":"2009","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/19744495","citation_count":202,"is_preprint":false},{"pmid":"10903523","id":"PMC_10903523","title":"Expression of silicatein and collagen genes in the marine sponge Suberites domuncula is controlled by silicate and myotrophin.","date":"2000","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10903523","citation_count":187,"is_preprint":false},{"pmid":"12486112","id":"PMC_12486112","title":"Activation of nuclear factor-kappaB is necessary for myotrophin-induced cardiac hypertrophy.","date":"2002","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12486112","citation_count":111,"is_preprint":false},{"pmid":"30076230","id":"PMC_30076230","title":"Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30076230","citation_count":108,"is_preprint":false},{"pmid":"38172636","id":"PMC_38172636","title":"Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/38172636","citation_count":94,"is_preprint":false},{"pmid":"29514831","id":"PMC_29514831","title":"Cardiac Kir2.1 and NaV1.5 Channels Traffic Together to the Sarcolemma to Control Excitability.","date":"2018","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/29514831","citation_count":92,"is_preprint":false},{"pmid":"18266933","id":"PMC_18266933","title":"Ca(v)1 L-type Ca2+ channel signaling complexes in neurons.","date":"2008","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18266933","citation_count":90,"is_preprint":false},{"pmid":"21088933","id":"PMC_21088933","title":"Ca(v)1.3 and BK channels for timing and regulating cell firing.","date":"2010","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/21088933","citation_count":89,"is_preprint":false},{"pmid":"34348157","id":"PMC_34348157","title":"Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34348157","citation_count":89,"is_preprint":false},{"pmid":"2144530","id":"PMC_2144530","title":"Myotrophin: purification of a novel peptide from spontaneously hypertensive rat heart that influences myocardial growth.","date":"1990","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2144530","citation_count":78,"is_preprint":false},{"pmid":"21190943","id":"PMC_21190943","title":"Reduced sodium channel Na(v)1.1 levels in BACE1-null mice.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21190943","citation_count":72,"is_preprint":false},{"pmid":"21729089","id":"PMC_21729089","title":"Alternative perspective on intestinal calcium absorption: proposed complementary actions of Ca(v)1.3 and TRPV6.","date":"2011","source":"Nutrition reviews","url":"https://pubmed.ncbi.nlm.nih.gov/21729089","citation_count":68,"is_preprint":false},{"pmid":"31904127","id":"PMC_31904127","title":"SCN1A/NaV 1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models.","date":"2019","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/31904127","citation_count":60,"is_preprint":false},{"pmid":"29643227","id":"PMC_29643227","title":"Voltage and pH sensing by the voltage-gated proton channel, HV1.","date":"2018","source":"Journal of the Royal Society, Interface","url":"https://pubmed.ncbi.nlm.nih.gov/29643227","citation_count":58,"is_preprint":false},{"pmid":"30755524","id":"PMC_30755524","title":"Cold sensing by NaV1.8-positive and NaV1.8-negative sensory neurons.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30755524","citation_count":56,"is_preprint":false},{"pmid":"28105664","id":"PMC_28105664","title":"Visceral and somatic pain modalities reveal NaV 1.7-independent visceral nociceptive pathways.","date":"2017","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28105664","citation_count":56,"is_preprint":false},{"pmid":"11023986","id":"PMC_11023986","title":"Stimulation of protein (collagen) synthesis in sponge cells by a cardiac myotrophin-related molecule from Suberites domuncula.","date":"2000","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/11023986","citation_count":56,"is_preprint":false},{"pmid":"16895918","id":"PMC_16895918","title":"Binding of myotrophin/V-1 to actin-capping protein: implications for how capping protein binds to the filament barbed end.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16895918","citation_count":55,"is_preprint":false},{"pmid":"27503742","id":"PMC_27503742","title":"Familial gain-of-function Nav1.9 mutation in a painful channelopathy.","date":"2016","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/27503742","citation_count":53,"is_preprint":false},{"pmid":"29186814","id":"PMC_29186814","title":"Alternative Splicing of L-type CaV1.2 Calcium Channels: Implications in Cardiovascular Diseases.","date":"2017","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/29186814","citation_count":53,"is_preprint":false},{"pmid":"35277491","id":"PMC_35277491","title":"Structural basis for modulation of human NaV1.3 by clinical drug and selective antagonist.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35277491","citation_count":52,"is_preprint":false},{"pmid":"32441256","id":"PMC_32441256","title":"Aberrant subchondral osteoblastic metabolism modifies NaV1.8 for osteoarthritis.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32441256","citation_count":52,"is_preprint":false},{"pmid":"19185186","id":"PMC_19185186","title":"Genetics and molecular pathophysiology of Na(v)1.7-related pain syndromes.","date":"2008","source":"Advances in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19185186","citation_count":49,"is_preprint":false},{"pmid":"32222817","id":"PMC_32222817","title":"Skeletal muscle CaV1.1 channelopathies.","date":"2020","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32222817","citation_count":48,"is_preprint":false},{"pmid":"14970239","id":"PMC_14970239","title":"Cardiac overexpression of myotrophin triggers myocardial hypertrophy and heart failure in transgenic mice.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14970239","citation_count":47,"is_preprint":false},{"pmid":"19527072","id":"PMC_19527072","title":"Protein kinase C isoforms differentially phosphorylate Ca(v)1.2 alpha(1c).","date":"2009","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19527072","citation_count":47,"is_preprint":false},{"pmid":"31612502","id":"PMC_31612502","title":"Voltage-dependent activation of Rac1 by Nav 1.5 channels promotes cell migration.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31612502","citation_count":47,"is_preprint":false},{"pmid":"36424916","id":"PMC_36424916","title":"Rad regulation of CaV1.2 channels controls cardiac fight-or-flight response.","date":"2022","source":"Nature cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/36424916","citation_count":46,"is_preprint":false},{"pmid":"9633917","id":"PMC_9633917","title":"Increased protein kinase C activity in myotrophin-induced myocyte growth.","date":"1998","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/9633917","citation_count":45,"is_preprint":false},{"pmid":"34126155","id":"PMC_34126155","title":"Targeting immunodominant Bet v 1 epitopes with monoclonal antibodies prevents the birch allergic response.","date":"2021","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34126155","citation_count":45,"is_preprint":false},{"pmid":"33086983","id":"PMC_33086983","title":"Adrenergic CaV1.2 Activation via Rad Phosphorylation Converges at α1C I-II Loop.","date":"2020","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/33086983","citation_count":44,"is_preprint":false},{"pmid":"11971907","id":"PMC_11971907","title":"Myotrophin/V-1, a protein up-regulated in the failing human heart and in postnatal cerebellum, converts NFkappa B p50-p65 heterodimers to p50-p50 and p65-p65 homodimers.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11971907","citation_count":43,"is_preprint":false},{"pmid":"8576259","id":"PMC_8576259","title":"Cardiac myotrophin exhibits rel/NF-kappa B interacting activity in vitro.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8576259","citation_count":39,"is_preprint":false},{"pmid":"29142310","id":"PMC_29142310","title":"Sodium channel NaV1.3 is important for enterochromaffin cell excitability and serotonin release.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29142310","citation_count":39,"is_preprint":false},{"pmid":"31087362","id":"PMC_31087362","title":"NaV 1.6 regulates excitability of mechanosensitive sensory neurons.","date":"2019","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31087362","citation_count":38,"is_preprint":false},{"pmid":"37498871","id":"PMC_37498871","title":"Identification and targeting of a unique NaV1.7 domain driving chronic pain.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37498871","citation_count":37,"is_preprint":false},{"pmid":"8508536","id":"PMC_8508536","title":"Myotrophin in human cardiomyopathic heart.","date":"1993","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/8508536","citation_count":37,"is_preprint":false},{"pmid":"20538588","id":"PMC_20538588","title":"Structural basis for capping protein sequestration by myotrophin (V-1).","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20538588","citation_count":36,"is_preprint":false},{"pmid":"32078054","id":"PMC_32078054","title":"Inhibition of NaV1.8 prevents atrial arrhythmogenesis in human and mice.","date":"2020","source":"Basic research in cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/32078054","citation_count":35,"is_preprint":false},{"pmid":"29650545","id":"PMC_29650545","title":"Regulation of Blood Pressure by Targeting CaV1.2-Galectin-1 Protein Interaction.","date":"2018","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/29650545","citation_count":35,"is_preprint":false},{"pmid":"36278870","id":"PMC_36278870","title":"NaV1.1 is essential for proprioceptive signaling and motor behaviors.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36278870","citation_count":30,"is_preprint":false},{"pmid":"18620706","id":"PMC_18620706","title":"Blockade of NF-kappaB using IkappaB alpha dominant-negative mice ameliorates cardiac hypertrophy in myotrophin-overexpressed transgenic mice.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18620706","citation_count":30,"is_preprint":false},{"pmid":"34202119","id":"PMC_34202119","title":"Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34202119","citation_count":29,"is_preprint":false},{"pmid":"32335140","id":"PMC_32335140","title":"A selective NaV1.1 activator with potential for treatment of Dravet syndrome epilepsy.","date":"2020","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32335140","citation_count":29,"is_preprint":false},{"pmid":"31398491","id":"PMC_31398491","title":"TRPV6 and Cav1.3 Mediate Distal Small Intestine Calcium Absorption Before Weaning.","date":"2019","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/31398491","citation_count":28,"is_preprint":false},{"pmid":"31916131","id":"PMC_31916131","title":"Absence of Functional Nav1.8 Channels in Non-diseased Atrial and Ventricular Cardiomyocytes.","date":"2019","source":"Cardiovascular drugs and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31916131","citation_count":28,"is_preprint":false},{"pmid":"34072954","id":"PMC_34072954","title":"Mechanisms and Regulation of Cardiac CaV1.2 Trafficking.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34072954","citation_count":27,"is_preprint":false},{"pmid":"29593552","id":"PMC_29593552","title":"KV4.3 Expression Modulates NaV1.5 Sodium Current.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29593552","citation_count":27,"is_preprint":false},{"pmid":"29854783","id":"PMC_29854783","title":"Channeling Vision: CaV1.4-A Critical Link in Retinal Signal Transmission.","date":"2018","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/29854783","citation_count":27,"is_preprint":false},{"pmid":"32128393","id":"PMC_32128393","title":"Sensory neuron-derived NaV1.7 contributes to dorsal horn neuron excitability.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/32128393","citation_count":27,"is_preprint":false},{"pmid":"32492370","id":"PMC_32492370","title":"Multiple Sequence Variants in STAC3 Affect Interactions with CaV1.1 and Excitation-Contraction Coupling.","date":"2020","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/32492370","citation_count":26,"is_preprint":false},{"pmid":"39089251","id":"PMC_39089251","title":"The V-ATPase/ATG16L1 axis is controlled by the V1H subunit.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/39089251","citation_count":25,"is_preprint":false},{"pmid":"36345826","id":"PMC_36345826","title":"Spatiotemporal Control of Vascular CaV1.2 by α1C S1928 Phosphorylation.","date":"2022","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/36345826","citation_count":25,"is_preprint":false},{"pmid":"37117223","id":"PMC_37117223","title":"Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37117223","citation_count":24,"is_preprint":false},{"pmid":"37025382","id":"PMC_37025382","title":"Pathophysiology of Cav1.3 L-type calcium channels in the heart.","date":"2023","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37025382","citation_count":24,"is_preprint":false},{"pmid":"35469063","id":"PMC_35469063","title":"Coordinated conformational changes in the V1 complex during V-ATPase reversible dissociation.","date":"2022","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35469063","citation_count":24,"is_preprint":false},{"pmid":"33478555","id":"PMC_33478555","title":"Non-SUMOylated CRMP2 decreases NaV1.7 currents via the endocytic proteins Numb, Nedd4-2 and Eps15.","date":"2021","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/33478555","citation_count":24,"is_preprint":false},{"pmid":"35219855","id":"PMC_35219855","title":"NaV1.1 haploinsufficiency impairs glutamatergic and GABAergic neuron function in the thalamus.","date":"2022","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/35219855","citation_count":23,"is_preprint":false},{"pmid":"12932609","id":"PMC_12932609","title":"Myotrophin in human heart failure.","date":"2003","source":"Journal of the American College of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/12932609","citation_count":23,"is_preprint":false},{"pmid":"27791032","id":"PMC_27791032","title":"V-1 regulates capping protein activity in vivo.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27791032","citation_count":22,"is_preprint":false},{"pmid":"10329199","id":"PMC_10329199","title":"cDNA sequence and characterization of the gene that encodes human myotrophin/V-1 protein, a mediator of cardiac hypertrophy.","date":"1999","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/10329199","citation_count":22,"is_preprint":false},{"pmid":"19151588","id":"PMC_19151588","title":"The Ca(v)1.4 calcium channel: more than meets the eye.","date":"2007","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19151588","citation_count":22,"is_preprint":false},{"pmid":"29847807","id":"PMC_29847807","title":"Allosteric Coupling of CARMIL and V-1 Binding to Capping Protein Revealed by Hydrogen-Deuterium Exchange.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29847807","citation_count":22,"is_preprint":false},{"pmid":"34011626","id":"PMC_34011626","title":"Nav1.7 target modulation and efficacy can be measured in nonhuman primate assays.","date":"2021","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34011626","citation_count":21,"is_preprint":false},{"pmid":"30772377","id":"PMC_30772377","title":"UBC9 regulates cardiac sodium channel Nav1.5 ubiquitination, degradation and sodium current density.","date":"2019","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/30772377","citation_count":21,"is_preprint":false},{"pmid":"9095231","id":"PMC_9095231","title":"Biological and immunological importance of Bet v 1 isoforms.","date":"1996","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/9095231","citation_count":21,"is_preprint":false},{"pmid":"32483895","id":"PMC_32483895","title":"Lysyl oxidase suppresses the inflammatory response in anterior cruciate ligament fibroblasts and promotes tissue regeneration by targeting myotrophin via the nuclear factor-kappa B pathway.","date":"2020","source":"Journal of tissue engineering and regenerative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32483895","citation_count":20,"is_preprint":false},{"pmid":"33342222","id":"PMC_33342222","title":"Structural and Functional Characterization of a Nav1.5-Mitochondrial Couplon.","date":"2020","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/33342222","citation_count":20,"is_preprint":false},{"pmid":"12031792","id":"PMC_12031792","title":"Myotrophin-kappaB DNA interaction in the initiation process of cardiac hypertrophy.","date":"2002","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/12031792","citation_count":18,"is_preprint":false},{"pmid":"7758156","id":"PMC_7758156","title":"Quantification of myotrophin from spontaneously hypertensive and normal rat hearts.","date":"1995","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/7758156","citation_count":18,"is_preprint":false},{"pmid":"29031710","id":"PMC_29031710","title":"Nav1.8 neurons are involved in limiting acute phase responses to dietary fat.","date":"2017","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29031710","citation_count":17,"is_preprint":false},{"pmid":"34375627","id":"PMC_34375627","title":"Regulation of the voltage-dependent sodium channel NaV1.1 by AKT1.","date":"2021","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34375627","citation_count":17,"is_preprint":false},{"pmid":"31958466","id":"PMC_31958466","title":"The cardiac CaMKII-Nav1.5 relationship: From physiology to pathology.","date":"2020","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/31958466","citation_count":16,"is_preprint":false},{"pmid":"34842957","id":"PMC_34842957","title":"PI-QUAL v.1: the first step towards good-quality prostate MRI.","date":"2021","source":"European radiology","url":"https://pubmed.ncbi.nlm.nih.gov/34842957","citation_count":16,"is_preprint":false},{"pmid":"37003485","id":"PMC_37003485","title":"Nav1.7 gain-of-function mutation I228M triggers age-dependent nociceptive insensitivity and C-LTMR dysregulation.","date":"2023","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37003485","citation_count":16,"is_preprint":false},{"pmid":"34170484","id":"PMC_34170484","title":"The ATO/miRNA-885-5p/MTPN axis induces reversal of drug-resistance in cholangiocarcinoma.","date":"2021","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/34170484","citation_count":16,"is_preprint":false},{"pmid":"28300567","id":"PMC_28300567","title":"9-cis Retinoic acid modulates myotrophin expression and its miR in physiological and pathophysiological cell models.","date":"2017","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28300567","citation_count":16,"is_preprint":false},{"pmid":"34312446","id":"PMC_34312446","title":"Kv1.1 channels mediate network excitability and feed-forward inhibition in local amygdala circuits.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34312446","citation_count":16,"is_preprint":false},{"pmid":"9194197","id":"PMC_9194197","title":"Nuclear magnetic resonance assignment and secondary structure of an ankyrin-like repeat-bearing protein: myotrophin.","date":"1997","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/9194197","citation_count":16,"is_preprint":false},{"pmid":"33370552","id":"PMC_33370552","title":"Elevated EZH2 in ischemic heart disease epigenetically mediates suppression of NaV1.5 expression.","date":"2020","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/33370552","citation_count":16,"is_preprint":false},{"pmid":"37751532","id":"PMC_37751532","title":"Intranasal CRMP2-Ubc9 inhibitor regulates Na V 1.7 to alleviate trigeminal neuropathic pain.","date":"2023","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/37751532","citation_count":15,"is_preprint":false},{"pmid":"33123007","id":"PMC_33123007","title":"Inhibitory Effect of Eslicarbazepine Acetate and S-Licarbazepine on Nav1.5 Channels.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33123007","citation_count":14,"is_preprint":false},{"pmid":"19502558","id":"PMC_19502558","title":"Silencing the myotrophin gene by RNA interference leads to the regression of cardiac hypertrophy.","date":"2009","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19502558","citation_count":13,"is_preprint":false},{"pmid":"29934995","id":"PMC_29934995","title":"Mutation in Nav 1.7 causes high olfactory sensitivity.","date":"2018","source":"European journal of pain (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29934995","citation_count":13,"is_preprint":false},{"pmid":"34355697","id":"PMC_34355697","title":"Discovery and characterization of Hv1-type proton channels in reef-building corals.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34355697","citation_count":13,"is_preprint":false},{"pmid":"11404186","id":"PMC_11404186","title":"S-myotrophin promotes the hypertrophy of myotube as insulin-like growth factor-I does.","date":"2001","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11404186","citation_count":12,"is_preprint":false},{"pmid":"36860665","id":"PMC_36860665","title":"Paclitaxel effects on axonal localization and vesicular trafficking of NaV1.8.","date":"2023","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36860665","citation_count":12,"is_preprint":false},{"pmid":"36424884","id":"PMC_36424884","title":"Bet v 1-independent sensitization to major allergens in Fagales pollen: Evidence at the T-cell level.","date":"2022","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/36424884","citation_count":12,"is_preprint":false},{"pmid":"35589958","id":"PMC_35589958","title":"Cytosolic peptides encoding CaV1 C-termini downregulate the calcium channel activity-neuritogenesis coupling.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/35589958","citation_count":12,"is_preprint":false},{"pmid":"34583989","id":"PMC_34583989","title":"Voltage sensor movements of CaV1.1 during an action potential in skeletal muscle fibers.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34583989","citation_count":12,"is_preprint":false},{"pmid":"30717088","id":"PMC_30717088","title":"Centipede KCNQ Inhibitor SsTx Also Targets KV1.3.","date":"2019","source":"Toxins","url":"https://pubmed.ncbi.nlm.nih.gov/30717088","citation_count":12,"is_preprint":false},{"pmid":"32948286","id":"PMC_32948286","title":"Pathogenic mutations perturb calmodulin regulation of Nav1.8 channel.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32948286","citation_count":12,"is_preprint":false},{"pmid":"37663247","id":"PMC_37663247","title":"Calmodulin mutations affecting Gly114 impair binding to the NaV1.5 IQ-domain.","date":"2023","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37663247","citation_count":12,"is_preprint":false},{"pmid":"28254884","id":"PMC_28254884","title":"A functional coupling between CRMP1 and Nav1.7 for retrograde propagation of Semaphorin3A signaling.","date":"2017","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/28254884","citation_count":12,"is_preprint":false},{"pmid":"21667249","id":"PMC_21667249","title":"Molecular characterization, expression patterns and subcellular localization of Myotrophin (MTPN) gene in porcine skeletal muscle.","date":"2011","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21667249","citation_count":11,"is_preprint":false},{"pmid":"36224259","id":"PMC_36224259","title":"Evaluation of Nav1.8 as a therapeutic target for Pitt Hopkins Syndrome.","date":"2022","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36224259","citation_count":11,"is_preprint":false},{"pmid":"33526839","id":"PMC_33526839","title":"Function of cone and cone-related pathways in CaV1.4 IT mice.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33526839","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51236,"output_tokens":4761,"usd":0.112561,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13139,"output_tokens":5289,"usd":0.09896,"stage2_stop_reason":"end_turn"},"total_usd":0.211521,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"Myotrophin was purified to apparent homogeneity from spontaneously hypertensive rat hearts as a novel 12 kDa protein that stimulates protein synthesis and myocardial cell growth in isolated neonatal cardiac myocytes, causing increased surface area and organized myofibril formation in a dose-dependent manner.\",\n      \"method\": \"Protein purification, bioassay (3H-leucine incorporation into myocyte protein), amino acid sequencing, morphological assessment of myocyte surface area and myofibril organization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purification to homogeneity with functional reconstitution in primary cardiomyocytes; foundational paper replicated in multiple subsequent studies\",\n      \"pmids\": [\"2144530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Human myotrophin purified from dilated cardiomyopathic hearts is a single 12 kDa polypeptide that stimulates adult myocardial protein synthesis and cell growth, with significantly elevated levels in dilated cardiomyopathic versus normal human hearts.\",\n      \"method\": \"Protein purification (reverse-phase HPLC, SDS-PAGE), 3H-leucine incorporation bioassay, Western blot, immunoblot with rat myotrophin antibody\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purification to homogeneity with functional bioassay; independently confirms rat findings in human tissue\",\n      \"pmids\": [\"8508536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Myotrophin protein contains ankyrin repeats with high homology to IκBα/rel ankyrin repeats, and recombinant myotrophin interacts directly with NF-κB/rel proteins (p50 and p65) as demonstrated by formation of ternary protein-DNA complexes in kappa B gel shift assays; myotrophin-specific antibodies inhibited these complexes.\",\n      \"method\": \"Sequence analysis, kappa B gel shift assay (EMSA), supershift assay with rel-specific p50 and p65 antibodies, antibody inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA with antibody supershift provides direct binding evidence; single lab but orthogonal methods (sequence analysis + functional assay)\",\n      \"pmids\": [\"8576259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"NMR analysis revealed that myotrophin consists of seven helices forming three helix-turn-helix motifs, with two full ankyrin repeats characterized by multiple turns followed by helix-turn-helix motifs; a hairpin-like turn in ANK repeat #1 (L32-R36) shows slow conformational averaging distinct from ANK repeat #2.\",\n      \"method\": \"Multidimensional heteronuclear NMR (2D and 3D) on uniformly 15N-labeled and 15N/13C-labeled protein; NOE analysis, NH exchange, coupling constants, chemical shift analysis\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR secondary structure determination with multiple orthogonal NMR experiments on isotopically labeled protein; single lab\",\n      \"pmids\": [\"9194197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Myotrophin stimulates PKC activity and protein synthesis in neonatal cardiac myocytes through a tyrosine kinase-coupled pathway; PKCα and PKCε isoforms mediate myotrophin-induced neonatal myocyte growth, whereas only PKCε mediates adult myocyte hypertrophy. Myotrophin-induced PKC activity is located predominantly in the particulate (membrane) fraction.\",\n      \"method\": \"PKC activity assay (32P incorporation into histone and PKCε substrate peptide), 3H-leucine incorporation, pharmacological inhibitors (staurosporine, H-7, calphostin C, genistein), Western blot with isoform-specific antibodies, antisense oligonucleotides, subcellular fractionation\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (kinase assays, inhibitors, antisense knockdown, fractionation) in single lab with rigorous controls\",\n      \"pmids\": [\"9633917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human myotrophin/V-1 cDNA was cloned and characterized; the protein is identical to previously described V-1 proteins, is ubiquitously expressed with high expression in heart, and recombinant human myotrophin produces cardiomyocyte hypertrophy in vitro.\",\n      \"method\": \"cDNA cloning, Northern blot, Southern blot, dot blot (50 tissues), recombinant protein expression and functional bioassay\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cloning with functional validation of recombinant protein; single lab\",\n      \"pmids\": [\"10329199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Myotrophin/V-1 is predominantly cytoplasmic but translocates to the nucleus during sustained NF-κB activation. It interacts physically with p65 and c-Rel proteins in vivo during NF-κB activation (co-IP), and in vitro promotes conversion of p50-p65 heterodimers into p50-p50 and p65-p65 homodimers. Adenoviral overexpression of myotrophin/V-1 increased p50-p50 homodimers and reduced κB-luciferase reporter activity.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), confocal microscopy (subcellular localization), 3D structural alignment, adenoviral overexpression, luciferase reporter assay, EMSA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, subcellular localization with functional consequence, reporter assay, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"11971907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NF-κB activation is required for myotrophin-induced cardiac hypertrophy: myotrophin treatment stimulates NF-κB nuclear translocation and transcriptional activity via IκB-α phosphorylation and degradation through a PKC-IKKβ-NF-κB pathway. Dominant-negative IKKβ or IκB-α blocked myotrophin-induced ANF and c-myc expression and protein synthesis.\",\n      \"method\": \"NF-κB reporter assay, Western blot for IκB-α phosphorylation/degradation, dominant-negative constructs (IKKβ, IκB-α), pharmacological inhibitors (PDTC, calphostin C), 3H-leucine incorporation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (dominant-negative) and pharmacological loss-of-function with defined molecular readouts; multiple orthogonal approaches; single lab\",\n      \"pmids\": [\"12486112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Myotrophin binds directly to κB DNA, as shown by gel mobility shift assay with nuclear extracts from neonatal and adult cardiomyocytes. Under cyclic stretch, myotrophin levels increase in the nucleus. Myotrophin gene expression is upregulated by cyclic stretch, TNF-α, IL-1β, and high pressure in beating hearts.\",\n      \"method\": \"Gel mobility shift assay (EMSA), confocal microscopy (subcellular localization), recombinant protein, cyclic stretch model, pharmacological treatment\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA with defined nuclear extract plus direct localization imaging; single lab\",\n      \"pmids\": [\"12031792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cardiac-specific overexpression of myotrophin in transgenic mice causes progressive cardiac hypertrophy by 4 weeks of age, progressing to heart failure by 9–12 months, with increased expression of proto-oncogenes, hypertrophy marker genes, growth factors, and cytokines mimicking human cardiomyopathy.\",\n      \"method\": \"Transgenic mouse model (cardiac-specific overexpression), echocardiography, histology, gene expression profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo gain-of-function with defined temporal progression and molecular characterization; replicated phenotype of prior in vitro findings\",\n      \"pmids\": [\"14970239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Myotrophin/V-1 binds directly to heterodimeric actin-capping protein (CP) in a 1:1 molar ratio with Kd of 10–50 nM. V-1 binding inhibits CP's ability to cap actin filament barbed ends. The CP β-subunit C-terminal 'tentacle' is the primary binding site on CP for V-1. Two loops of V-1 extending from its ankyrin repeat backbone are necessary for V-1 to bind CP. V-1 appears unable to bind CP already on the barbed end and has no uncapping activity.\",\n      \"method\": \"In vitro binding assays, actin barbed-end capping assays, uncapping assays, site-directed mutagenesis (V-1 loops and CP subunit regions), computational modeling and molecular dynamics simulations\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro binding with Kd determination, mutagenesis of both interaction partners, and computational validation; multiple orthogonal methods\",\n      \"pmids\": [\"16895918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Genetic blockade of NF-κB (via IκBα triple mutant mice crossed with myotrophin-overexpressing transgenic mice) attenuates myotrophin-induced cardiac hypertrophy and improves cardiac function, demonstrating that continuous NF-κB blockade is effective against myotrophin-driven cardiac remodeling.\",\n      \"method\": \"Double transgenic mice (Myo-Tg × IκBα triple mutant), echocardiography, histology, NF-κB gene array profiling, apoptosis markers\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis (double transgenic) with defined physiological and molecular readouts\",\n      \"pmids\": [\"18620706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RNA interference (shRNA lentiviral delivery) silencing of myotrophin in myotrophin-overexpressing transgenic mice causes regression of cardiac mass and reduction in NF-κB signaling and ANF expression, establishing a causal role for myotrophin in NF-κB-dependent cardiac hypertrophy.\",\n      \"method\": \"Lentiviral shRNA delivery in vivo and in vitro (neonatal rat myocytes), qRT-PCR, Western blot, cardiac mass measurement\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function (RNAi) in both cell and animal models with defined molecular and physiological readouts\",\n      \"pmids\": [\"19502558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NMR chemical shift mapping and intermolecular paramagnetic relaxation enhancement experiments revealed that the ankyrin loops of V-1 bind to the basic patch near the joint of the α tentacle of CP. Site-directed mutagenesis of CP confirmed that V-1 and the electrostatic barbed-end binding site on CP compete for this same basic patch, explaining how V-1 inactivates barbed end capping and why V-1 cannot uncap CP-capped actin filaments.\",\n      \"method\": \"NMR (chemical shift mapping, intermolecular PRE experiments), site-directed mutagenesis of CP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure-function study with mutagenesis validation; provides atomic-resolution mechanism for V-1/CP interaction\",\n      \"pmids\": [\"20538588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Porcine MTPN protein is localized to the cytoplasm of Pig Kidney Epithelial (PK15) cells as determined by transient transfection, and is widely expressed across tissues with high levels in spleen, liver, and uterus; expression peaks at embryonic day 65 and is down-regulated postnatally during skeletal muscle development.\",\n      \"method\": \"Transient transfection with subcellular localization imaging, RT-PCR, qRT-PCR, cDNA cloning, genomic structure analysis\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization by transfection imaging confirmed in multiple tissues; single lab\",\n      \"pmids\": [\"21667249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"V-1/Myotrophin regulates capping protein (CP) activity in vivo in Dictyostelium: overexpression of V-1 reduced pseudopod size and cortical Arp2/3 content and induced filopodia in a CP-binding-dependent manner (a V-1 mutant unable to bind CP had no effect). V-1-null cells showed decreased cellular F-actin content and defects in macropinocytosis and chemotactic aggregation rescued by wild-type but not CP-binding-deficient V-1. V-1 is present in molar excess over CP suggesting it tonically suppresses CP activity in the cytoplasm. Evidence that V-1's CP-sequestering activity is regulated by phosphorylation was also obtained.\",\n      \"method\": \"Dictyostelium overexpression and knockout genetics, fluorescence microscopy (Arp2/3 and F-actin quantification), macropinocytosis assay, chemotaxis assay, rescue experiments with WT and mutant V-1\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ortholog in Dictyostelium (consistent domain architecture and CP-binding mechanism); loss-of-function and gain-of-function with mutant rescue; multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"27791032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"V-1 and CARMIL bind to distinct sites on capping protein and induce allosteric conformational changes in CP detected by hydrogen-deuterium exchange mass spectrometry. Both V-1 and CARMIL affect the conformation of CP's ββ subunit tentacle (a second actin-binding site distal from their respective binding sites), revealing allosteric coupling between CP modulator and actin binding sites.\",\n      \"method\": \"Hydrogen-deuterium exchange mass spectrometry (HDX-MS)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — HDX-MS provides structural dynamics evidence for allosteric mechanism; single lab but rigorous biophysical method\",\n      \"pmids\": [\"29847807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Lysyl oxidase (LOX) suppresses TNF-α-induced inflammatory responses in ACL fibroblasts partly via MTPN: silencing MTPN expression alleviated the anti-inflammatory effect of LOX, suggesting LOX interacts with MTPN to regulate inflammation through the NF-κB signaling pathway.\",\n      \"method\": \"RNA sequencing, protein-protein interaction network analysis, siRNA knockdown of MTPN, immunofluorescence, in vivo animal model\",\n      \"journal\": \"Journal of tissue engineering and regenerative medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, MTPN knockdown as one element in a larger study; mechanistic link between LOX and MTPN not directly established by binding or co-IP\",\n      \"pmids\": [\"32483895\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTPN (Myotrophin/V-1) is a small ~12 kDa cytoplasmic ankyrin-repeat protein with two established molecular functions: (1) it acts as a cardiac hypertrophy initiator by activating the PKC–IKKβ–NF-κB signaling axis (interacting directly with NF-κB subunits p50 and p65 and with κB DNA, translocating to the nucleus under hypertrophic stimuli, and promoting homodimer formation that modulates transcriptional output), and (2) it regulates actin dynamics by directly binding and sequestering heterodimeric actin-capping protein (CP) at the CP β-subunit tentacle with nanomolar affinity, thereby inhibiting barbed-end capping and influencing Arp2/3-dependent branched actin network formation and cell motility; the CP-sequestering activity is regulated by phosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTPN (myotrophin/V-1) is a small cytoplasmic ankyrin-repeat protein with two distinct, well-evidenced activities: it initiates cardiac hypertrophic signaling and it sequesters heterodimeric actin-capping protein to tune actin filament dynamics [#0, #6, #10]. Originally purified from hypertensive rat and human cardiomyopathic hearts as a 12 kDa factor that stimulates myocyte protein synthesis, growth, and myofibril organization [#0, #1], its NMR structure comprises two ankyrin repeats forming helix-turn-helix motifs [#3]. In the hypertrophic arm, MTPN activates a PKC\\u2013IKK\\u03b2\\u2013NF-\\u03baB axis: it stimulates PKC\\u03b1/PKC\\u03b5-dependent signaling that drives I\\u03baB-\\u03b1 phosphorylation/degradation and NF-\\u03baB activation, which is required for MTPN-induced ANF and c-myc expression and protein synthesis [#4, #7]. Through its I\\u03baB\\u03b1/Rel-homologous ankyrin repeats, MTPN binds directly to NF-\\u03baB subunits p50, p65, and c-Rel and to \\u03baB DNA, translocates to the nucleus during sustained NF-\\u03baB activation, and shifts p50-p65 heterodimers toward homodimers to modulate transcriptional output [#2, #6, #8]. Cardiac-specific overexpression in mice produces progressive hypertrophy and heart failure, while genetic NF-\\u03baB blockade or RNAi silencing of MTPN reverses these phenotypes, establishing MTPN as a causal, NF-\\u03baB-dependent driver of cardiac remodeling [#9, #11, #12]. In the cytoskeletal arm, MTPN/V-1 binds heterodimeric capping protein 1:1 with nanomolar affinity via loops extending from its ankyrin backbone that engage a basic patch near the CP \\u03b1/\\u03b2 tentacle, sterically and electrostatically competing with the actin barbed end; it inhibits capping without uncapping pre-capped filaments and allosterically perturbs the CP \\u03b2-tentacle [#10, #13, #16]. In Dictyostelium, V-1 is present in molar excess over CP and tonically suppresses its activity, controlling Arp2/3 cortical content, F-actin levels, macropinocytosis, and chemotaxis in a CP-binding-dependent, phosphorylation-regulated manner [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that a discrete 12 kDa cardiac factor could itself drive myocyte growth, defining myotrophin as a candidate hypertrophy initiator rather than a generic growth correlate.\",\n      \"evidence\": \"Purification to homogeneity from hypertensive rat hearts with 3H-leucine incorporation and myofibril morphology bioassay in neonatal cardiomyocytes\",\n      \"pmids\": [\"2144530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No receptor or signaling mechanism identified\", \"Relevance to human disease not yet addressed\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Extended the hypertrophic activity to human pathology by showing elevated myotrophin in dilated cardiomyopathic hearts, linking the factor to human disease.\",\n      \"evidence\": \"Protein purification and 3H-leucine bioassay from human hearts with immunoblot comparison of diseased vs normal tissue\",\n      \"pmids\": [\"8508536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Correlation, not causation, in human tissue\", \"No mechanistic pathway defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Connected myotrophin to transcriptional control by revealing I\\u03baB\\u03b1-like ankyrin repeats and direct interaction with NF-\\u03baB/Rel subunits, suggesting a nuclear signaling role.\",\n      \"evidence\": \"Sequence analysis plus \\u03baB EMSA with p50/p65 supershift and antibody inhibition using recombinant protein\",\n      \"pmids\": [\"8576259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EMSA-based binding without in vivo confirmation at this stage\", \"Functional consequence on transcription not yet shown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Provided the structural basis for myotrophin's interactions by determining its two-ankyrin-repeat fold with characteristic helix-turn-helix motifs.\",\n      \"evidence\": \"Multidimensional heteronuclear NMR on isotopically labeled protein\",\n      \"pmids\": [\"9194197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure alone does not define binding partners or functional surfaces\", \"No bound-complex structure\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the upstream kinase logic of hypertrophy, showing PKC\\u03b1/PKC\\u03b5 isoform-specific mediation downstream of a tyrosine kinase-coupled pathway.\",\n      \"evidence\": \"PKC activity assays, isoform-specific antisense and antibodies, inhibitors, and subcellular fractionation in cardiomyocytes\",\n      \"pmids\": [\"9633917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between PKC activation and transcriptional effectors not yet established\", \"Receptor/membrane sensor upstream of PKC unidentified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Cloned human myotrophin and identified it as identical to V-1, unifying two literatures and confirming ubiquitous expression with cardiac functional activity.\",\n      \"evidence\": \"cDNA cloning, multi-tissue expression profiling, recombinant protein hypertrophy bioassay\",\n      \"pmids\": [\"10329199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific functions outside heart not addressed\", \"Single-lab cloning characterization\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Integrated the signaling pathway by demonstrating that myotrophin acts through PKC\\u2013IKK\\u03b2\\u2013NF-\\u03baB and that NF-\\u03baB activation is required for its hypertrophic gene program.\",\n      \"evidence\": \"NF-\\u03baB reporter assays, I\\u03baB-\\u03b1 phosphorylation/degradation Westerns, dominant-negative IKK\\u03b2 and I\\u03baB-\\u03b1, and pharmacological inhibitors in cardiomyocytes\",\n      \"pmids\": [\"12486112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How extracellular myotrophin engages this intracellular pathway unresolved\", \"Direct vs indirect NF-\\u03baB engagement not separated here\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved the nuclear function by showing stimulus-dependent nuclear translocation, in vivo association with p65/c-Rel, and conversion of NF-\\u03baB heterodimers into homodimers that alters reporter output.\",\n      \"evidence\": \"Co-IP (in vivo and in vitro), confocal localization, adenoviral overexpression, luciferase reporter, EMSA\",\n      \"pmids\": [\"11971907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of homodimer shift on endogenous genes not fully mapped\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that myotrophin binds \\u03baB DNA directly and is itself a mechano- and cytokine-responsive gene, embedding it in stress-responsive transcriptional circuits.\",\n      \"evidence\": \"EMSA with cardiomyocyte nuclear extracts, confocal localization, cyclic stretch and TNF-\\u03b1/IL-1\\u03b2 treatment\",\n      \"pmids\": [\"12031792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA binding by a small ankyrin protein needs structural validation\", \"Single-lab EMSA evidence\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated sufficiency in vivo: cardiac-specific myotrophin overexpression recapitulates progressive hypertrophy to heart failure with disease-like gene expression.\",\n      \"evidence\": \"Cardiac-specific transgenic mice with echocardiography, histology, and expression profiling\",\n      \"pmids\": [\"14970239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Gain-of-function does not establish requirement of endogenous protein\", \"Pathway dependence in vivo not yet tested genetically\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established genetic epistasis placing NF-\\u03baB downstream of myotrophin in vivo, since NF-\\u03baB blockade attenuates myotrophin-driven hypertrophy and improves function.\",\n      \"evidence\": \"Myo-Tg \\u00d7 I\\u03baB\\u03b1 triple-mutant double transgenic mice with echocardiography, histology, and NF-\\u03baB gene arrays\",\n      \"pmids\": [\"18620706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not isolate NF-\\u03baB from parallel PKC effects\", \"Cell-type contributions not dissected\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Confirmed requirement of endogenous myotrophin by RNAi-induced regression of cardiac mass and NF-\\u03baB signaling, completing the causal loss-of-function case.\",\n      \"evidence\": \"Lentiviral shRNA in transgenic mice and neonatal myocytes with qRT-PCR, Western, and cardiac mass measurement\",\n      \"pmids\": [\"19502558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic durability not assessed\", \"Off-target effects of shRNA not fully excluded\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Opened the second functional arm by showing nanomolar, 1:1 binding of V-1 to capping protein at the CP \\u03b2-tentacle that inhibits barbed-end capping without uncapping.\",\n      \"evidence\": \"In vitro binding, capping/uncapping assays, mutagenesis of both partners, and molecular dynamics\",\n      \"pmids\": [\"16895918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular relevance of CP sequestration not yet shown\", \"Regulation of the interaction unknown at this point\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided atomic-level mechanism showing V-1 loops bind the CP \\u03b1-tentacle basic patch in direct competition with the barbed-end electrostatic site, explaining inhibition and the absence of uncapping.\",\n      \"evidence\": \"NMR chemical shift mapping, intermolecular PRE, and CP site-directed mutagenesis\",\n      \"pmids\": [\"20538588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo concentration dependence not addressed here\", \"Phosphoregulation not yet defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established physiological function of CP sequestration in cells, showing V-1 tonically suppresses CP to control Arp2/3 networks, F-actin, macropinocytosis, and chemotaxis in a CP-binding-dependent manner.\",\n      \"evidence\": \"Dictyostelium knockout/overexpression genetics, F-actin and Arp2/3 imaging, motility assays, WT vs CP-binding-mutant rescue\",\n      \"pmids\": [\"27791032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of equivalent role in mammalian cells absent from corpus\", \"Identity of the regulatory kinase and phosphosites unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed an allosteric dimension to CP regulation, showing V-1 and CARMIL bind distinct sites yet both reshape the CP \\u03b2-tentacle, coupling modulator binding to actin-binding surfaces.\",\n      \"evidence\": \"Hydrogen-deuterium exchange mass spectrometry on CP complexes\",\n      \"pmids\": [\"29847807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of allosteric coupling in cells not measured\", \"Single-lab biophysical study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated MTPN in inflammatory signaling beyond the heart, with LOX-mediated suppression of TNF-\\u03b1 responses dependent in part on MTPN.\",\n      \"evidence\": \"RNA-seq, interaction network analysis, MTPN siRNA, immunofluorescence in ACL fibroblasts and an animal model\",\n      \"pmids\": [\"32483895\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"LOX\\u2013MTPN interaction not established by binding or co-IP\", \"MTPN role inferred from knockdown within a larger study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MTPN's two activities\\u2014NF-\\u03baB modulation and CP sequestration\\u2014are coordinated within the same cell, and what kinase and signals control the phosphoregulation of CP binding, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No identified kinase or phosphosite for CP-binding regulation\", \"No integrated model linking transcriptional and cytoskeletal functions\", \"Mammalian-cell role of CP sequestration not directly demonstrated in corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 6, 8]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10, 13, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 13, 16]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [10, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 7, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NFKB1\", \"RELA\", \"REL\", \"CAPZB\", \"CAPZA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}