{"gene":"MRTFB","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2017,"finding":"EWS-FLI1 strongly represses MRTFB transcriptional activity in Ewing sarcoma by occupying overlapping chromatin regions, thereby suppressing a MRTFB/YAP-1/TEAD transcriptional module that regulates cytoskeletal genes through the Rho-F-actin signal pathway, disrupting actin cytoskeletal autoregulatory feedback.","method":"ChIP-seq, transcriptome analysis, knockdown experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP-seq, transcriptomics, functional knockdown) in a single study with mechanistic pathway placement","pmids":["28671673"],"is_preprint":false},{"year":2012,"finding":"MKL2 (MRTFB) plays redundant and crucial roles with MKL1 in megakaryocyte maturation and platelet formation, including regulation of cytoskeletal and membrane organization, platelet granule complexity, and both SRF-dependent and SRF-independent transcriptional programs in megakaryocytopoiesis.","method":"Megakaryocyte-specific Mkl2 knockout mice on Mkl1 KO background (double KO), electron microscopy, immunofluorescence, gene expression profiling","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with specific cellular phenotypes and gene expression analysis, replicated across multiple readouts","pmids":["22806889"],"is_preprint":false},{"year":2014,"finding":"MRTFB forms a complex with TRIM27, and this TRIM27/MRTFB complex posttranscriptionally regulates integrin β1 mRNA stability and translation via microRNA-124 in leading cancer cells, defining their invasive capacity during collective cancer cell invasion.","method":"Co-immunoprecipitation, knockdown assays, in vitro and in vivo invasion assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal complex identification with functional validation in vitro and in vivo using multiple orthogonal methods","pmids":["24794433"],"is_preprint":false},{"year":2019,"finding":"MRTFB functions as a colorectal cancer tumor suppressor by inhibiting cell invasion and migration, acting upstream of transcriptional targets MCAM and SPDL1, which mediate these tumor-suppressive effects.","method":"siRNA knockdown, xenograft assays, Mrtfb knockout mice, RNA-seq, functional invasion/migration assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches including in vivo KO mouse and xenograft models with defined transcriptional targets","pmids":["31690663"],"is_preprint":false},{"year":2021,"finding":"MAPK phosphorylates the C-terminal domain of MKL2 (MRTFB) in neurons, and PKA-MAPK signaling (downstream of dopamine D1R) induces nuclear localization of MKL2 and increases SRF-dependent transcriptional activity; MKL2 forms a ternary complex with CBP and SRF, and its interaction with CBP is regulated in a phosphorylation-dependent manner.","method":"Phosphoproteomic analysis, co-immunoprecipitation, domain interaction assays, live-cell imaging of nuclear localization, reporter assays","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing PTM, complex formation, and subcellular localization with functional consequence","pmids":["33449379"],"is_preprint":false},{"year":2023,"finding":"De novo variants in MRTFB (p.R104G and p.A91P) within RPEL domains decrease actin binding, resulting in increased MRTFB transcriptional activity and disorganization of the actin cytoskeleton, acting as gain-of-function mutations causing a neurodevelopmental disorder.","method":"Actin binding assays, Drosophila humanized model with wing morphology assays, reporter assays","journal":"Genetics in medicine","confidence":"High","confidence_rationale":"Tier 1 — in vitro actin binding assay combined with in vivo Drosophila functional model and mutagenesis","pmids":["37013900"],"is_preprint":false},{"year":2018,"finding":"MKL2 (MRTFB) coactivates SRF at the synaptic activity-responsive element (SARE) of the Arc gene in cortical neurons in response to BDNF stimulation; MKL2 (not MKL1) specifically occupies the SARE by chromatin immunoprecipitation, and its knockdown significantly reduces BDNF-induced Arc transcription.","method":"Chromatin immunoprecipitation, reporter assays, siRNA knockdown, transfection in cultured cortical neurons","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and functional reporter assays in primary neurons, single lab study","pmids":["30244496"],"is_preprint":false},{"year":2018,"finding":"MKL2 (MRTFB) promotes transcription of endothelin type B receptor (EDNRB) in vascular smooth muscle cells, an effect antagonized by myocardin (MYOCD); silencing of MKL2 reduces basal EDNRB expression, placing MKL2 as a positive regulator of EDNRB expression downstream of actin dynamics.","method":"Overexpression, siRNA silencing, actin depolymerization with latrunculin B, qPCR","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function and loss-of-function with multiple pharmacological perturbations, single lab","pmids":["30332284"],"is_preprint":false},{"year":2020,"finding":"A novel neuronal isoform of MRTFB (SOLOIST/MRTFB i4) negatively regulates dendritic complexity in cortical neurons, while isoform 1 positively regulates it; these isoforms differentially regulate SRF target gene expression (isoform 1 strongly induces IEGs; SOLOIST/MRTFB i4 does not), with isoform 1 competitively counteracting SOLOIST/MRTFB i4's effects on dendrites.","method":"Overexpression in cortical neurons, morphological analysis, reporter assays, qPCR","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — overexpression with morphological and gene expression readouts, single lab, multiple isoforms compared","pmids":["32639614"],"is_preprint":false},{"year":2023,"finding":"Hair cell-specific deletion of Mrtfb (but not Mrtfa) leads to defects in stereocilia dimensions and cuticular plate integrity in cochlear hair cells; transcriptome analysis revealed a distinct set of genes regulated by Mrtfb compared to Srf, indicating MRTFB has SRF-independent transcriptional regulation of actin cytoskeleton genes in hair cells.","method":"Hair cell-specific conditional knockout mice, FACS-based hair cell RNA-seq, AAV rescue experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with specific cellular phenotype, transcriptome analysis, and rescue experiment providing mechanistic insight","pmids":["37982489"],"is_preprint":false},{"year":2024,"finding":"KLF15 physically interacts with MRTFB and cooperates with it to promote expression of contractile genes in vascular smooth muscle cells; KLF15 silencing represses MRTFB-induced activation of contractile genes, and Klf15 KO mice show susceptibility to aortic dissection with reduced VSMC contractility.","method":"Co-immunoprecipitation, KO mouse model, gene expression analysis, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus KO mouse model with functional phenotype, single lab","pmids":["38582447"],"is_preprint":false},{"year":2011,"finding":"Wnt2 signaling is necessary and sufficient to activate the airway smooth muscle program including myocardin/Mrtf-B expression and Fgf10 in the lung mesenchyme, placing Mrtf-B downstream of Wnt2 in a transcriptional hierarchy governing smooth muscle specification and differentiation.","method":"Wnt2 loss-of-function and gain-of-function mouse models, gene expression analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis via loss/gain of function models, single lab","pmids":["21704027"],"is_preprint":false},{"year":2013,"finding":"Rare variants in MKL2 combined with deletion of upstream CArG transcription factor binding sites reduce downstream PCTAIRE1 (a target of MKL2:SRF heterodimer transcriptional activation) gene and protein expression in human brain, implicating the MKL2:SRF axis in human brain development and microcephaly.","method":"Familial exome sequencing, SNP array, gene expression comparison, targeted immunohistochemistry in fetal cortical tissue","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 3 — human genetics with expression correlates, limited mechanistic follow-up, single family study","pmids":["23692340"],"is_preprint":false},{"year":2023,"finding":"Endogenous SOLOIST/MRTFB i4 isoform positively regulates egr1 and Arc SRF-target IEG expression and negatively regulates c-fos expression in Neuro-2a cells, in part by modulating levels of MRTFB isoform 1.","method":"Isoform-specific siRNA knockdown, qPCR","journal":"Biological & pharmaceutical bulletin","confidence":"Low","confidence_rationale":"Tier 3 — single method (knockdown + qPCR), single lab, neuroblastoma cell line","pmids":["37286514"],"is_preprint":false},{"year":2024,"finding":"MICAL2 induces actin depolymerization and indirectly promotes SRF transcription by modulating availability of MRTFB; MRTFB (but not MRTFA) phenocopies MICAL2-driven in vivo tumor growth and metastasis in pancreatic cancer, and MRTFB influences PDAC cell proliferation, migration, and cell cycle progression.","method":"Loss- and gain-of-function experiments, in vivo tumor xenograft, cell proliferation/migration assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, functional assays without direct mechanistic dissection of MRTFB-specific mechanism","pmids":[],"is_preprint":true}],"current_model":"MRTFB (MKL2) is an SRF transcriptional coactivator regulated by actin dynamics through its RPEL domains, which sense G-actin availability; upon Rho-GTPase activation and F-actin polymerization, MRTFB translocates to the nucleus, forms complexes with SRF and co-factors such as CBP and KLF15, and drives expression of cytoskeletal, contractile, and immediate early genes in contexts including vascular smooth muscle cells, neurons, megakaryocytes, and hair cells, with its activity further modulated by MAPK-dependent phosphorylation, isoform-specific splicing, and oncogenic perturbations such as EWS-FLI1 repression."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing that MRTFB expression is positioned downstream of Wnt2 signaling resolved how smooth muscle transcriptional programs are initiated during lung development, placing MRTFB within a developmental signaling hierarchy.","evidence":"Wnt2 loss- and gain-of-function mouse models with gene expression analysis","pmids":["21704027"],"confidence":"Medium","gaps":["Whether Wnt2 directly activates Mrtfb transcription or acts through intermediate factors","Whether this hierarchy operates in non-pulmonary smooth muscle lineages"]},{"year":2012,"claim":"Demonstrating that MKL1/MKL2 double knockout in megakaryocytes causes severe defects in platelet formation and cytoskeletal organization established that MRTFB functions redundantly with MKL1 to drive both SRF-dependent and SRF-independent transcription in megakaryocytopoiesis.","evidence":"Megakaryocyte-specific conditional double KO mice with electron microscopy, immunofluorescence, and expression profiling","pmids":["22806889"],"confidence":"High","gaps":["Specific gene targets unique to MRTFB versus MKL1 in megakaryocytes","The nature of SRF-independent MRTFB transcriptional programs in this lineage"]},{"year":2013,"claim":"Identification of rare MKL2 variants linked to reduced PCTAIRE1 expression in fetal brain provided the first genetic evidence connecting the MKL2:SRF axis to human brain development and microcephaly.","evidence":"Familial exome sequencing, SNP array, targeted immunohistochemistry in fetal cortex","pmids":["23692340"],"confidence":"Low","gaps":["Single family study without independent replication","No direct demonstration that MKL2 variants are causative rather than contributory","Mechanism linking reduced PCTAIRE1 to microcephaly phenotype not established"]},{"year":2014,"claim":"Discovery of the TRIM27/MRTFB complex revealed an unexpected non-transcriptional role for MRTFB in posttranscriptional regulation of integrin β1 mRNA via miR-124 during collective cancer cell invasion.","evidence":"Co-immunoprecipitation, knockdown, in vitro and in vivo invasion assays","pmids":["24794433"],"confidence":"High","gaps":["Molecular mechanism by which MRTFB/TRIM27 modulates miR-124 activity on integrin β1 mRNA","Whether this posttranscriptional role extends beyond cancer invasion contexts"]},{"year":2017,"claim":"Showing that EWS-FLI1 represses MRTFB activity by occupying overlapping chromatin regions established how an oncogenic fusion disrupts actin cytoskeletal autoregulatory feedback through a MRTFB/YAP-1/TEAD transcriptional module in Ewing sarcoma.","evidence":"ChIP-seq, transcriptome analysis, knockdown experiments in Ewing sarcoma cells","pmids":["28671673"],"confidence":"High","gaps":["Whether restoring MRTFB activity suppresses Ewing sarcoma phenotypes","Direct physical interaction between EWS-FLI1 and MRTFB not demonstrated"]},{"year":2018,"claim":"Demonstrating that MKL2 specifically occupies the SARE enhancer of Arc and is required for BDNF-induced Arc transcription in cortical neurons established a neuron-specific, paralog-selective role for MRTFB as an SRF coactivator at activity-regulated genes.","evidence":"ChIP, reporter assays, siRNA knockdown in cultured cortical neurons","pmids":["30244496"],"confidence":"Medium","gaps":["Whether MRTFB SARE occupancy is stimulus-dependent or constitutive","Mechanism conferring MKL2 versus MKL1 specificity at this enhancer"]},{"year":2018,"claim":"Identifying MRTFB as a positive regulator of EDNRB expression in vascular smooth muscle, antagonized by myocardin, revealed context-dependent competition among SRF coactivators at specific target promoters.","evidence":"Overexpression, siRNA silencing, latrunculin B treatment, qPCR in VSMCs","pmids":["30332284"],"confidence":"Medium","gaps":["Whether MRTFB directly binds the EDNRB promoter or acts indirectly through SRF","Physiological consequence of MRTFB-regulated EDNRB in vascular tone"]},{"year":2019,"claim":"Showing that MRTFB suppresses colorectal cancer invasion and migration through transcriptional targets MCAM and SPDL1 established a tumor-suppressive function, contrasting with its pro-invasive role in other cancer contexts.","evidence":"siRNA, Mrtfb KO mice, xenograft assays, RNA-seq, invasion/migration assays","pmids":["31690663"],"confidence":"High","gaps":["How MCAM and SPDL1 mediate the anti-invasive phenotype mechanistically","Whether the tumor-suppressive role is SRF-dependent"]},{"year":2020,"claim":"Discovery of a neuronal isoform (SOLOIST/MRTFB i4) that negatively regulates dendritic complexity, in opposition to isoform 1, revealed isoform-specific functional divergence in MRTFB's control of neuronal morphology and immediate early gene expression.","evidence":"Overexpression in cortical neurons, morphological analysis, reporter and qPCR assays","pmids":["32639614"],"confidence":"Medium","gaps":["Endogenous expression levels and splicing regulation of MRTFB isoforms in neurons","Structural basis for differential SRF coactivation between isoforms"]},{"year":2021,"claim":"Mapping MAPK phosphorylation on the MRTFB C-terminal domain and showing it promotes nuclear localization and phosphorylation-dependent CBP interaction resolved a key signal-transduction step linking dopamine D1R-PKA-MAPK signaling to SRF-dependent transcription in neurons.","evidence":"Phosphoproteomics, co-immunoprecipitation, domain interaction assays, live-cell imaging, reporter assays","pmids":["33449379"],"confidence":"High","gaps":["Specific phosphorylation sites on the C-terminal domain not fully mapped","Whether MAPK-dependent regulation of MRTFB operates in non-neuronal cells"]},{"year":2023,"claim":"Identifying de novo RPEL-domain mutations (R104G, A91P) that decrease actin binding and constitutively activate MRTFB, causing a neurodevelopmental disorder, provided the definitive mechanistic link between G-actin sensing and human disease.","evidence":"Actin binding assays, Drosophila humanized model, reporter assays, patient variant analysis","pmids":["37013900"],"confidence":"High","gaps":["Full phenotypic spectrum and penetrance of MRTFB gain-of-function variants","Which downstream target genes mediate the neurodevelopmental phenotype"]},{"year":2023,"claim":"Hair cell-specific Mrtfb deletion causing stereocilia and cuticular plate defects, with transcriptome analysis revealing gene targets distinct from SRF targets, established a physiologically essential SRF-independent transcriptional role for MRTFB in inner ear mechanosensory cells.","evidence":"Conditional KO mice, FACS-based hair cell RNA-seq, AAV rescue","pmids":["37982489"],"confidence":"High","gaps":["Identity of the transcription factor(s) MRTFB partners with in SRF-independent regulation","Whether SRF-independent MRTFB functions extend to other cell types"]},{"year":2024,"claim":"Demonstrating that KLF15 physically interacts with MRTFB and is required for MRTFB-driven contractile gene expression in VSMCs identified a cofactor that provides target-gene specificity to the MRTFB-SRF axis in vascular biology.","evidence":"Co-immunoprecipitation, Klf15 KO mice, gene expression analysis, siRNA knockdown","pmids":["38582447"],"confidence":"Medium","gaps":["Whether KLF15 and MRTFB form a complex on chromatin or interact off-DNA","Whether KLF15 interaction is exclusive to MRTFB or shared with MKL1/myocardin"]},{"year":null,"claim":"The identity of transcription factor partners mediating MRTFB's SRF-independent transcription, the structural basis for isoform-specific functions, and the full spectrum of downstream targets responsible for neurodevelopmental phenotypes remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of MRTFB or its complexes","SRF-independent partner transcription factors not identified","Genome-wide direct binding targets in neurons not mapped","Relative contributions of MRTFB isoforms to disease phenotypes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,4,6,7,8,9,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,6]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,4,6,7,8,9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,9,11]}],"complexes":[],"partners":["SRF","CBP","KLF15","TRIM27","MKL1","YAP1"],"other_free_text":[]},"mechanistic_narrative":"MRTFB (MKL2) is a transcriptional coactivator of serum response factor (SRF) that couples actin cytoskeletal dynamics to gene expression programs governing smooth muscle differentiation, neuronal plasticity, megakaryocytopoiesis, and sensory hair cell morphogenesis. MRTFB senses G-actin availability through its RPEL domains: gain-of-function mutations in these domains decrease actin binding and constitutively activate transcription, causing a neurodevelopmental disorder [PMID:37013900]. Upon stimulation (e.g., BDNF, dopamine D1R-PKA-MAPK signaling), MAPK phosphorylation of the MRTFB C-terminal domain promotes its nuclear translocation and formation of a ternary complex with SRF and CBP to drive immediate early gene and contractile gene transcription, with partner specificity provided by cofactors such as KLF15 in vascular smooth muscle and TRIM27 in invasive cancer cells [PMID:33449379, PMID:38582447, PMID:24794433]. MRTFB also regulates distinct gene sets independently of SRF, as demonstrated by hair cell-specific knockout revealing SRF-independent control of actin cytoskeleton genes essential for stereocilia and cuticular plate integrity [PMID:37982489]."},"prefetch_data":{"uniprot":{"accession":"Q9ULH7","full_name":"Myocardin-related transcription factor B","aliases":["MKL/myocardin-like protein 2","Megakaryoblastic leukemia 2"],"length_aa":1088,"mass_kda":118.1,"function":"Acts as a transcriptional coactivator of serum response factor (SRF). Required for skeletal myogenic differentiation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9ULH7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MRTFB","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":"ACTB","stoichiometry":0.2},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MRTFB","total_profiled":1310},"omim":[{"mim_id":"619222","title":"SUPPRESSOR OF CANCER CELL INVASION; SCAI","url":"https://www.omim.org/entry/619222"},{"mim_id":"609747","title":"ACTIN-BINDING RHO-ACTIVATING PROTEIN; ABRA","url":"https://www.omim.org/entry/609747"},{"mim_id":"609463","title":"MYOCARDIN-RELATED TRANSCRIPTION FACTOR B; MRTFB","url":"https://www.omim.org/entry/609463"},{"mim_id":"102540","title":"ACTIN, ALPHA, CARDIAC MUSCLE; ACTC1","url":"https://www.omim.org/entry/102540"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MRTFB"},"hgnc":{"alias_symbol":["MRTF-B","FLJ31823"],"prev_symbol":["MKL2"]},"alphafold":{"accession":"Q9ULH7","domains":[{"cath_id":"-","chopping":"37-94","consensus_level":"high","plddt":95.9095,"start":37,"end":94},{"cath_id":"1.20.5","chopping":"106-151","consensus_level":"medium","plddt":93.1415,"start":106,"end":151}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULH7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULH7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULH7-F1-predicted_aligned_error_v6.png","plddt_mean":52.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MRTFB","jax_strain_url":"https://www.jax.org/strain/search?query=MRTFB"},"sequence":{"accession":"Q9ULH7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULH7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULH7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULH7"}},"corpus_meta":[{"pmid":"21704027","id":"PMC_21704027","title":"Wnt2 signaling is necessary and sufficient to activate the airway smooth muscle program in the lung by regulating myocardin/Mrtf-B and Fgf10 expression.","date":"2011","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/21704027","citation_count":75,"is_preprint":false},{"pmid":"29912715","id":"PMC_29912715","title":"Ectomesenchymal Chondromyxoid Tumor: A Neoplasm Characterized by Recurrent RREB1-MKL2 Fusions.","date":"2018","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29912715","citation_count":59,"is_preprint":false},{"pmid":"20607705","id":"PMC_20607705","title":"C11orf95-MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma.","date":"2010","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20607705","citation_count":55,"is_preprint":false},{"pmid":"28671673","id":"PMC_28671673","title":"EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28671673","citation_count":48,"is_preprint":false},{"pmid":"22806889","id":"PMC_22806889","title":"MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22806889","citation_count":45,"is_preprint":false},{"pmid":"23672313","id":"PMC_23672313","title":"Presence of C11orf95-MKL2 fusion is a consistent finding in chondroid lipomas: a study of eight cases.","date":"2013","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/23672313","citation_count":40,"is_preprint":false},{"pmid":"24794433","id":"PMC_24794433","title":"TRIM27/MRTF-B-dependent integrin β1 expression defines leading cells in cancer cell collectives.","date":"2014","source":"Cell 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29266774","citation_count":27,"is_preprint":false},{"pmid":"31690663","id":"PMC_31690663","title":"MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31690663","citation_count":26,"is_preprint":false},{"pmid":"35763541","id":"PMC_35763541","title":"RREB1::MRTFB fusion-positive extra-glossal mesenchymal neoplasms: A series of five cases expanding their anatomic distribution and highlighting significant morphological and phenotypic diversity.","date":"2022","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35763541","citation_count":19,"is_preprint":false},{"pmid":"31991003","id":"PMC_31991003","title":"Mesenchymal tumours with RREB1-MRTFB fusion involving the mediastinum: extra-glossal ectomesenchymal chondromyxoid 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Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30332284","citation_count":10,"is_preprint":false},{"pmid":"33449379","id":"PMC_33449379","title":"Dynamic subcellular localization and transcription activity of the SRF cofactor MKL2 in the striatum are regulated by MAPK.","date":"2021","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33449379","citation_count":8,"is_preprint":false},{"pmid":"35776191","id":"PMC_35776191","title":"RNA-sequencing of myxoinflammatory fibroblastic sarcomas reveals a novel SND1::BRAF fusion and 3 different molecular aberrations with the potential to upregulate the TEAD1 gene including SEC23IP::VGLL3 and TEAD1::MRTFB gene fusions.","date":"2022","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35776191","citation_count":8,"is_preprint":false},{"pmid":"38582447","id":"PMC_38582447","title":"KLF15 maintains contractile phenotype of vascular smooth muscle cells and prevents thoracic aortic dissection by interacting with MRTFB.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38582447","citation_count":7,"is_preprint":false},{"pmid":"32639614","id":"PMC_32639614","title":"Expression of SOLOIST/MRTFB i4, a novel neuronal isoform of the mouse serum response factor coactivator myocardin-related transcription factor-B, negatively regulates dendritic complexity in cortical neurons.","date":"2020","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32639614","citation_count":6,"is_preprint":false},{"pmid":"32626937","id":"PMC_32626937","title":"Downregulation of miR‑142‑5p inhibits human aortic smooth muscle cell proliferation and migration by targeting MKL2.","date":"2020","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/32626937","citation_count":6,"is_preprint":false},{"pmid":"37013900","id":"PMC_37013900","title":"De novo variants in MRTFB have gain-of-function activity in Drosophila and are associated with a novel neurodevelopmental phenotype with dysmorphic features.","date":"2023","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37013900","citation_count":6,"is_preprint":false},{"pmid":"37982489","id":"PMC_37982489","title":"Differential regulation of hair cell actin cytoskeleton mediated by SRF and MRTFB.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37982489","citation_count":4,"is_preprint":false},{"pmid":"38763420","id":"PMC_38763420","title":"Novel CRTC1::MRTFB(MKL2) Gene Fusion Detected in Myxoid Mesenchymal Neoplasms With Myogenic Differentiation Involving Bone and Soft Tissues.","date":"2024","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/38763420","citation_count":3,"is_preprint":false},{"pmid":"36726902","id":"PMC_36726902","title":"A Novel Tongue-Based Tumor With an RREB1-MRTFB Fusion: Variant Rhabdomyosarcoma or Aggressive Variant of Ectomesenchymal Chondromyxoid Tumor.","date":"2022","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/36726902","citation_count":2,"is_preprint":false},{"pmid":"40022218","id":"PMC_40022218","title":"An extralingual Ectomesenchymal chondromyxoid tumor with RREB1::MRTFB fusion: a rare case report of plantar fascia involvement.","date":"2025","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40022218","citation_count":2,"is_preprint":false},{"pmid":"39150441","id":"PMC_39150441","title":"LncRNA NONHSAT227443.1 Confers Esophageal Squamous Cell Carcinoma Chemotherapy Resistance by Activating PI3K/AKT Signaling via Targeting MRTFB.","date":"2024","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/39150441","citation_count":1,"is_preprint":false},{"pmid":"40658185","id":"PMC_40658185","title":"Unusual Locations of Extra-Glossal Ectomesenchymal Chondromyxoid Tumors with RREB1-MRTFB Gene Fusions: A Report of Two Cases.","date":"2025","source":"Head and neck pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40658185","citation_count":0,"is_preprint":false},{"pmid":"41449216","id":"PMC_41449216","title":"Cutaneous/subcutaneous RREB1::MRTFB fusion-positive extra-glossal mesenchymal neoplasm-two cases expanding the anatomical spectrum of an emerging entity.","date":"2025","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/41449216","citation_count":0,"is_preprint":false},{"pmid":"37286514","id":"PMC_37286514","title":"Endogenous SOLOIST/MRTFB i4, a Neuronal Isoform of MKL2/MRTFB, Positively and Negatively Regulates SRF Target Immediate Early Genes in Neuro-2a Cells.","date":"2023","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/37286514","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.26.24317461","title":"Whole Exome Sequencing Uncovers Key Genetic Variants in Congenital Tooth Agenesis: An Integrative Omics Approach","date":"2024-11-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.26.24317461","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.26.600548","title":"MICAL2 Is a Super Enhancer Associated Gene that Promotes Pancreatic Cancer Growth and Metastasis","date":"2024-06-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.26.600548","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19787,"output_tokens":3408,"usd":0.05524},"stage2":{"model":"claude-opus-4-6","input_tokens":6803,"output_tokens":3288,"usd":0.174322},"total_usd":0.229562,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"EWS-FLI1 strongly represses MRTFB transcriptional activity in Ewing sarcoma by occupying overlapping chromatin regions, thereby suppressing a MRTFB/YAP-1/TEAD transcriptional module that regulates cytoskeletal genes through the Rho-F-actin signal pathway, disrupting actin cytoskeletal autoregulatory feedback.\",\n      \"method\": \"ChIP-seq, transcriptome analysis, knockdown experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP-seq, transcriptomics, functional knockdown) in a single study with mechanistic pathway placement\",\n      \"pmids\": [\"28671673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MKL2 (MRTFB) plays redundant and crucial roles with MKL1 in megakaryocyte maturation and platelet formation, including regulation of cytoskeletal and membrane organization, platelet granule complexity, and both SRF-dependent and SRF-independent transcriptional programs in megakaryocytopoiesis.\",\n      \"method\": \"Megakaryocyte-specific Mkl2 knockout mice on Mkl1 KO background (double KO), electron microscopy, immunofluorescence, gene expression profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with specific cellular phenotypes and gene expression analysis, replicated across multiple readouts\",\n      \"pmids\": [\"22806889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MRTFB forms a complex with TRIM27, and this TRIM27/MRTFB complex posttranscriptionally regulates integrin β1 mRNA stability and translation via microRNA-124 in leading cancer cells, defining their invasive capacity during collective cancer cell invasion.\",\n      \"method\": \"Co-immunoprecipitation, knockdown assays, in vitro and in vivo invasion assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal complex identification with functional validation in vitro and in vivo using multiple orthogonal methods\",\n      \"pmids\": [\"24794433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MRTFB functions as a colorectal cancer tumor suppressor by inhibiting cell invasion and migration, acting upstream of transcriptional targets MCAM and SPDL1, which mediate these tumor-suppressive effects.\",\n      \"method\": \"siRNA knockdown, xenograft assays, Mrtfb knockout mice, RNA-seq, functional invasion/migration assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches including in vivo KO mouse and xenograft models with defined transcriptional targets\",\n      \"pmids\": [\"31690663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAPK phosphorylates the C-terminal domain of MKL2 (MRTFB) in neurons, and PKA-MAPK signaling (downstream of dopamine D1R) induces nuclear localization of MKL2 and increases SRF-dependent transcriptional activity; MKL2 forms a ternary complex with CBP and SRF, and its interaction with CBP is regulated in a phosphorylation-dependent manner.\",\n      \"method\": \"Phosphoproteomic analysis, co-immunoprecipitation, domain interaction assays, live-cell imaging of nuclear localization, reporter assays\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing PTM, complex formation, and subcellular localization with functional consequence\",\n      \"pmids\": [\"33449379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"De novo variants in MRTFB (p.R104G and p.A91P) within RPEL domains decrease actin binding, resulting in increased MRTFB transcriptional activity and disorganization of the actin cytoskeleton, acting as gain-of-function mutations causing a neurodevelopmental disorder.\",\n      \"method\": \"Actin binding assays, Drosophila humanized model with wing morphology assays, reporter assays\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro actin binding assay combined with in vivo Drosophila functional model and mutagenesis\",\n      \"pmids\": [\"37013900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MKL2 (MRTFB) coactivates SRF at the synaptic activity-responsive element (SARE) of the Arc gene in cortical neurons in response to BDNF stimulation; MKL2 (not MKL1) specifically occupies the SARE by chromatin immunoprecipitation, and its knockdown significantly reduces BDNF-induced Arc transcription.\",\n      \"method\": \"Chromatin immunoprecipitation, reporter assays, siRNA knockdown, transfection in cultured cortical neurons\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and functional reporter assays in primary neurons, single lab study\",\n      \"pmids\": [\"30244496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MKL2 (MRTFB) promotes transcription of endothelin type B receptor (EDNRB) in vascular smooth muscle cells, an effect antagonized by myocardin (MYOCD); silencing of MKL2 reduces basal EDNRB expression, placing MKL2 as a positive regulator of EDNRB expression downstream of actin dynamics.\",\n      \"method\": \"Overexpression, siRNA silencing, actin depolymerization with latrunculin B, qPCR\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function and loss-of-function with multiple pharmacological perturbations, single lab\",\n      \"pmids\": [\"30332284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A novel neuronal isoform of MRTFB (SOLOIST/MRTFB i4) negatively regulates dendritic complexity in cortical neurons, while isoform 1 positively regulates it; these isoforms differentially regulate SRF target gene expression (isoform 1 strongly induces IEGs; SOLOIST/MRTFB i4 does not), with isoform 1 competitively counteracting SOLOIST/MRTFB i4's effects on dendrites.\",\n      \"method\": \"Overexpression in cortical neurons, morphological analysis, reporter assays, qPCR\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with morphological and gene expression readouts, single lab, multiple isoforms compared\",\n      \"pmids\": [\"32639614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hair cell-specific deletion of Mrtfb (but not Mrtfa) leads to defects in stereocilia dimensions and cuticular plate integrity in cochlear hair cells; transcriptome analysis revealed a distinct set of genes regulated by Mrtfb compared to Srf, indicating MRTFB has SRF-independent transcriptional regulation of actin cytoskeleton genes in hair cells.\",\n      \"method\": \"Hair cell-specific conditional knockout mice, FACS-based hair cell RNA-seq, AAV rescue experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with specific cellular phenotype, transcriptome analysis, and rescue experiment providing mechanistic insight\",\n      \"pmids\": [\"37982489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KLF15 physically interacts with MRTFB and cooperates with it to promote expression of contractile genes in vascular smooth muscle cells; KLF15 silencing represses MRTFB-induced activation of contractile genes, and Klf15 KO mice show susceptibility to aortic dissection with reduced VSMC contractility.\",\n      \"method\": \"Co-immunoprecipitation, KO mouse model, gene expression analysis, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus KO mouse model with functional phenotype, single lab\",\n      \"pmids\": [\"38582447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Wnt2 signaling is necessary and sufficient to activate the airway smooth muscle program including myocardin/Mrtf-B expression and Fgf10 in the lung mesenchyme, placing Mrtf-B downstream of Wnt2 in a transcriptional hierarchy governing smooth muscle specification and differentiation.\",\n      \"method\": \"Wnt2 loss-of-function and gain-of-function mouse models, gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via loss/gain of function models, single lab\",\n      \"pmids\": [\"21704027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rare variants in MKL2 combined with deletion of upstream CArG transcription factor binding sites reduce downstream PCTAIRE1 (a target of MKL2:SRF heterodimer transcriptional activation) gene and protein expression in human brain, implicating the MKL2:SRF axis in human brain development and microcephaly.\",\n      \"method\": \"Familial exome sequencing, SNP array, gene expression comparison, targeted immunohistochemistry in fetal cortical tissue\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — human genetics with expression correlates, limited mechanistic follow-up, single family study\",\n      \"pmids\": [\"23692340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Endogenous SOLOIST/MRTFB i4 isoform positively regulates egr1 and Arc SRF-target IEG expression and negatively regulates c-fos expression in Neuro-2a cells, in part by modulating levels of MRTFB isoform 1.\",\n      \"method\": \"Isoform-specific siRNA knockdown, qPCR\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method (knockdown + qPCR), single lab, neuroblastoma cell line\",\n      \"pmids\": [\"37286514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MICAL2 induces actin depolymerization and indirectly promotes SRF transcription by modulating availability of MRTFB; MRTFB (but not MRTFA) phenocopies MICAL2-driven in vivo tumor growth and metastasis in pancreatic cancer, and MRTFB influences PDAC cell proliferation, migration, and cell cycle progression.\",\n      \"method\": \"Loss- and gain-of-function experiments, in vivo tumor xenograft, cell proliferation/migration assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, functional assays without direct mechanistic dissection of MRTFB-specific mechanism\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MRTFB (MKL2) is an SRF transcriptional coactivator regulated by actin dynamics through its RPEL domains, which sense G-actin availability; upon Rho-GTPase activation and F-actin polymerization, MRTFB translocates to the nucleus, forms complexes with SRF and co-factors such as CBP and KLF15, and drives expression of cytoskeletal, contractile, and immediate early genes in contexts including vascular smooth muscle cells, neurons, megakaryocytes, and hair cells, with its activity further modulated by MAPK-dependent phosphorylation, isoform-specific splicing, and oncogenic perturbations such as EWS-FLI1 repression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MRTFB (MKL2) is a transcriptional coactivator of serum response factor (SRF) that couples actin cytoskeletal dynamics to gene expression programs governing smooth muscle differentiation, neuronal plasticity, megakaryocytopoiesis, and sensory hair cell morphogenesis. MRTFB senses G-actin availability through its RPEL domains: gain-of-function mutations in these domains decrease actin binding and constitutively activate transcription, causing a neurodevelopmental disorder [PMID:37013900]. Upon stimulation (e.g., BDNF, dopamine D1R-PKA-MAPK signaling), MAPK phosphorylation of the MRTFB C-terminal domain promotes its nuclear translocation and formation of a ternary complex with SRF and CBP to drive immediate early gene and contractile gene transcription, with partner specificity provided by cofactors such as KLF15 in vascular smooth muscle and TRIM27 in invasive cancer cells [PMID:33449379, PMID:38582447, PMID:24794433]. MRTFB also regulates distinct gene sets independently of SRF, as demonstrated by hair cell-specific knockout revealing SRF-independent control of actin cytoskeleton genes essential for stereocilia and cuticular plate integrity [PMID:37982489].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that MRTFB expression is positioned downstream of Wnt2 signaling resolved how smooth muscle transcriptional programs are initiated during lung development, placing MRTFB within a developmental signaling hierarchy.\",\n      \"evidence\": \"Wnt2 loss- and gain-of-function mouse models with gene expression analysis\",\n      \"pmids\": [\"21704027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Wnt2 directly activates Mrtfb transcription or acts through intermediate factors\",\n        \"Whether this hierarchy operates in non-pulmonary smooth muscle lineages\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that MKL1/MKL2 double knockout in megakaryocytes causes severe defects in platelet formation and cytoskeletal organization established that MRTFB functions redundantly with MKL1 to drive both SRF-dependent and SRF-independent transcription in megakaryocytopoiesis.\",\n      \"evidence\": \"Megakaryocyte-specific conditional double KO mice with electron microscopy, immunofluorescence, and expression profiling\",\n      \"pmids\": [\"22806889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific gene targets unique to MRTFB versus MKL1 in megakaryocytes\",\n        \"The nature of SRF-independent MRTFB transcriptional programs in this lineage\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of rare MKL2 variants linked to reduced PCTAIRE1 expression in fetal brain provided the first genetic evidence connecting the MKL2:SRF axis to human brain development and microcephaly.\",\n      \"evidence\": \"Familial exome sequencing, SNP array, targeted immunohistochemistry in fetal cortex\",\n      \"pmids\": [\"23692340\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single family study without independent replication\",\n        \"No direct demonstration that MKL2 variants are causative rather than contributory\",\n        \"Mechanism linking reduced PCTAIRE1 to microcephaly phenotype not established\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery of the TRIM27/MRTFB complex revealed an unexpected non-transcriptional role for MRTFB in posttranscriptional regulation of integrin β1 mRNA via miR-124 during collective cancer cell invasion.\",\n      \"evidence\": \"Co-immunoprecipitation, knockdown, in vitro and in vivo invasion assays\",\n      \"pmids\": [\"24794433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which MRTFB/TRIM27 modulates miR-124 activity on integrin β1 mRNA\",\n        \"Whether this posttranscriptional role extends beyond cancer invasion contexts\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing that EWS-FLI1 represses MRTFB activity by occupying overlapping chromatin regions established how an oncogenic fusion disrupts actin cytoskeletal autoregulatory feedback through a MRTFB/YAP-1/TEAD transcriptional module in Ewing sarcoma.\",\n      \"evidence\": \"ChIP-seq, transcriptome analysis, knockdown experiments in Ewing sarcoma cells\",\n      \"pmids\": [\"28671673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether restoring MRTFB activity suppresses Ewing sarcoma phenotypes\",\n        \"Direct physical interaction between EWS-FLI1 and MRTFB not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that MKL2 specifically occupies the SARE enhancer of Arc and is required for BDNF-induced Arc transcription in cortical neurons established a neuron-specific, paralog-selective role for MRTFB as an SRF coactivator at activity-regulated genes.\",\n      \"evidence\": \"ChIP, reporter assays, siRNA knockdown in cultured cortical neurons\",\n      \"pmids\": [\"30244496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MRTFB SARE occupancy is stimulus-dependent or constitutive\",\n        \"Mechanism conferring MKL2 versus MKL1 specificity at this enhancer\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying MRTFB as a positive regulator of EDNRB expression in vascular smooth muscle, antagonized by myocardin, revealed context-dependent competition among SRF coactivators at specific target promoters.\",\n      \"evidence\": \"Overexpression, siRNA silencing, latrunculin B treatment, qPCR in VSMCs\",\n      \"pmids\": [\"30332284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MRTFB directly binds the EDNRB promoter or acts indirectly through SRF\",\n        \"Physiological consequence of MRTFB-regulated EDNRB in vascular tone\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that MRTFB suppresses colorectal cancer invasion and migration through transcriptional targets MCAM and SPDL1 established a tumor-suppressive function, contrasting with its pro-invasive role in other cancer contexts.\",\n      \"evidence\": \"siRNA, Mrtfb KO mice, xenograft assays, RNA-seq, invasion/migration assays\",\n      \"pmids\": [\"31690663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How MCAM and SPDL1 mediate the anti-invasive phenotype mechanistically\",\n        \"Whether the tumor-suppressive role is SRF-dependent\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery of a neuronal isoform (SOLOIST/MRTFB i4) that negatively regulates dendritic complexity, in opposition to isoform 1, revealed isoform-specific functional divergence in MRTFB's control of neuronal morphology and immediate early gene expression.\",\n      \"evidence\": \"Overexpression in cortical neurons, morphological analysis, reporter and qPCR assays\",\n      \"pmids\": [\"32639614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous expression levels and splicing regulation of MRTFB isoforms in neurons\",\n        \"Structural basis for differential SRF coactivation between isoforms\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapping MAPK phosphorylation on the MRTFB C-terminal domain and showing it promotes nuclear localization and phosphorylation-dependent CBP interaction resolved a key signal-transduction step linking dopamine D1R-PKA-MAPK signaling to SRF-dependent transcription in neurons.\",\n      \"evidence\": \"Phosphoproteomics, co-immunoprecipitation, domain interaction assays, live-cell imaging, reporter assays\",\n      \"pmids\": [\"33449379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific phosphorylation sites on the C-terminal domain not fully mapped\",\n        \"Whether MAPK-dependent regulation of MRTFB operates in non-neuronal cells\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying de novo RPEL-domain mutations (R104G, A91P) that decrease actin binding and constitutively activate MRTFB, causing a neurodevelopmental disorder, provided the definitive mechanistic link between G-actin sensing and human disease.\",\n      \"evidence\": \"Actin binding assays, Drosophila humanized model, reporter assays, patient variant analysis\",\n      \"pmids\": [\"37013900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full phenotypic spectrum and penetrance of MRTFB gain-of-function variants\",\n        \"Which downstream target genes mediate the neurodevelopmental phenotype\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Hair cell-specific Mrtfb deletion causing stereocilia and cuticular plate defects, with transcriptome analysis revealing gene targets distinct from SRF targets, established a physiologically essential SRF-independent transcriptional role for MRTFB in inner ear mechanosensory cells.\",\n      \"evidence\": \"Conditional KO mice, FACS-based hair cell RNA-seq, AAV rescue\",\n      \"pmids\": [\"37982489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the transcription factor(s) MRTFB partners with in SRF-independent regulation\",\n        \"Whether SRF-independent MRTFB functions extend to other cell types\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that KLF15 physically interacts with MRTFB and is required for MRTFB-driven contractile gene expression in VSMCs identified a cofactor that provides target-gene specificity to the MRTFB-SRF axis in vascular biology.\",\n      \"evidence\": \"Co-immunoprecipitation, Klf15 KO mice, gene expression analysis, siRNA knockdown\",\n      \"pmids\": [\"38582447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether KLF15 and MRTFB form a complex on chromatin or interact off-DNA\",\n        \"Whether KLF15 interaction is exclusive to MRTFB or shared with MKL1/myocardin\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of transcription factor partners mediating MRTFB's SRF-independent transcription, the structural basis for isoform-specific functions, and the full spectrum of downstream targets responsible for neurodevelopmental phenotypes remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of MRTFB or its complexes\",\n        \"SRF-independent partner transcription factors not identified\",\n        \"Genome-wide direct binding targets in neurons not mapped\",\n        \"Relative contributions of MRTFB isoforms to disease phenotypes unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 4, 6, 7, 8, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 4, 6, 7, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 9, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SRF\",\n      \"CBP\",\n      \"KLF15\",\n      \"TRIM27\",\n      \"MKL1\",\n      \"YAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}