{"gene":"MAST3","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2005,"finding":"MAST3 binds PTEN via its PDZ domain, and this interaction facilitates phosphorylation of PTEN at its C-terminus by MAST3 kinase activity. The C-terminal tail of PTEN (residues 350-403) is required for selective PDZ domain binding.","method":"Co-immunoprecipitation, PTEN chimera/mutation panel, in vitro kinase assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding shown with mutation panel and chimeras, kinase assay performed, single lab with two orthogonal methods","pmids":["15951562"],"is_preprint":false},{"year":2008,"finding":"Knockdown of MAST3 specifically decreased Toll-like receptor-4 (TLR4)-dependent NF-κB activity, placing MAST3 as a modulator of TLR4/NF-κB signaling in antigen-presenting cells and lymphocytes.","method":"siRNA knockdown with NF-κB reporter assay","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, reporter assay with knockdown; pathway placement established but limited mechanistic depth","pmids":["18650832"],"is_preprint":false},{"year":2011,"finding":"Overexpression and knockdown of MAST3 in epithelial and macrophage cell lines modulates expression of NF-κB-related inflammatory genes including CCL20, IL8, TNFAIP3, LY96, NFKBIA, IFIT1, ISG15, CD44, and TMOD1, confirming MAST3 as a modulator of inflammatory gene expression.","method":"MAST3 overexpression/knockdown with genome-wide expression profiling","journal":"Inflammatory bowel diseases","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genome-wide expression profiling with both overexpression and knockdown in two cell types, single lab","pmids":["21994190"],"is_preprint":false},{"year":2017,"finding":"MAST3 kinase directly phosphorylates ARPP-16 at Ser46 both in vitro and in vivo, converting ARPP-16 into a selective inhibitor of B55α- and B56δ-containing PP2A heterotrimers. Conditional knockout of ARPP-16/19 results in dephosphorylation of PP2A substrates including phospho-Thr75-DARPP-32, phospho-T308-Akt, and phospho-T202/Y204-ERK, confirming basal PP2A inhibition by the MAST3-ARPP-16 axis in striatal neurons.","method":"In vitro kinase assay, in vivo phosphorylation (striatal tissue), conditional knockout mouse model with phosphoprotein analysis, Co-IP (ARPP-16 with PP2A subunit)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, in vivo phosphorylation confirmed, genetic knockout with multiple downstream substrate readouts, direct binding demonstrated; multiple orthogonal methods","pmids":["28167675"],"is_preprint":false},{"year":2017,"finding":"PKA phosphorylates MAST3 at multiple sites resulting in its inhibition. Phosphorylation of ARPP-16 by PKA mutually suppresses MAST3-mediated phosphorylation of ARPP-16, and vice versa, creating a switch-like cAMP-regulated mechanism for PP2A disinhibition in striatal neurons.","method":"In vitro kinase assay, mass spectrometry phosphosite mapping, mathematical modeling","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assays with site identification, reciprocal inhibition demonstrated by two orthogonal methods, corroborated by companion paper (PMID:28167675)","pmids":["28613156"],"is_preprint":false},{"year":2018,"finding":"In animals harboring Mast1 microdeletions, Mast2 and Mast3 protein levels are diminished, suggesting MAST1 dominant-negative mutations affect MAST3 stability or expression, implicating functional interdependence among MAST family members.","method":"Mast1 mutant mouse model with western blot quantification of Mast3 levels","journal":"Neuron","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single observation in a mouse model focused on MAST1, mechanism of MAST3 level reduction not directly probed","pmids":["30449657"],"is_preprint":false},{"year":2021,"finding":"De novo missense variants in the MAST3 STK (serine-threonine kinase) domain (e.g., p.G510S, p.G515S) result in variable but generally lower MAST3 protein expression yet increased phosphorylation of the MAST3 target ARPP-16 in HEK293T cells, suggesting a gain-of-function mechanism for the kinase activity. MAST3 expression is restricted to excitatory neurons in the cortex postnatally.","method":"Transfection of patient-variant MAST3 cDNA in HEK293T cells, immunoblotting for ARPP-16 phosphorylation, single-nuclei RNA sequencing, immunohistochemistry","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assay with patient variants measuring known substrate phosphorylation, localization confirmed by snRNA-seq and IHC, single lab","pmids":["34185323"],"is_preprint":false},{"year":2019,"finding":"MAST3 overexpression in fibroblast-like synoviocytes promotes their proliferation and inflammatory response, and this effect involves the NF-κB signaling pathway.","method":"MAST3 overexpression in rat adjuvant-arthritis FLS cell model with proliferation assay and NF-κB pathway analysis","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression with NF-κB pathway readout but no direct mechanistic enzyme-substrate link established","pmids":["31644963"],"is_preprint":false},{"year":2025,"finding":"MAST3 interacts directly with YAP (Yes-Associated Protein) and promotes phosphorylation of YAP, leading to YAP ubiquitin-proteasome degradation and reduced nuclear translocation, acting independently of the canonical MST-LATS kinase cascade of the Hippo pathway to suppress breast cancer cell proliferation and invasion.","method":"Co-immunoprecipitation, immunoblotting, shRNA knockdown/overexpression with proliferation/invasion assays, luciferase reporter assay for Hippo target genes","journal":"Breast cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional assays with bidirectional regulation (overexpression and KO), single lab with multiple orthogonal methods","pmids":["40312366"],"is_preprint":false},{"year":2025,"finding":"Large-scale phosphoproteomic analysis identified four predominant MAST3 phosphosites (S134, S146 in the DUF domain; S792, S793 in the C-terminal region), with coregulated phosphosites enriched for cytoskeleton-associated functions including actin filament organization, microtubule organization, and spindle assembly. Predicted substrates include KIF15, EPB41L1, CP110, and HNRNPU, and binary interactors include LMNA, CKAP4, and CAMSAP2.","method":"Large-scale phosphoproteomics (562 datasets), bioinformatic co-regulation analysis","journal":"Omics: a journal of integrative biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/proteomic analysis without direct experimental validation of substrate phosphorylation or binding interactions for MAST3 specifically","pmids":["41203242"],"is_preprint":false}],"current_model":"MAST3 is a microtubule-associated serine/threonine kinase that phosphorylates ARPP-16 at Ser46 to convert it into a selective inhibitor of specific PP2A heterotrimers (B55α/B56δ) in striatal neurons, while PKA opposes this by phosphorylating and inhibiting MAST3 and by phosphorylating ARPP-16 at a competing site, creating a cAMP-regulated PP2A activity switch; MAST3 also binds PTEN via its PDZ domain to facilitate PTEN C-terminal phosphorylation, modulates TLR4/NF-κB inflammatory signaling, and in breast cancer directly phosphorylates YAP to promote its proteasomal degradation independently of the canonical MST-LATS pathway."},"narrative":{"mechanistic_narrative":"MAST3 is a serine/threonine kinase that operates as a node controlling phosphatase activity, inflammatory signaling, and growth regulation across neuronal and non-neuronal contexts [PMID:28167675, PMID:21994190, PMID:40312366]. Its best-defined activity is in striatal neurons, where MAST3 directly phosphorylates ARPP-16 at Ser46 to convert it into a selective inhibitor of B55α- and B56δ-containing PP2A heterotrimers, establishing a basal brake on PP2A substrate dephosphorylation [PMID:28167675]. This axis is wired into cAMP signaling: PKA phosphorylates and inhibits MAST3 while also phosphorylating ARPP-16 at a competing site, so that the two kinase inputs mutually antagonize each other to produce a switch-like control of PP2A disinhibition [PMID:28613156]. Through its PDZ domain MAST3 binds the C-terminal tail of PTEN and promotes PTEN C-terminal phosphorylation [PMID:15951562], and it modulates TLR4-dependent NF-κB activity and downstream inflammatory gene expression [PMID:18650832, PMID:21994190]. In breast cancer cells MAST3 interacts directly with YAP and drives its phosphorylation and ubiquitin-proteasome degradation independently of the canonical MST–LATS cascade, thereby suppressing proliferation and invasion [PMID:40312366]. De novo missense variants in the MAST3 kinase domain elevate ARPP-16 phosphorylation in a gain-of-function manner and define a neurodevelopmental disorder, consistent with MAST3 expression being restricted to excitatory cortical neurons postnatally [PMID:34185323].","teleology":[{"year":2005,"claim":"Established the first molecular partner and a structural basis for MAST3 target engagement, showing the PDZ domain recruits a substrate whose C-terminus it then phosphorylates.","evidence":"Co-IP, PTEN chimera/mutation panel, and in vitro kinase assay defining residues 350-403 of PTEN as the PDZ-binding region","pmids":["15951562"],"confidence":"Medium","gaps":["Functional consequence of PTEN C-terminal phosphorylation by MAST3 not resolved","Cellular context and physiological role of the MAST3–PTEN interaction unaddressed"]},{"year":2008,"claim":"Placed MAST3 within innate immune signaling by showing it is required for TLR4-specific NF-κB output, the first link of MAST3 to inflammation.","evidence":"siRNA knockdown with NF-κB reporter assay in antigen-presenting cells and lymphocytes","pmids":["18650832"],"confidence":"Medium","gaps":["Direct kinase substrate in the TLR4/NF-κB cascade not identified","Reporter readout only; endogenous target unknown"]},{"year":2011,"claim":"Extended the inflammatory role to a defined transcriptional program, showing MAST3 dosage tunes NF-κB-related inflammatory gene expression.","evidence":"MAST3 overexpression/knockdown with genome-wide expression profiling in epithelial and macrophage lines","pmids":["21994190"],"confidence":"Medium","gaps":["Whether transcriptional changes are direct or downstream of an undefined kinase event is unresolved","No enzyme-substrate link to the NF-κB machinery"]},{"year":2017,"claim":"Defined the central catalytic function of MAST3: direct phosphorylation of ARPP-16 at Ser46 to selectively inhibit specific PP2A heterotrimers, with genetic knockout confirming basal PP2A inhibition in vivo.","evidence":"In vitro and in vivo kinase assays, conditional ARPP-16/19 knockout with phospho-substrate readouts, and Co-IP of ARPP-16 with PP2A","pmids":["28167675"],"confidence":"High","gaps":["Structural basis of ARPP-16 Ser46 selectivity for B55α/B56δ PP2A not defined","Full set of physiological PP2A substrates downstream unenumerated"]},{"year":2017,"claim":"Embedded the MAST3–ARPP-16 axis in cAMP signaling, showing PKA inhibits MAST3 and the two phosphorylation events mutually antagonize to create a switch-like control of PP2A activity.","evidence":"In vitro kinase assays, mass-spectrometry phosphosite mapping, and mathematical modeling","pmids":["28613156"],"confidence":"High","gaps":["In vivo dynamics of the proposed switch in intact neurons not directly measured","Functional identity of all PKA phosphosites on MAST3 not fully characterized"]},{"year":2018,"claim":"Raised the possibility of functional interdependence among MAST family members, observing reduced MAST3 protein in Mast1-mutant animals.","evidence":"Mast1 mutant mouse model with western blot quantification of Mast3","pmids":["30449657"],"confidence":"Low","gaps":["Mechanism of MAST3 level reduction not directly probed","Observation incidental to a MAST1-focused study; no MAST3-specific manipulation"]},{"year":2019,"claim":"Connected MAST3 to a disease-relevant inflammatory phenotype, showing overexpression drives synoviocyte proliferation and inflammation via NF-κB.","evidence":"MAST3 overexpression in rat adjuvant-arthritis fibroblast-like synoviocytes with proliferation and NF-κB pathway analysis","pmids":["31644963"],"confidence":"Low","gaps":["No direct enzyme-substrate link to the NF-κB pathway established","Overexpression-only design without loss-of-function corroboration"]},{"year":2021,"claim":"Linked MAST3 to a human neurodevelopmental disorder, showing kinase-domain de novo variants act through gain-of-function on the ARPP-16 substrate in cells restricted to excitatory cortical neurons.","evidence":"Patient-variant cDNA transfection in HEK293T with ARPP-16 phosphorylation immunoblotting, single-nuclei RNA-seq, and IHC","pmids":["34185323"],"confidence":"Medium","gaps":["In vivo neuronal consequence of variant gain-of-function not modeled","How elevated ARPP-16 phosphorylation with reduced protein produces net gain-of-function unresolved"]},{"year":2025,"claim":"Identified a non-canonical growth-suppressive function, showing MAST3 directly phosphorylates YAP to trigger its proteasomal degradation independently of the MST-LATS Hippo cascade.","evidence":"Co-IP, immunoblotting, shRNA knockdown/overexpression with proliferation and invasion assays, and Hippo target luciferase reporters in breast cancer cells","pmids":["40312366"],"confidence":"Medium","gaps":["Specific YAP phosphosites targeted by MAST3 not mapped","How MAST3 substrate choice is partitioned between ARPP-16, PTEN, and YAP in different tissues unknown"]},{"year":2025,"claim":"Generated a systems-level hypothesis that MAST3 acts in cytoskeletal regulation, nominating candidate substrates and interactors from large-scale phosphoproteomics.","evidence":"Phosphoproteomic co-regulation analysis across 562 datasets identifying MAST3 phosphosites and predicted partners (KIF15, EPB41L1, CP110, HNRNPU, LMNA, CKAP4, CAMSAP2)","pmids":["41203242"],"confidence":"Low","gaps":["No direct experimental validation of any predicted substrate or interactor for MAST3","Cytoskeletal role inferred from co-regulation, not functional assay"]},{"year":null,"claim":"How MAST3 partitions its kinase activity among ARPP-16, PTEN, YAP, and inflammatory targets across tissues, and whether a unifying recruitment or substrate-selection mechanism governs these distinct roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of MAST3 substrate selectivity","Tissue-specific determinants of which substrate MAST3 engages are unknown","Direct demonstration of a microtubule-associated cytoskeletal function still lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,8]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,4]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["PTEN","ARPP-16","YAP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60307","full_name":"Microtubule-associated serine/threonine-protein kinase 3","aliases":[],"length_aa":1309,"mass_kda":143.1,"function":"","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O60307/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAST3","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAST3","total_profiled":1310},"omim":[{"mim_id":"620115","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 108; DEE108","url":"https://www.omim.org/entry/620115"},{"mim_id":"618002","title":"MICROTUBULE-ASSOCIATED SERINE/THREONINE KINASE 4; MAST4","url":"https://www.omim.org/entry/618002"},{"mim_id":"612258","title":"MICROTUBULE-ASSOCIATED SERINE/THREONINE KINASE 3; MAST3","url":"https://www.omim.org/entry/612258"},{"mim_id":"612257","title":"MICROTUBULE-ASSOCIATED SERINE/THREONINE KINASE 2; MAST2","url":"https://www.omim.org/entry/612257"},{"mim_id":"612256","title":"MICROTUBULE-ASSOCIATED SERINE/THREONINE KINASE 1; MAST1","url":"https://www.omim.org/entry/612256"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":44.9}],"url":"https://www.proteinatlas.org/search/MAST3"},"hgnc":{"alias_symbol":["KIAA0561"],"prev_symbol":[]},"alphafold":{"accession":"O60307","domains":[{"cath_id":"1.20.1480.20","chopping":"167-298","consensus_level":"high","plddt":84.9342,"start":167,"end":298},{"cath_id":"3.30.200.20","chopping":"362-449_673-680_694-710","consensus_level":"medium","plddt":80.8888,"start":362,"end":710},{"cath_id":"1.10.510.10","chopping":"454-659","consensus_level":"medium","plddt":82.8748,"start":454,"end":659},{"cath_id":"2.30.42.10","chopping":"952-1040","consensus_level":"high","plddt":86.1783,"start":952,"end":1040}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60307","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60307-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60307-F1-predicted_aligned_error_v6.png","plddt_mean":57.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAST3","jax_strain_url":"https://www.jax.org/strain/search?query=MAST3"},"sequence":{"accession":"O60307","fasta_url":"https://rest.uniprot.org/uniprotkb/O60307.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60307/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60307"}},"corpus_meta":[{"pmid":"15951562","id":"PMC_15951562","title":"Binding 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structural features, regulation, and substrates.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41237908","citation_count":0,"is_preprint":false},{"pmid":"41685341","id":"PMC_41685341","title":"PSMA4 as a Druggable Target in Hidradenitis Suppurativa: Evidence From Mendelian Randomization and Single-Cell Transcriptomics.","date":"2026","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/41685341","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19544,"output_tokens":2578,"usd":0.048651,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9733,"output_tokens":3459,"usd":0.06757,"stage2_stop_reason":"end_turn"},"total_usd":0.116221,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"MAST3 binds PTEN via its PDZ domain, and this interaction facilitates phosphorylation of PTEN at its C-terminus by MAST3 kinase activity. The C-terminal tail of PTEN (residues 350-403) is required for selective PDZ domain binding.\",\n      \"method\": \"Co-immunoprecipitation, PTEN chimera/mutation panel, in vitro kinase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding shown with mutation panel and chimeras, kinase assay performed, single lab with two orthogonal methods\",\n      \"pmids\": [\"15951562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Knockdown of MAST3 specifically decreased Toll-like receptor-4 (TLR4)-dependent NF-κB activity, placing MAST3 as a modulator of TLR4/NF-κB signaling in antigen-presenting cells and lymphocytes.\",\n      \"method\": \"siRNA knockdown with NF-κB reporter assay\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, reporter assay with knockdown; pathway placement established but limited mechanistic depth\",\n      \"pmids\": [\"18650832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression and knockdown of MAST3 in epithelial and macrophage cell lines modulates expression of NF-κB-related inflammatory genes including CCL20, IL8, TNFAIP3, LY96, NFKBIA, IFIT1, ISG15, CD44, and TMOD1, confirming MAST3 as a modulator of inflammatory gene expression.\",\n      \"method\": \"MAST3 overexpression/knockdown with genome-wide expression profiling\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genome-wide expression profiling with both overexpression and knockdown in two cell types, single lab\",\n      \"pmids\": [\"21994190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAST3 kinase directly phosphorylates ARPP-16 at Ser46 both in vitro and in vivo, converting ARPP-16 into a selective inhibitor of B55α- and B56δ-containing PP2A heterotrimers. Conditional knockout of ARPP-16/19 results in dephosphorylation of PP2A substrates including phospho-Thr75-DARPP-32, phospho-T308-Akt, and phospho-T202/Y204-ERK, confirming basal PP2A inhibition by the MAST3-ARPP-16 axis in striatal neurons.\",\n      \"method\": \"In vitro kinase assay, in vivo phosphorylation (striatal tissue), conditional knockout mouse model with phosphoprotein analysis, Co-IP (ARPP-16 with PP2A subunit)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, in vivo phosphorylation confirmed, genetic knockout with multiple downstream substrate readouts, direct binding demonstrated; multiple orthogonal methods\",\n      \"pmids\": [\"28167675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PKA phosphorylates MAST3 at multiple sites resulting in its inhibition. Phosphorylation of ARPP-16 by PKA mutually suppresses MAST3-mediated phosphorylation of ARPP-16, and vice versa, creating a switch-like cAMP-regulated mechanism for PP2A disinhibition in striatal neurons.\",\n      \"method\": \"In vitro kinase assay, mass spectrometry phosphosite mapping, mathematical modeling\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assays with site identification, reciprocal inhibition demonstrated by two orthogonal methods, corroborated by companion paper (PMID:28167675)\",\n      \"pmids\": [\"28613156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In animals harboring Mast1 microdeletions, Mast2 and Mast3 protein levels are diminished, suggesting MAST1 dominant-negative mutations affect MAST3 stability or expression, implicating functional interdependence among MAST family members.\",\n      \"method\": \"Mast1 mutant mouse model with western blot quantification of Mast3 levels\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single observation in a mouse model focused on MAST1, mechanism of MAST3 level reduction not directly probed\",\n      \"pmids\": [\"30449657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"De novo missense variants in the MAST3 STK (serine-threonine kinase) domain (e.g., p.G510S, p.G515S) result in variable but generally lower MAST3 protein expression yet increased phosphorylation of the MAST3 target ARPP-16 in HEK293T cells, suggesting a gain-of-function mechanism for the kinase activity. MAST3 expression is restricted to excitatory neurons in the cortex postnatally.\",\n      \"method\": \"Transfection of patient-variant MAST3 cDNA in HEK293T cells, immunoblotting for ARPP-16 phosphorylation, single-nuclei RNA sequencing, immunohistochemistry\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assay with patient variants measuring known substrate phosphorylation, localization confirmed by snRNA-seq and IHC, single lab\",\n      \"pmids\": [\"34185323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAST3 overexpression in fibroblast-like synoviocytes promotes their proliferation and inflammatory response, and this effect involves the NF-κB signaling pathway.\",\n      \"method\": \"MAST3 overexpression in rat adjuvant-arthritis FLS cell model with proliferation assay and NF-κB pathway analysis\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression with NF-κB pathway readout but no direct mechanistic enzyme-substrate link established\",\n      \"pmids\": [\"31644963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAST3 interacts directly with YAP (Yes-Associated Protein) and promotes phosphorylation of YAP, leading to YAP ubiquitin-proteasome degradation and reduced nuclear translocation, acting independently of the canonical MST-LATS kinase cascade of the Hippo pathway to suppress breast cancer cell proliferation and invasion.\",\n      \"method\": \"Co-immunoprecipitation, immunoblotting, shRNA knockdown/overexpression with proliferation/invasion assays, luciferase reporter assay for Hippo target genes\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional assays with bidirectional regulation (overexpression and KO), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40312366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Large-scale phosphoproteomic analysis identified four predominant MAST3 phosphosites (S134, S146 in the DUF domain; S792, S793 in the C-terminal region), with coregulated phosphosites enriched for cytoskeleton-associated functions including actin filament organization, microtubule organization, and spindle assembly. Predicted substrates include KIF15, EPB41L1, CP110, and HNRNPU, and binary interactors include LMNA, CKAP4, and CAMSAP2.\",\n      \"method\": \"Large-scale phosphoproteomics (562 datasets), bioinformatic co-regulation analysis\",\n      \"journal\": \"Omics: a journal of integrative biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/proteomic analysis without direct experimental validation of substrate phosphorylation or binding interactions for MAST3 specifically\",\n      \"pmids\": [\"41203242\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAST3 is a microtubule-associated serine/threonine kinase that phosphorylates ARPP-16 at Ser46 to convert it into a selective inhibitor of specific PP2A heterotrimers (B55α/B56δ) in striatal neurons, while PKA opposes this by phosphorylating and inhibiting MAST3 and by phosphorylating ARPP-16 at a competing site, creating a cAMP-regulated PP2A activity switch; MAST3 also binds PTEN via its PDZ domain to facilitate PTEN C-terminal phosphorylation, modulates TLR4/NF-κB inflammatory signaling, and in breast cancer directly phosphorylates YAP to promote its proteasomal degradation independently of the canonical MST-LATS pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAST3 is a serine/threonine kinase that operates as a node controlling phosphatase activity, inflammatory signaling, and growth regulation across neuronal and non-neuronal contexts [#3, #2, #8]. Its best-defined activity is in striatal neurons, where MAST3 directly phosphorylates ARPP-16 at Ser46 to convert it into a selective inhibitor of B55\\u03b1- and B56\\u03b4-containing PP2A heterotrimers, establishing a basal brake on PP2A substrate dephosphorylation [#3]. This axis is wired into cAMP signaling: PKA phosphorylates and inhibits MAST3 while also phosphorylating ARPP-16 at a competing site, so that the two kinase inputs mutually antagonize each other to produce a switch-like control of PP2A disinhibition [#4]. Through its PDZ domain MAST3 binds the C-terminal tail of PTEN and promotes PTEN C-terminal phosphorylation [#0], and it modulates TLR4-dependent NF-\\u03baB activity and downstream inflammatory gene expression [#1, #2]. In breast cancer cells MAST3 interacts directly with YAP and drives its phosphorylation and ubiquitin-proteasome degradation independently of the canonical MST\\u2013LATS cascade, thereby suppressing proliferation and invasion [#8]. De novo missense variants in the MAST3 kinase domain elevate ARPP-16 phosphorylation in a gain-of-function manner and define a neurodevelopmental disorder, consistent with MAST3 expression being restricted to excitatory cortical neurons postnatally [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the first molecular partner and a structural basis for MAST3 target engagement, showing the PDZ domain recruits a substrate whose C-terminus it then phosphorylates.\",\n      \"evidence\": \"Co-IP, PTEN chimera/mutation panel, and in vitro kinase assay defining residues 350-403 of PTEN as the PDZ-binding region\",\n      \"pmids\": [\"15951562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PTEN C-terminal phosphorylation by MAST3 not resolved\", \"Cellular context and physiological role of the MAST3\\u2013PTEN interaction unaddressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed MAST3 within innate immune signaling by showing it is required for TLR4-specific NF-\\u03baB output, the first link of MAST3 to inflammation.\",\n      \"evidence\": \"siRNA knockdown with NF-\\u03baB reporter assay in antigen-presenting cells and lymphocytes\",\n      \"pmids\": [\"18650832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase substrate in the TLR4/NF-\\u03baB cascade not identified\", \"Reporter readout only; endogenous target unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the inflammatory role to a defined transcriptional program, showing MAST3 dosage tunes NF-\\u03baB-related inflammatory gene expression.\",\n      \"evidence\": \"MAST3 overexpression/knockdown with genome-wide expression profiling in epithelial and macrophage lines\",\n      \"pmids\": [\"21994190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether transcriptional changes are direct or downstream of an undefined kinase event is unresolved\", \"No enzyme-substrate link to the NF-\\u03baB machinery\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the central catalytic function of MAST3: direct phosphorylation of ARPP-16 at Ser46 to selectively inhibit specific PP2A heterotrimers, with genetic knockout confirming basal PP2A inhibition in vivo.\",\n      \"evidence\": \"In vitro and in vivo kinase assays, conditional ARPP-16/19 knockout with phospho-substrate readouts, and Co-IP of ARPP-16 with PP2A\",\n      \"pmids\": [\"28167675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ARPP-16 Ser46 selectivity for B55\\u03b1/B56\\u03b4 PP2A not defined\", \"Full set of physiological PP2A substrates downstream unenumerated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Embedded the MAST3\\u2013ARPP-16 axis in cAMP signaling, showing PKA inhibits MAST3 and the two phosphorylation events mutually antagonize to create a switch-like control of PP2A activity.\",\n      \"evidence\": \"In vitro kinase assays, mass-spectrometry phosphosite mapping, and mathematical modeling\",\n      \"pmids\": [\"28613156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo dynamics of the proposed switch in intact neurons not directly measured\", \"Functional identity of all PKA phosphosites on MAST3 not fully characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Raised the possibility of functional interdependence among MAST family members, observing reduced MAST3 protein in Mast1-mutant animals.\",\n      \"evidence\": \"Mast1 mutant mouse model with western blot quantification of Mast3\",\n      \"pmids\": [\"30449657\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism of MAST3 level reduction not directly probed\", \"Observation incidental to a MAST1-focused study; no MAST3-specific manipulation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected MAST3 to a disease-relevant inflammatory phenotype, showing overexpression drives synoviocyte proliferation and inflammation via NF-\\u03baB.\",\n      \"evidence\": \"MAST3 overexpression in rat adjuvant-arthritis fibroblast-like synoviocytes with proliferation and NF-\\u03baB pathway analysis\",\n      \"pmids\": [\"31644963\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct enzyme-substrate link to the NF-\\u03baB pathway established\", \"Overexpression-only design without loss-of-function corroboration\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked MAST3 to a human neurodevelopmental disorder, showing kinase-domain de novo variants act through gain-of-function on the ARPP-16 substrate in cells restricted to excitatory cortical neurons.\",\n      \"evidence\": \"Patient-variant cDNA transfection in HEK293T with ARPP-16 phosphorylation immunoblotting, single-nuclei RNA-seq, and IHC\",\n      \"pmids\": [\"34185323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo neuronal consequence of variant gain-of-function not modeled\", \"How elevated ARPP-16 phosphorylation with reduced protein produces net gain-of-function unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a non-canonical growth-suppressive function, showing MAST3 directly phosphorylates YAP to trigger its proteasomal degradation independently of the MST-LATS Hippo cascade.\",\n      \"evidence\": \"Co-IP, immunoblotting, shRNA knockdown/overexpression with proliferation and invasion assays, and Hippo target luciferase reporters in breast cancer cells\",\n      \"pmids\": [\"40312366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific YAP phosphosites targeted by MAST3 not mapped\", \"How MAST3 substrate choice is partitioned between ARPP-16, PTEN, and YAP in different tissues unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Generated a systems-level hypothesis that MAST3 acts in cytoskeletal regulation, nominating candidate substrates and interactors from large-scale phosphoproteomics.\",\n      \"evidence\": \"Phosphoproteomic co-regulation analysis across 562 datasets identifying MAST3 phosphosites and predicted partners (KIF15, EPB41L1, CP110, HNRNPU, LMNA, CKAP4, CAMSAP2)\",\n      \"pmids\": [\"41203242\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct experimental validation of any predicted substrate or interactor for MAST3\", \"Cytoskeletal role inferred from co-regulation, not functional assay\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAST3 partitions its kinase activity among ARPP-16, PTEN, YAP, and inflammatory targets across tissues, and whether a unifying recruitment or substrate-selection mechanism governs these distinct roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of MAST3 substrate selectivity\", \"Tissue-specific determinants of which substrate MAST3 engages are unknown\", \"Direct demonstration of a microtubule-associated cytoskeletal function still lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 8]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PTEN\", \"ARPP-16\", \"YAP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}