{"gene":"AMOT","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2006,"finding":"Amot binds the Cdc42 RhoGAP Rich1 via its coiled-coil domain and is thereby targeted to a tight junction complex containing the PDZ-domain proteins Pals1, Patj, and Par-3 in MDCK epithelial cells. The coiled-coil domain of Amot is required for apical membrane localization and for relocalization of Pals1 and Par-3 to internal puncta.","method":"Functional and proteomic screens, co-immunoprecipitation, domain mutagenesis, confocal imaging in MDCK cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, domain mutagenesis, and functional imaging in epithelial cells; widely replicated finding","pmids":["16678097"],"is_preprint":false},{"year":2008,"finding":"Amot forms a ternary complex with the PDZ protein Patj (or Mupp1) and the RhoGEF Syx, and this complex controls spatial targeting of RhoA activity to lamellipodia in migrating endothelial cells. Amot interacts with Syx through its C-terminal PDZ-binding motif.","method":"Peptide pull-down, yeast two-hybrid screening, FRET analysis of RhoA activity, morpholino knockdown in zebrafish","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, pull-down, FRET, in vivo morpholino); consistent results across in vitro and in vivo models","pmids":["18824598"],"is_preprint":false},{"year":2010,"finding":"Amot contains a novel lipid-binding domain (later termed ACCH domain) that selectively binds membranes containing monophosphorylated phosphatidylinositols and cholesterol with high affinity, enables membrane tubulation in vitro, and targets Amot to juxtanuclear endocytic recycling compartments marked by Rab11 and Arf6.","method":"Lipid-binding assays, in vitro membrane tubulation assay, fluorescence co-localization with Rab11/Arf6/cholesterol markers, cell fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of lipid binding and tubulation plus cellular localization with multiple markers, single lab but multiple orthogonal methods","pmids":["20080965"],"is_preprint":false},{"year":2011,"finding":"Amot80 (the 80 kDa isoform) promotes ERK1/2-dependent proliferation of mammary epithelial cells; a mutant lacking the polarity protein interaction domain fails to enhance ERK1/2-dependent proliferation, indicating this domain is required for the pro-proliferative effect.","method":"Isoform expression in MCF7 and MCF10A cells, Matrigel 3D culture, ERK1/2 activity assays, domain-deletion mutagenesis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion mutagenesis plus multiple cell-based assays in one lab","pmids":["21285250"],"is_preprint":false},{"year":2015,"finding":"AMOT interacts dynamically with the endosomal integral membrane protein endotubin (EDTB) at the endosomal membrane; EDTB competes with YAP for binding to AMOT in subconfluent cells. Overexpression of EDTB displaces YAP from AMOT, promoting YAP nuclear translocation and an overgrowth phenotype in a YAP-dependent manner.","method":"Co-immunoprecipitation, overexpression of full-length and cytoplasmic-domain EDTB, soft-agar growth assay, YAP nuclear translocation imaging","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and functional rescue experiments, single lab","pmids":["25995376"],"is_preprint":false},{"year":2017,"finding":"Active Rho GTPase prevents phosphorylation of Amot Ser176, stabilizing the Amot–F-actin interaction and restricting Amot–Nf2 binding. Additionally, Rho directly binds the coiled-coil domain of Amot to attenuate Amot–Nf2 association, thereby suppressing Hippo signaling in trophectoderm cells of the blastocyst.","method":"Inhibitor/activator screen in blastocysts, co-immunoprecipitation, phosphorylation assays, domain mapping","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and phospho-site analysis with inhibitor validation, single lab","pmids":["28947533"],"is_preprint":false},{"year":2017,"finding":"CREB transcriptionally activates Mpp7, which in turn controls the subcellular localization and protein level of AMOT; MPP7 and AMOT are individually required for YAP1 nuclear accumulation and for the proliferative state of myoblasts. Thus AMOT functions downstream of CREB-MPP7 to relay signals to YAP1 in muscle satellite cells.","method":"Conditional knockout mice, loss-of-function in myoblasts, subcellular fractionation/immunofluorescence, Western blot","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo and cellular loss-of-function, single lab","pmids":["29091764"],"is_preprint":false},{"year":2017,"finding":"DUB3 deubiquitylating enzymes regulate the protein stability of AMOT family members (as well as LATS kinases and the E3 ligase ITCH), thereby modulating Hippo pathway activity and YAP/TAZ levels.","method":"Overexpression and knockdown of DUB3 in cell lines, Western blot for protein stability, ubiquitination assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, Western blot-based stability assay with knockdown; limited mechanistic detail in abstract","pmids":["28061504"],"is_preprint":false},{"year":2019,"finding":"Amot is required for dendritic morphogenesis in hippocampal neurons and Purkinje cells. Its function in dendrite growth depends on interaction with Yap1 and does not require TEAD transcription factors; instead, Amot and Yap1 regulate dendrite arborization by affecting phosphorylation of S6 kinase and its target S6 ribosomal protein. Conditional deletion of Amot in neurons reduces Purkinje cell dendritic tree complexity and impairs motor coordination.","method":"Conditional neuronal knockout mice, in vitro hippocampal culture knockdown, immunofluorescence, Western blot for S6K/S6 phosphorylation, motor behavior assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo with defined cerebellar phenotype plus mechanistic pathway dissection (TEAD independence, S6K phosphorylation), multiple orthogonal methods","pmids":["31042703"],"is_preprint":false},{"year":2019,"finding":"The lncRNA UCA1 directly binds AMOT protein (identified by in vivo RNA antisense purification), enhances the AMOT–YAP interaction, and promotes YAP dephosphorylation and nuclear translocation. Loss-of-function experiments confirm AMOT mediates YAP activation downstream of UCA1.","method":"In vivo RNA antisense purification (iRAP), RPPA, co-immunoprecipitation, loss-of-function siRNA, YAP phosphorylation and nuclear translocation assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iRAP for direct binding plus functional epistasis by AMOT knockdown, single lab","pmids":["31307004"],"is_preprint":false},{"year":2021,"finding":"AMOT binds Talin and is an essential component of the endothelial integrin adhesome; endothelial-specific deletion of Amot in mice inhibits tip cell migration, filopodia extension, and vascular network expansion. Amot relays mechanical forces between fibronectin and the cytoskeleton.","method":"Endothelial-specific conditional knockout mice, in vitro molecular binding assays, traction force measurements, retinal and tumor vascular imaging","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with defined vascular phenotype plus in vitro binding (Talin interaction) and force transmission assays; multiple orthogonal methods","pmids":["34433061"],"is_preprint":false},{"year":2021,"finding":"AMOT PPxY motifs interact with NEDD4L WW domains to promote HIV-1 virion envelopment and infectivity. The AMOT PPxY1–NEDD4L WW3 interaction has unusually high affinity due to complementary ionic and hydrophobic contacts beyond the WW-PPxY core, and is the dominant interaction driving HIV-1 release. Structural analysis revealed the molecular basis of this selectivity.","method":"Structural analysis (X-ray crystallography implied by 'comparative structural analyses'), binding affinity measurements, site-directed mutagenesis of PPxY motifs and WW domains, HIV-1 virological infectivity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural resolution of binding interface plus mutagenesis and functional virological readout in one study","pmids":["34284061"],"is_preprint":false},{"year":2021,"finding":"Fragment-based X-ray crystallography resolved the first structure of the 14-3-3 binding motif of Amot-p130, characterizing the binding mode and affinities of the 14-3-3/Amot-p130 protein–protein interaction interface.","method":"X-ray crystallography, fragment-based screening, binding affinity measurements (SPR/ITC implied)","journal":"Current research in structural biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure of the complex, single lab, limited functional validation described in abstract","pmids":["35036934"],"is_preprint":false},{"year":2022,"finding":"RICH1 competes with Merlin for binding to Amot-p80 via its BAR domain; this competition displaces Amot-p80 from the Amot-Merlin complex and activates the Hippo kinase cascade, suppressing YAP/TAZ and breast cancer stem cell traits. Deletion of the BAR domain of RICH1 abolishes its ability to displace Merlin from Amot-p80.","method":"Co-immunoprecipitation, domain deletion mutagenesis (BAR domain), loss-of-function in MCF10A cells, stem cell trait assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mutagenesis and functional phenotype, single lab","pmids":["35064101"],"is_preprint":false},{"year":2023,"finding":"WWC1 and WWC2 directly bind AMOT family proteins (Motins) and recruit the deubiquitylase USP9X to deubiquitinate and stabilize Motins. Neuron-specific deletion of Wwc1/2 in mice reduces Motin protein levels, decreases dendritic spine density in cortex and hippocampus, and impairs memory/learning; ectopic AMOT expression partially rescues these neuronal phenotypes.","method":"Direct binding assays, USP9X recruitment and deubiquitination assays, conditional double-knockout mice, immunofluorescence of dendritic spines, cognitive behavioral tests, rescue by AMOT overexpression","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with defined neuronal phenotype, biochemical reconstitution of USP9X-mediated deubiquitination, and functional rescue by AMOT, multiple orthogonal methods","pmids":["37528078"],"is_preprint":false},{"year":2024,"finding":"AMOT nuclear translocation (driven by actomyosin activity consequent to cell size reduction) suppresses YAP activity and promotes definitive endoderm differentiation of human pluripotent stem cells. Blocking actomyosin activity prevents both AMOT nuclear translocation and endoderm specification.","method":"Hypertonic pressure treatment, chemical inhibitors of actomyosin, immunofluorescence of AMOT and YAP subcellular localization, endoderm marker expression assays","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional intervention with mechanosensitive elements, subcellular localization imaging linked to differentiation outcome, single lab","pmids":["39094563"],"is_preprint":false},{"year":2024,"finding":"AMOT expression gradually decreases during epiblast formation through tankyrase-mediated degradation; SOX2 expression in the ICM is necessary for this reduction of AMOT and consequent decrease in YAP phosphorylation, enabling YAP nuclear localization. Blastocoel expansion and AMOT degradation act in parallel to promote YAP nuclear translocation.","method":"Mouse preimplantation embryo analysis, tankyrase inhibition, SOX2 loss-of-function, immunofluorescence of AMOT/YAP phosphorylation and localization","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological epistasis in embryos with imaging readout, single lab","pmids":["39486633"],"is_preprint":false},{"year":2025,"finding":"AMOT protein stability serves as the primary mechanical rheostat controlling YAP/TAZ: AMOT is stable in mechanically inhibited cells where it sequesters YAP/TAZ in the cytoplasm, but in mechanically activated cells, microtubules reorganize into a radial centrosomal array, allowing dynein/dynactin-mediated retrograde transport of AMOT to the pericentrosomal proteasome for rapid degradation. LATS kinases phosphorylate AMOT and shield it from this degradation route, thereby indirectly restraining YAP/TAZ. Loss of AMOT renders cells insensitive to mechanical modulations.","method":"Live-cell imaging, AMOT degradation assays, dynein/dynactin co-immunoprecipitation, NLP1 overexpression to restore centrosomal condensation, AMOT knockout cells, LATS phosphorylation assays, proteasome inhibition","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including transport assays, proteasome inhibition, kinase phosphorylation, genetic rescue, and structural reorganization imaging; published in peer-reviewed journal","pmids":["41034521"],"is_preprint":false},{"year":2025,"finding":"A pathogenic N-terminal truncation of AMOT (loss of first 91 amino acids) causes loss of both an N-degron degradation signal and the tankyrase-binding domain, leading to abnormally increased AMOT protein levels that disrupt cellular barrier integrity and cause X-linked congenital hydrocephalus in affected males.","method":"Exome sequencing, expression of truncation mutant, protein stability assays, barrier integrity assays in cells","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — variant characterization with mechanistic follow-up (N-degron and tankyrase-binding domain loss, barrier integrity assay), single family/lab","pmids":["40892511"],"is_preprint":false},{"year":2025,"finding":"SIPA1L3 interacts with AMOT through its PDZ domain, inhibiting the binding of AMOT to Patj (PALS1-associated tight junction protein) and decreasing AMOT anchoring to tight junctions, thereby promoting a malignant phenotype in NSCLC.","method":"Co-immunoprecipitation, PDZ domain mutant of SIPA1L3, Western blot, immunofluorescence, in vitro and in vivo proliferation/invasion assays","journal":"Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mutant and functional phenotype in cancer cells, single lab","pmids":["41088697"],"is_preprint":false}],"current_model":"AMOT is a scaffold adaptor protein that functions as a central hub in Hippo/YAP-TAZ mechanosignaling: it sequesters YAP/TAZ in the cytoplasm and its stability—regulated by microtubule-mediated dynein/dynactin transport to the pericentrosomal proteasome, tankyrase-dependent degradation, LATS-mediated phosphorylation, and WWC/USP9X-mediated deubiquitylation—acts as the primary mechanical rheostat linking cytoskeletal state to YAP/TAZ activity; additionally, AMOT organizes apical polarity at tight junctions by scaffolding Rich1-Cdc42, Patj, Pals1, and Par-3, controls directional endothelial migration via an Amot-Patj-Syx ternary complex that spatially restricts RhoA activity, binds Talin to transmit extracellular matrix forces to the cytoskeleton, and targets apical polarity proteins to endocytic recycling compartments through a lipid-binding ACCH domain selective for phosphatidylinositols and cholesterol."},"narrative":{"mechanistic_narrative":"AMOT is a multifunctional scaffold adaptor that integrates cytoskeletal and mechanical state with Hippo/YAP-TAZ signaling, cell polarity, and directed migration [PMID:16678097, PMID:41034521]. As a YAP/TAZ regulator, AMOT acts as a mechanical rheostat: it is stabilized in mechanically inhibited cells where it sequesters YAP/TAZ in the cytoplasm, but mechanical activation reorganizes microtubules into a radial centrosomal array that enables dynein/dynactin-mediated retrograde transport of AMOT to the pericentrosomal proteasome for degradation, with LATS-mediated phosphorylation shielding AMOT from this route, so that loss of AMOT renders cells mechanically insensitive [PMID:41034521]. AMOT abundance is further set by competing degradation and stabilization inputs, including tankyrase-mediated degradation [PMID:39486633] and WWC1/WWC2-dependent recruitment of the deubiquitylase USP9X that stabilizes AMOT-family proteins [PMID:37528078]. At the cellular level AMOT scaffolds apical polarity, binding the Cdc42 RhoGAP Rich1 through its coiled-coil domain to assemble a tight-junction complex with Pals1, Patj, and Par-3 [PMID:16678097], and forming an Amot-Patj-Syx ternary complex that spatially restricts RhoA activity during endothelial migration [PMID:18824598]. A lipid-binding ACCH domain selective for monophosphorylated phosphatidylinositols and cholesterol targets AMOT to Rab11/Arf6 endocytic recycling compartments and supports membrane tubulation [PMID:20080965]. AMOT also couples mechanical force to the cytoskeleton by binding Talin within the endothelial integrin adhesome, where its loss impairs tip-cell migration and vascular expansion [PMID:34433061], and it controls dendritic morphogenesis through a YAP1-dependent, TEAD-independent pathway acting on S6 kinase/S6 phosphorylation [PMID:31042703]. A pathogenic N-terminal truncation removing an N-degron and the tankyrase-binding domain stabilizes AMOT and causes X-linked congenital hydrocephalus [PMID:40892511]. AMOT PPxY motifs are also exploited by HIV-1, engaging NEDD4L WW domains to promote virion envelopment [PMID:34284061].","teleology":[{"year":2006,"claim":"Established AMOT as a scaffold organizing apical tight-junction polarity by linking a Cdc42 RhoGAP to PDZ polarity proteins, defining its founding role in epithelial junction architecture.","evidence":"Proteomic/functional screens, reciprocal co-IP, coiled-coil domain mutagenesis and confocal imaging in MDCK cells","pmids":["16678097"],"confidence":"High","gaps":["Did not connect junction scaffolding to YAP/TAZ control","Mechanism by which the coiled-coil drives Pals1/Par-3 relocalization not resolved"]},{"year":2008,"claim":"Showed AMOT spatially confines RhoA signaling during migration via an Amot-Patj-Syx ternary complex, extending its scaffold role from static junctions to directional endothelial motility.","evidence":"Peptide pull-down, yeast two-hybrid, FRET RhoA biosensor, and zebrafish morpholino knockdown","pmids":["18824598"],"confidence":"High","gaps":["How Syx GEF activity is spatially gated by the complex not fully defined","Link to downstream cytoskeletal output incomplete"]},{"year":2010,"claim":"Identified the ACCH lipid-binding domain, explaining how AMOT is targeted to specific membranes and recycling compartments and can deform membranes.","evidence":"In vitro lipid-binding and membrane tubulation assays, co-localization with Rab11/Arf6/cholesterol, cell fractionation","pmids":["20080965"],"confidence":"High","gaps":["Functional consequence of tubulation in cells not established","Relationship between lipid binding and YAP regulation unknown"]},{"year":2011,"claim":"Linked an AMOT isoform to proliferative signaling, showing the polarity-interaction domain is required for ERK1/2-dependent growth.","evidence":"Isoform and domain-deletion expression in MCF7/MCF10A cells, 3D Matrigel culture, ERK1/2 activity assays","pmids":["21285250"],"confidence":"Medium","gaps":["Direct biochemical link between AMOT and ERK pathway components absent","Isoform-specific mechanism not resolved"]},{"year":2015,"claim":"Demonstrated that competitive binding at AMOT controls YAP availability, with endotubin displacing YAP to drive nuclear translocation and overgrowth.","evidence":"Reciprocal co-IP, EDTB overexpression, soft-agar assay, YAP nuclear translocation imaging","pmids":["25995376"],"confidence":"Medium","gaps":["Physiological context where EDTB competition operates unclear","Stoichiometry of AMOT-YAP-EDTB interactions undefined"]},{"year":2017,"claim":"Multiple studies positioned AMOT abundance and Nf2/F-actin engagement as a regulated node: Rho prevents AMOT Ser176 phosphorylation to stabilize F-actin binding and restrict Nf2 association, CREB-MPP7 sets AMOT level/localization for YAP1, and DUB3 controls AMOT-family protein stability.","evidence":"Blastocyst inhibitor/activator screens with phospho-site mapping and co-IP; conditional knockout mice and myoblast loss-of-function; DUB3 overexpression/knockdown with ubiquitination assays","pmids":["28947533","29091764","28061504"],"confidence":"Medium","gaps":["How distinct upstream inputs are integrated on AMOT not unified","DUB3 mechanistic detail limited"]},{"year":2019,"claim":"Defined a TEAD-independent AMOT-YAP1 axis controlling dendritic morphogenesis through S6K/S6 phosphorylation, broadening AMOT function into neuronal development, and identified lncRNA UCA1 as a direct binder that enhances AMOT-YAP coupling.","evidence":"Conditional neuronal knockout mice, hippocampal culture knockdown, S6K/S6 phospho Western blots, motor behavior; iRAP, RPPA, co-IP, siRNA epistasis","pmids":["31042703","31307004"],"confidence":"High","gaps":["Mechanism linking AMOT-YAP1 to S6K activation undefined","How UCA1 binding alters AMOT conformation/activity unknown"]},{"year":2021,"claim":"Established AMOT as a force-transmitting component of the integrin adhesome via Talin binding, and structurally resolved AMOT PPxY/14-3-3 and NEDD4L WW interactions, including a hijacked role in HIV-1 envelopment.","evidence":"Endothelial conditional KO mice with traction force and vascular imaging plus Talin binding assays; X-ray crystallography and mutagenesis of PPxY/WW and 14-3-3 interfaces with virological readout","pmids":["34433061","34284061","35036934"],"confidence":"High","gaps":["How Talin-AMOT force transmission feeds back to YAP/TAZ not established","Functional role of the 14-3-3/Amot-p130 interaction in cells not defined"]},{"year":2022,"claim":"Showed RICH1 competes with Merlin for AMOT-p80 via its BAR domain, providing a molecular switch that activates Hippo and suppresses breast cancer stem cell traits.","evidence":"Reciprocal co-IP, BAR-domain deletion mutagenesis, MCF10A loss-of-function and stem cell trait assays","pmids":["35064101"],"confidence":"Medium","gaps":["What controls the RICH1-vs-Merlin equilibrium in vivo unknown","Generalizability beyond breast cells untested"]},{"year":2023,"claim":"Identified WWC1/WWC2 as direct AMOT binders that recruit USP9X to deubiquitinate and stabilize AMOT-family proteins, with in vivo neuronal and cognitive consequences rescuable by AMOT.","evidence":"Direct binding and USP9X deubiquitination assays, conditional double-knockout mice, dendritic spine imaging, behavioral tests, AMOT rescue","pmids":["37528078"],"confidence":"High","gaps":["Which AMOT lysines USP9X acts on not mapped","Counterbalancing E3 ligase not identified"]},{"year":2024,"claim":"Connected actomyosin-driven AMOT nuclear translocation to YAP suppression and definitive endoderm specification, and embryonic tankyrase/SOX2-dependent AMOT degradation to YAP nuclear localization, establishing AMOT abundance and localization as developmental mechanosensors.","evidence":"Actomyosin inhibitor and hypertonic treatment with AMOT/YAP localization imaging and endoderm markers in hPSCs; tankyrase inhibition and SOX2 loss-of-function in mouse embryos with phospho/localization imaging","pmids":["39094563","39486633"],"confidence":"Medium","gaps":["Mechanism of AMOT nuclear import not defined","How AMOT in the nucleus suppresses YAP unclear"]},{"year":2025,"claim":"Unified AMOT stability as the primary mechanical rheostat for YAP/TAZ through microtubule-dependent dynein/dynactin transport to the pericentrosomal proteasome shielded by LATS phosphorylation, and linked AMOT stabilization by a pathogenic N-terminal truncation to X-linked congenital hydrocephalus, while a PDZ-domain interactor SIPA1L3 was shown to delocalize AMOT from tight junctions in NSCLC.","evidence":"Live-cell imaging, dynein/dynactin co-IP, proteasome inhibition, centrosomal condensation rescue, AMOT KO and LATS phosphorylation assays; exome sequencing with truncation-mutant stability and barrier assays; co-IP with SIPA1L3 PDZ mutant and tumor assays","pmids":["41034521","40892511","41088697"],"confidence":"High","gaps":["How LATS phosphorylation physically blocks dynein-mediated transport not resolved","Tissue-specificity of the hydrocephalus barrier defect incompletely defined"]},{"year":null,"claim":"How AMOT's many regulatory inputs—mechanical microtubule transport, tankyrase/N-degron degradation, USP9X stabilization, lipid and Talin binding, and nuclear translocation—are integrated and prioritized within a single cell to set a defined YAP/TAZ output remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No quantitative model relating AMOT abundance/localization to YAP/TAZ activity","Cross-talk hierarchy among competing stabilization and degradation pathways unknown","Structural basis of the active vs. cytoplasmic-sequestering AMOT states undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[17,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,0,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[17,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,10,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,11,19]}],"complexes":["Rich1-Pals1-Patj-Par-3 tight junction complex","Amot-Patj-Syx ternary complex","endothelial integrin adhesome"],"partners":["RICH1","PATJ","PALS1","PARD3","YAP1","NF2","TLN1","NEDD4L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q4VCS5","full_name":"Angiomotin","aliases":[],"length_aa":1084,"mass_kda":118.1,"function":"Plays a central role in tight junction maintenance via the complex formed with ARHGAP17, which acts by regulating the uptake of polarity proteins at tight junctions. Appears to regulate endothelial cell migration and tube formation. May also play a role in the assembly of endothelial cell-cell junctions. Repressor of YAP1 and WWTR1/TAZ transcription of target genes, potentially via regulation of Hippo signaling-mediated phosphorylation of YAP1 which results in its recruitment to tight junctions (PubMed:21205866)","subcellular_location":"Cell junction, tight junction","url":"https://www.uniprot.org/uniprotkb/Q4VCS5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AMOT","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CD151","stoichiometry":10.0},{"gene":"DYNLL2","stoichiometry":10.0},{"gene":"DYNLL1","stoichiometry":4.0},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/AMOT","total_profiled":1310},"omim":[{"mim_id":"620871","title":"DNA DAMAGE-INDUCIBLE 1 HOMOLOG 2; DDI2","url":"https://www.omim.org/entry/620871"},{"mim_id":"614658","title":"ANGIOMOTIN-LIKE 2; AMOTL2","url":"https://www.omim.org/entry/614658"},{"mim_id":"614657","title":"ANGIOMOTIN-LIKE 1; AMOTL1","url":"https://www.omim.org/entry/614657"},{"mim_id":"608293","title":"RHO GTPase-ACTIVATING PROTEIN 17; ARHGAP17","url":"https://www.omim.org/entry/608293"},{"mim_id":"300410","title":"ANGIOMOTIN; AMOT","url":"https://www.omim.org/entry/300410"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cell Junctions","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"epididymis","ntpm":137.7},{"tissue":"tongue","ntpm":51.2}],"url":"https://www.proteinatlas.org/search/AMOT"},"hgnc":{"alias_symbol":["KIAA1071"],"prev_symbol":[]},"alphafold":{"accession":"Q4VCS5","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4VCS5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q4VCS5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q4VCS5-F1-predicted_aligned_error_v6.png","plddt_mean":56.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AMOT","jax_strain_url":"https://www.jax.org/strain/search?query=AMOT"},"sequence":{"accession":"Q4VCS5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q4VCS5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q4VCS5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4VCS5"}},"corpus_meta":[{"pmid":"16678097","id":"PMC_16678097","title":"A Rich1/Amot complex regulates the Cdc42 GTPase and apical-polarity proteins in epithelial cells.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16678097","citation_count":303,"is_preprint":false},{"pmid":"18824598","id":"PMC_18824598","title":"The Amot/Patj/Syx signaling complex spatially controls RhoA GTPase activity in migrating endothelial cells.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18824598","citation_count":115,"is_preprint":false},{"pmid":"31307004","id":"PMC_31307004","title":"Super-Enhancer-Associated LncRNA UCA1 Interacts Directly with AMOT to Activate YAP Target Genes in Epithelial Ovarian Cancer.","date":"2019","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/31307004","citation_count":64,"is_preprint":false},{"pmid":"20080965","id":"PMC_20080965","title":"Amot recognizes a juxtanuclear endocytic recycling compartment via a novel lipid binding domain.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20080965","citation_count":50,"is_preprint":false},{"pmid":"21285250","id":"PMC_21285250","title":"The adaptor protein AMOT promotes the proliferation of mammary epithelial cells via the prolonged activation of the extracellular signal-regulated kinases.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21285250","citation_count":45,"is_preprint":false},{"pmid":"26855583","id":"PMC_26855583","title":"MicroRNA-497 inhibits cell proliferation, migration, and invasion by targeting AMOT in human osteosarcoma cells.","date":"2016","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/26855583","citation_count":44,"is_preprint":false},{"pmid":"26239614","id":"PMC_26239614","title":"MicroRNA-205 inhibits the proliferation and invasion of breast cancer by regulating AMOT expression.","date":"2015","source":"Oncology 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for YAP function in high glucose induced liver malignancy.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29217192","citation_count":23,"is_preprint":false},{"pmid":"27875740","id":"PMC_27875740","title":"Conditional knockout of TFPI-1 in VSMCs of mice accelerates atherosclerosis by enhancing AMOT/YAP pathway.","date":"2016","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/27875740","citation_count":23,"is_preprint":false},{"pmid":"36244032","id":"PMC_36244032","title":"Fluid shear stress promotes periodontal ligament cells proliferation via p38-AMOT-YAP.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/36244032","citation_count":22,"is_preprint":false},{"pmid":"34284061","id":"PMC_34284061","title":"Interactions between AMOT PPxY motifs and NEDD4L WW domains function in HIV-1 release.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34284061","citation_count":17,"is_preprint":false},{"pmid":"38862095","id":"PMC_38862095","title":"Rapamycin promotes the intestinal barrier repair in ulcerative colitis via the mTOR/PBLD/AMOT signaling pathway.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38862095","citation_count":16,"is_preprint":false},{"pmid":"35064101","id":"PMC_35064101","title":"RICH1 inhibits breast cancer stem cell traits through activating kinases cascade of Hippo signaling by competing with Merlin for binding to Amot-p80.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35064101","citation_count":16,"is_preprint":false},{"pmid":"37528078","id":"PMC_37528078","title":"WWC1/2 regulate spinogenesis and cognition in mice by stabilizing AMOT.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37528078","citation_count":13,"is_preprint":false},{"pmid":"39739271","id":"PMC_39739271","title":"PSAT1 promotes the progression of colorectal cancer by regulating Hippo-YAP/TAZ-ID1 axis via AMOT.","date":"2024","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39739271","citation_count":13,"is_preprint":false},{"pmid":"32656583","id":"PMC_32656583","title":"CLIC1 knockout inhibits invasion and migration of gastric cancer by upregulating AMOT-p130 expression.","date":"2020","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/32656583","citation_count":12,"is_preprint":false},{"pmid":"29752344","id":"PMC_29752344","title":"MiR-4463 inhibits the migration of human aortic smooth muscle cells by AMOT.","date":"2018","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/29752344","citation_count":11,"is_preprint":false},{"pmid":"29036193","id":"PMC_29036193","title":"Gestational age-related patterns of AMOT methylation are revealed in preterm infant endothelial progenitors.","date":"2017","source":"PloS 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Proteins.","date":"2021","source":"Membranes","url":"https://pubmed.ncbi.nlm.nih.gov/34564504","citation_count":9,"is_preprint":false},{"pmid":"41034521","id":"PMC_41034521","title":"Microtubule architecture connects AMOT stability to YAP/TAZ mechanotransduction and Hippo signalling.","date":"2025","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/41034521","citation_count":8,"is_preprint":false},{"pmid":"37545216","id":"PMC_37545216","title":"Investigating whether exosomal miR-205-5p derived from tongue squamous cell carcinoma cells stimulates the angiogenic activity of HUVECs by targeting AMOT.","date":"2023","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/37545216","citation_count":8,"is_preprint":false},{"pmid":"33414519","id":"PMC_33414519","title":"AMOT suppresses tumor progression via regulating DNA damage response signaling in diffuse large B-cell lymphoma.","date":"2021","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33414519","citation_count":7,"is_preprint":false},{"pmid":"39094563","id":"PMC_39094563","title":"Cell size regulates human endoderm specification through actomyosin-dependent AMOT-YAP signaling.","date":"2024","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39094563","citation_count":4,"is_preprint":false},{"pmid":"39021301","id":"PMC_39021301","title":"Induced expression of AMOT reverses adriamycin resistance in breast cancer cells.","date":"2024","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/39021301","citation_count":3,"is_preprint":false},{"pmid":"39486633","id":"PMC_39486633","title":"Blastocoel expansion and AMOT degradation cooperatively promote YAP nuclear localization during epiblast formation.","date":"2024","source":"Developmental 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proteins","date":"2025-06-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.02.657518","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19455,"output_tokens":5070,"usd":0.067208,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13344,"output_tokens":4907,"usd":0.094698,"stage2_stop_reason":"end_turn"},"total_usd":0.161906,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Amot binds the Cdc42 RhoGAP Rich1 via its coiled-coil domain and is thereby targeted to a tight junction complex containing the PDZ-domain proteins Pals1, Patj, and Par-3 in MDCK epithelial cells. The coiled-coil domain of Amot is required for apical membrane localization and for relocalization of Pals1 and Par-3 to internal puncta.\",\n      \"method\": \"Functional and proteomic screens, co-immunoprecipitation, domain mutagenesis, confocal imaging in MDCK cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, domain mutagenesis, and functional imaging in epithelial cells; widely replicated finding\",\n      \"pmids\": [\"16678097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Amot forms a ternary complex with the PDZ protein Patj (or Mupp1) and the RhoGEF Syx, and this complex controls spatial targeting of RhoA activity to lamellipodia in migrating endothelial cells. Amot interacts with Syx through its C-terminal PDZ-binding motif.\",\n      \"method\": \"Peptide pull-down, yeast two-hybrid screening, FRET analysis of RhoA activity, morpholino knockdown in zebrafish\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, pull-down, FRET, in vivo morpholino); consistent results across in vitro and in vivo models\",\n      \"pmids\": [\"18824598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Amot contains a novel lipid-binding domain (later termed ACCH domain) that selectively binds membranes containing monophosphorylated phosphatidylinositols and cholesterol with high affinity, enables membrane tubulation in vitro, and targets Amot to juxtanuclear endocytic recycling compartments marked by Rab11 and Arf6.\",\n      \"method\": \"Lipid-binding assays, in vitro membrane tubulation assay, fluorescence co-localization with Rab11/Arf6/cholesterol markers, cell fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of lipid binding and tubulation plus cellular localization with multiple markers, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"20080965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Amot80 (the 80 kDa isoform) promotes ERK1/2-dependent proliferation of mammary epithelial cells; a mutant lacking the polarity protein interaction domain fails to enhance ERK1/2-dependent proliferation, indicating this domain is required for the pro-proliferative effect.\",\n      \"method\": \"Isoform expression in MCF7 and MCF10A cells, Matrigel 3D culture, ERK1/2 activity assays, domain-deletion mutagenesis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion mutagenesis plus multiple cell-based assays in one lab\",\n      \"pmids\": [\"21285250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AMOT interacts dynamically with the endosomal integral membrane protein endotubin (EDTB) at the endosomal membrane; EDTB competes with YAP for binding to AMOT in subconfluent cells. Overexpression of EDTB displaces YAP from AMOT, promoting YAP nuclear translocation and an overgrowth phenotype in a YAP-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, overexpression of full-length and cytoplasmic-domain EDTB, soft-agar growth assay, YAP nuclear translocation imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and functional rescue experiments, single lab\",\n      \"pmids\": [\"25995376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Active Rho GTPase prevents phosphorylation of Amot Ser176, stabilizing the Amot–F-actin interaction and restricting Amot–Nf2 binding. Additionally, Rho directly binds the coiled-coil domain of Amot to attenuate Amot–Nf2 association, thereby suppressing Hippo signaling in trophectoderm cells of the blastocyst.\",\n      \"method\": \"Inhibitor/activator screen in blastocysts, co-immunoprecipitation, phosphorylation assays, domain mapping\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and phospho-site analysis with inhibitor validation, single lab\",\n      \"pmids\": [\"28947533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CREB transcriptionally activates Mpp7, which in turn controls the subcellular localization and protein level of AMOT; MPP7 and AMOT are individually required for YAP1 nuclear accumulation and for the proliferative state of myoblasts. Thus AMOT functions downstream of CREB-MPP7 to relay signals to YAP1 in muscle satellite cells.\",\n      \"method\": \"Conditional knockout mice, loss-of-function in myoblasts, subcellular fractionation/immunofluorescence, Western blot\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo and cellular loss-of-function, single lab\",\n      \"pmids\": [\"29091764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DUB3 deubiquitylating enzymes regulate the protein stability of AMOT family members (as well as LATS kinases and the E3 ligase ITCH), thereby modulating Hippo pathway activity and YAP/TAZ levels.\",\n      \"method\": \"Overexpression and knockdown of DUB3 in cell lines, Western blot for protein stability, ubiquitination assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, Western blot-based stability assay with knockdown; limited mechanistic detail in abstract\",\n      \"pmids\": [\"28061504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Amot is required for dendritic morphogenesis in hippocampal neurons and Purkinje cells. Its function in dendrite growth depends on interaction with Yap1 and does not require TEAD transcription factors; instead, Amot and Yap1 regulate dendrite arborization by affecting phosphorylation of S6 kinase and its target S6 ribosomal protein. Conditional deletion of Amot in neurons reduces Purkinje cell dendritic tree complexity and impairs motor coordination.\",\n      \"method\": \"Conditional neuronal knockout mice, in vitro hippocampal culture knockdown, immunofluorescence, Western blot for S6K/S6 phosphorylation, motor behavior assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo with defined cerebellar phenotype plus mechanistic pathway dissection (TEAD independence, S6K phosphorylation), multiple orthogonal methods\",\n      \"pmids\": [\"31042703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The lncRNA UCA1 directly binds AMOT protein (identified by in vivo RNA antisense purification), enhances the AMOT–YAP interaction, and promotes YAP dephosphorylation and nuclear translocation. Loss-of-function experiments confirm AMOT mediates YAP activation downstream of UCA1.\",\n      \"method\": \"In vivo RNA antisense purification (iRAP), RPPA, co-immunoprecipitation, loss-of-function siRNA, YAP phosphorylation and nuclear translocation assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iRAP for direct binding plus functional epistasis by AMOT knockdown, single lab\",\n      \"pmids\": [\"31307004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AMOT binds Talin and is an essential component of the endothelial integrin adhesome; endothelial-specific deletion of Amot in mice inhibits tip cell migration, filopodia extension, and vascular network expansion. Amot relays mechanical forces between fibronectin and the cytoskeleton.\",\n      \"method\": \"Endothelial-specific conditional knockout mice, in vitro molecular binding assays, traction force measurements, retinal and tumor vascular imaging\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with defined vascular phenotype plus in vitro binding (Talin interaction) and force transmission assays; multiple orthogonal methods\",\n      \"pmids\": [\"34433061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AMOT PPxY motifs interact with NEDD4L WW domains to promote HIV-1 virion envelopment and infectivity. The AMOT PPxY1–NEDD4L WW3 interaction has unusually high affinity due to complementary ionic and hydrophobic contacts beyond the WW-PPxY core, and is the dominant interaction driving HIV-1 release. Structural analysis revealed the molecular basis of this selectivity.\",\n      \"method\": \"Structural analysis (X-ray crystallography implied by 'comparative structural analyses'), binding affinity measurements, site-directed mutagenesis of PPxY motifs and WW domains, HIV-1 virological infectivity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural resolution of binding interface plus mutagenesis and functional virological readout in one study\",\n      \"pmids\": [\"34284061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fragment-based X-ray crystallography resolved the first structure of the 14-3-3 binding motif of Amot-p130, characterizing the binding mode and affinities of the 14-3-3/Amot-p130 protein–protein interaction interface.\",\n      \"method\": \"X-ray crystallography, fragment-based screening, binding affinity measurements (SPR/ITC implied)\",\n      \"journal\": \"Current research in structural biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure of the complex, single lab, limited functional validation described in abstract\",\n      \"pmids\": [\"35036934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RICH1 competes with Merlin for binding to Amot-p80 via its BAR domain; this competition displaces Amot-p80 from the Amot-Merlin complex and activates the Hippo kinase cascade, suppressing YAP/TAZ and breast cancer stem cell traits. Deletion of the BAR domain of RICH1 abolishes its ability to displace Merlin from Amot-p80.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutagenesis (BAR domain), loss-of-function in MCF10A cells, stem cell trait assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mutagenesis and functional phenotype, single lab\",\n      \"pmids\": [\"35064101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WWC1 and WWC2 directly bind AMOT family proteins (Motins) and recruit the deubiquitylase USP9X to deubiquitinate and stabilize Motins. Neuron-specific deletion of Wwc1/2 in mice reduces Motin protein levels, decreases dendritic spine density in cortex and hippocampus, and impairs memory/learning; ectopic AMOT expression partially rescues these neuronal phenotypes.\",\n      \"method\": \"Direct binding assays, USP9X recruitment and deubiquitination assays, conditional double-knockout mice, immunofluorescence of dendritic spines, cognitive behavioral tests, rescue by AMOT overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with defined neuronal phenotype, biochemical reconstitution of USP9X-mediated deubiquitination, and functional rescue by AMOT, multiple orthogonal methods\",\n      \"pmids\": [\"37528078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AMOT nuclear translocation (driven by actomyosin activity consequent to cell size reduction) suppresses YAP activity and promotes definitive endoderm differentiation of human pluripotent stem cells. Blocking actomyosin activity prevents both AMOT nuclear translocation and endoderm specification.\",\n      \"method\": \"Hypertonic pressure treatment, chemical inhibitors of actomyosin, immunofluorescence of AMOT and YAP subcellular localization, endoderm marker expression assays\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional intervention with mechanosensitive elements, subcellular localization imaging linked to differentiation outcome, single lab\",\n      \"pmids\": [\"39094563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AMOT expression gradually decreases during epiblast formation through tankyrase-mediated degradation; SOX2 expression in the ICM is necessary for this reduction of AMOT and consequent decrease in YAP phosphorylation, enabling YAP nuclear localization. Blastocoel expansion and AMOT degradation act in parallel to promote YAP nuclear translocation.\",\n      \"method\": \"Mouse preimplantation embryo analysis, tankyrase inhibition, SOX2 loss-of-function, immunofluorescence of AMOT/YAP phosphorylation and localization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological epistasis in embryos with imaging readout, single lab\",\n      \"pmids\": [\"39486633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AMOT protein stability serves as the primary mechanical rheostat controlling YAP/TAZ: AMOT is stable in mechanically inhibited cells where it sequesters YAP/TAZ in the cytoplasm, but in mechanically activated cells, microtubules reorganize into a radial centrosomal array, allowing dynein/dynactin-mediated retrograde transport of AMOT to the pericentrosomal proteasome for rapid degradation. LATS kinases phosphorylate AMOT and shield it from this degradation route, thereby indirectly restraining YAP/TAZ. Loss of AMOT renders cells insensitive to mechanical modulations.\",\n      \"method\": \"Live-cell imaging, AMOT degradation assays, dynein/dynactin co-immunoprecipitation, NLP1 overexpression to restore centrosomal condensation, AMOT knockout cells, LATS phosphorylation assays, proteasome inhibition\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including transport assays, proteasome inhibition, kinase phosphorylation, genetic rescue, and structural reorganization imaging; published in peer-reviewed journal\",\n      \"pmids\": [\"41034521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A pathogenic N-terminal truncation of AMOT (loss of first 91 amino acids) causes loss of both an N-degron degradation signal and the tankyrase-binding domain, leading to abnormally increased AMOT protein levels that disrupt cellular barrier integrity and cause X-linked congenital hydrocephalus in affected males.\",\n      \"method\": \"Exome sequencing, expression of truncation mutant, protein stability assays, barrier integrity assays in cells\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — variant characterization with mechanistic follow-up (N-degron and tankyrase-binding domain loss, barrier integrity assay), single family/lab\",\n      \"pmids\": [\"40892511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIPA1L3 interacts with AMOT through its PDZ domain, inhibiting the binding of AMOT to Patj (PALS1-associated tight junction protein) and decreasing AMOT anchoring to tight junctions, thereby promoting a malignant phenotype in NSCLC.\",\n      \"method\": \"Co-immunoprecipitation, PDZ domain mutant of SIPA1L3, Western blot, immunofluorescence, in vitro and in vivo proliferation/invasion assays\",\n      \"journal\": \"Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mutant and functional phenotype in cancer cells, single lab\",\n      \"pmids\": [\"41088697\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AMOT is a scaffold adaptor protein that functions as a central hub in Hippo/YAP-TAZ mechanosignaling: it sequesters YAP/TAZ in the cytoplasm and its stability—regulated by microtubule-mediated dynein/dynactin transport to the pericentrosomal proteasome, tankyrase-dependent degradation, LATS-mediated phosphorylation, and WWC/USP9X-mediated deubiquitylation—acts as the primary mechanical rheostat linking cytoskeletal state to YAP/TAZ activity; additionally, AMOT organizes apical polarity at tight junctions by scaffolding Rich1-Cdc42, Patj, Pals1, and Par-3, controls directional endothelial migration via an Amot-Patj-Syx ternary complex that spatially restricts RhoA activity, binds Talin to transmit extracellular matrix forces to the cytoskeleton, and targets apical polarity proteins to endocytic recycling compartments through a lipid-binding ACCH domain selective for phosphatidylinositols and cholesterol.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AMOT is a multifunctional scaffold adaptor that integrates cytoskeletal and mechanical state with Hippo/YAP-TAZ signaling, cell polarity, and directed migration [#0, #17]. As a YAP/TAZ regulator, AMOT acts as a mechanical rheostat: it is stabilized in mechanically inhibited cells where it sequesters YAP/TAZ in the cytoplasm, but mechanical activation reorganizes microtubules into a radial centrosomal array that enables dynein/dynactin-mediated retrograde transport of AMOT to the pericentrosomal proteasome for degradation, with LATS-mediated phosphorylation shielding AMOT from this route, so that loss of AMOT renders cells mechanically insensitive [#17]. AMOT abundance is further set by competing degradation and stabilization inputs, including tankyrase-mediated degradation [#16] and WWC1/WWC2-dependent recruitment of the deubiquitylase USP9X that stabilizes AMOT-family proteins [#14]. At the cellular level AMOT scaffolds apical polarity, binding the Cdc42 RhoGAP Rich1 through its coiled-coil domain to assemble a tight-junction complex with Pals1, Patj, and Par-3 [#0], and forming an Amot-Patj-Syx ternary complex that spatially restricts RhoA activity during endothelial migration [#1]. A lipid-binding ACCH domain selective for monophosphorylated phosphatidylinositols and cholesterol targets AMOT to Rab11/Arf6 endocytic recycling compartments and supports membrane tubulation [#2]. AMOT also couples mechanical force to the cytoskeleton by binding Talin within the endothelial integrin adhesome, where its loss impairs tip-cell migration and vascular expansion [#10], and it controls dendritic morphogenesis through a YAP1-dependent, TEAD-independent pathway acting on S6 kinase/S6 phosphorylation [#8]. A pathogenic N-terminal truncation removing an N-degron and the tankyrase-binding domain stabilizes AMOT and causes X-linked congenital hydrocephalus [#18]. AMOT PPxY motifs are also exploited by HIV-1, engaging NEDD4L WW domains to promote virion envelopment [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established AMOT as a scaffold organizing apical tight-junction polarity by linking a Cdc42 RhoGAP to PDZ polarity proteins, defining its founding role in epithelial junction architecture.\",\n      \"evidence\": \"Proteomic/functional screens, reciprocal co-IP, coiled-coil domain mutagenesis and confocal imaging in MDCK cells\",\n      \"pmids\": [\"16678097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect junction scaffolding to YAP/TAZ control\", \"Mechanism by which the coiled-coil drives Pals1/Par-3 relocalization not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed AMOT spatially confines RhoA signaling during migration via an Amot-Patj-Syx ternary complex, extending its scaffold role from static junctions to directional endothelial motility.\",\n      \"evidence\": \"Peptide pull-down, yeast two-hybrid, FRET RhoA biosensor, and zebrafish morpholino knockdown\",\n      \"pmids\": [\"18824598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Syx GEF activity is spatially gated by the complex not fully defined\", \"Link to downstream cytoskeletal output incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the ACCH lipid-binding domain, explaining how AMOT is targeted to specific membranes and recycling compartments and can deform membranes.\",\n      \"evidence\": \"In vitro lipid-binding and membrane tubulation assays, co-localization with Rab11/Arf6/cholesterol, cell fractionation\",\n      \"pmids\": [\"20080965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of tubulation in cells not established\", \"Relationship between lipid binding and YAP regulation unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked an AMOT isoform to proliferative signaling, showing the polarity-interaction domain is required for ERK1/2-dependent growth.\",\n      \"evidence\": \"Isoform and domain-deletion expression in MCF7/MCF10A cells, 3D Matrigel culture, ERK1/2 activity assays\",\n      \"pmids\": [\"21285250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between AMOT and ERK pathway components absent\", \"Isoform-specific mechanism not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that competitive binding at AMOT controls YAP availability, with endotubin displacing YAP to drive nuclear translocation and overgrowth.\",\n      \"evidence\": \"Reciprocal co-IP, EDTB overexpression, soft-agar assay, YAP nuclear translocation imaging\",\n      \"pmids\": [\"25995376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context where EDTB competition operates unclear\", \"Stoichiometry of AMOT-YAP-EDTB interactions undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple studies positioned AMOT abundance and Nf2/F-actin engagement as a regulated node: Rho prevents AMOT Ser176 phosphorylation to stabilize F-actin binding and restrict Nf2 association, CREB-MPP7 sets AMOT level/localization for YAP1, and DUB3 controls AMOT-family protein stability.\",\n      \"evidence\": \"Blastocyst inhibitor/activator screens with phospho-site mapping and co-IP; conditional knockout mice and myoblast loss-of-function; DUB3 overexpression/knockdown with ubiquitination assays\",\n      \"pmids\": [\"28947533\", \"29091764\", \"28061504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How distinct upstream inputs are integrated on AMOT not unified\", \"DUB3 mechanistic detail limited\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a TEAD-independent AMOT-YAP1 axis controlling dendritic morphogenesis through S6K/S6 phosphorylation, broadening AMOT function into neuronal development, and identified lncRNA UCA1 as a direct binder that enhances AMOT-YAP coupling.\",\n      \"evidence\": \"Conditional neuronal knockout mice, hippocampal culture knockdown, S6K/S6 phospho Western blots, motor behavior; iRAP, RPPA, co-IP, siRNA epistasis\",\n      \"pmids\": [\"31042703\", \"31307004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking AMOT-YAP1 to S6K activation undefined\", \"How UCA1 binding alters AMOT conformation/activity unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established AMOT as a force-transmitting component of the integrin adhesome via Talin binding, and structurally resolved AMOT PPxY/14-3-3 and NEDD4L WW interactions, including a hijacked role in HIV-1 envelopment.\",\n      \"evidence\": \"Endothelial conditional KO mice with traction force and vascular imaging plus Talin binding assays; X-ray crystallography and mutagenesis of PPxY/WW and 14-3-3 interfaces with virological readout\",\n      \"pmids\": [\"34433061\", \"34284061\", \"35036934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Talin-AMOT force transmission feeds back to YAP/TAZ not established\", \"Functional role of the 14-3-3/Amot-p130 interaction in cells not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed RICH1 competes with Merlin for AMOT-p80 via its BAR domain, providing a molecular switch that activates Hippo and suppresses breast cancer stem cell traits.\",\n      \"evidence\": \"Reciprocal co-IP, BAR-domain deletion mutagenesis, MCF10A loss-of-function and stem cell trait assays\",\n      \"pmids\": [\"35064101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What controls the RICH1-vs-Merlin equilibrium in vivo unknown\", \"Generalizability beyond breast cells untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified WWC1/WWC2 as direct AMOT binders that recruit USP9X to deubiquitinate and stabilize AMOT-family proteins, with in vivo neuronal and cognitive consequences rescuable by AMOT.\",\n      \"evidence\": \"Direct binding and USP9X deubiquitination assays, conditional double-knockout mice, dendritic spine imaging, behavioral tests, AMOT rescue\",\n      \"pmids\": [\"37528078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which AMOT lysines USP9X acts on not mapped\", \"Counterbalancing E3 ligase not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected actomyosin-driven AMOT nuclear translocation to YAP suppression and definitive endoderm specification, and embryonic tankyrase/SOX2-dependent AMOT degradation to YAP nuclear localization, establishing AMOT abundance and localization as developmental mechanosensors.\",\n      \"evidence\": \"Actomyosin inhibitor and hypertonic treatment with AMOT/YAP localization imaging and endoderm markers in hPSCs; tankyrase inhibition and SOX2 loss-of-function in mouse embryos with phospho/localization imaging\",\n      \"pmids\": [\"39094563\", \"39486633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of AMOT nuclear import not defined\", \"How AMOT in the nucleus suppresses YAP unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Unified AMOT stability as the primary mechanical rheostat for YAP/TAZ through microtubule-dependent dynein/dynactin transport to the pericentrosomal proteasome shielded by LATS phosphorylation, and linked AMOT stabilization by a pathogenic N-terminal truncation to X-linked congenital hydrocephalus, while a PDZ-domain interactor SIPA1L3 was shown to delocalize AMOT from tight junctions in NSCLC.\",\n      \"evidence\": \"Live-cell imaging, dynein/dynactin co-IP, proteasome inhibition, centrosomal condensation rescue, AMOT KO and LATS phosphorylation assays; exome sequencing with truncation-mutant stability and barrier assays; co-IP with SIPA1L3 PDZ mutant and tumor assays\",\n      \"pmids\": [\"41034521\", \"40892511\", \"41088697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LATS phosphorylation physically blocks dynein-mediated transport not resolved\", \"Tissue-specificity of the hydrocephalus barrier defect incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AMOT's many regulatory inputs—mechanical microtubule transport, tankyrase/N-degron degradation, USP9X stabilization, lipid and Talin binding, and nuclear translocation—are integrated and prioritized within a single cell to set a defined YAP/TAZ output remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative model relating AMOT abundance/localization to YAP/TAZ activity\", \"Cross-talk hierarchy among competing stabilization and degradation pathways unknown\", \"Structural basis of the active vs. cytoplasmic-sequestering AMOT states undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [17, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 0, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [17, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 10, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 11, 19]}\n    ],\n    \"complexes\": [\"Rich1-Pals1-Patj-Par-3 tight junction complex\", \"Amot-Patj-Syx ternary complex\", \"endothelial integrin adhesome\"],\n    \"partners\": [\"RICH1\", \"PATJ\", \"PALS1\", \"PARD3\", \"YAP1\", \"NF2\", \"TLN1\", \"NEDD4L\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}