{"gene":"AKAP11","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1999,"finding":"AKAP220 (AKAP11) binds the type 1 protein phosphatase catalytic subunit (PP1c) with a KD of ~12 nM in vitro, and immunoprecipitation of PP1 from cell extracts co-enriches PKA activity, establishing AKAP220 as a multivalent anchoring protein that simultaneously scaffolds both PKA and PP1 in a signaling complex.","method":"In vitro binding assay (KD measurement), affinity chromatography on microcystin-Sepharose, co-immunoprecipitation from cell extracts, immunocytochemistry in rat hippocampal neurons","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution with KD measurement plus reciprocal co-IP and affinity chromatography, multiple orthogonal methods","pmids":["10209101"],"is_preprint":false},{"year":2001,"finding":"AKAP220 (AKAP11) acts as a competitive inhibitor of PP1c activity (Ki = 2.9 µM); a consensus targeting motif (residues 1195–1198, KVQF) mediates PP1 binding without inhibiting it, while a distinct region (residues 1711–1901) is required for inhibition. Addition of PKA regulatory subunit (RII) to the complex further enhances PP1 inhibition, indicating synergistic intra- and inter-molecular regulation.","method":"In vitro PP1 phosphatase activity assay with AKAP220 fragments, deletion/truncation mapping, chimeric PP1/PP2A catalytic subunit analysis","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with mutagenesis/truncation mapping and multiple orthogonal approaches in a single rigorous study","pmids":["11152471"],"is_preprint":false},{"year":2002,"finding":"AKAP220 (AKAP11) binds GSK-3β via yeast two-hybrid and forms a quaternary complex with GSK-3β, PKA, and PP1 in intact cells. PKA activation (via dibutyryl-cAMP) reduces GSK-3β activity within the AKAP220-bound pool more markedly than total cellular GSK-3β activity, demonstrating that the scaffold enables efficient PKA-dependent inhibition of GSK-3β.","method":"Yeast two-hybrid screen, co-immunoprecipitation from COS cells at endogenous level, GSK-3β kinase activity assay after PKA activation, calyculin A (phosphatase inhibitor) treatment","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus functional kinase assay, two orthogonal methods confirming complex and functional consequence","pmids":["12147701"],"is_preprint":false},{"year":2008,"finding":"AKAP220 (AKAP11) binds AQP2 (aquaporin-2) identified by yeast two-hybrid, co-localizes with AQP2 in the cytosol of inner medullary collecting ducts by immunofluorescence and immunoelectron microscopy, and its co-expression in COS cells increases forskolin-stimulated PKA phosphorylation of AQP2 at Ser256.","method":"Yeast two-hybrid, double immunofluorescence, immunoelectron microscopy, co-expression phosphorylation assay in COS cells","journal":"Kidney International","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus localization plus functional phosphorylation assay, single lab","pmids":["19008911"],"is_preprint":false},{"year":2011,"finding":"AKAP220 (AKAP11) interacts with the cytoskeletal scaffolding protein IQGAP1, and this complex positions signaling enzymes (including GSK-3β suppression) at leading edges of migrating cells. AKAP220 suppresses GSK-3β activity locally to allow CLASP2 (a plus-end microtubule tracking protein) recruitment. Gene silencing of AKAP220 alters microtubule polymerization rate, lateral microtubule tracking, and retards cell migration in metastatic human cancer cells.","method":"Co-immunoprecipitation (AKAP220–IQGAP1 interaction), gene silencing (siRNA), live-cell imaging of microtubule dynamics, cell migration assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus siRNA knockdown with defined cellular phenotypes, single lab","pmids":["21890631"],"is_preprint":false},{"year":2014,"finding":"AKAP220 (AKAP11) localizes to endothelial junctions and immunoprecipitation shows it interacts not only with PKA but also with VE-cadherin and β-catenin. Depletion of AKAP220 impairs endothelial barrier function, and displacement of PKA from AKAPs with a competing peptide (TAT-Ahx-AKAPis) disrupts adherens junctions, actin cytoskeleton, and causes Rac1 inactivation.","method":"Co-immunoprecipitation (AKAP220 with VE-cadherin/β-catenin), siRNA depletion, transendothelial electrical resistance measurement, immunofluorescence, in vivo microvessel hydraulic conductivity","journal":"PLOS ONE","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus functional KD phenotype, multiple cell/tissue systems, single lab","pmids":["25188285"],"is_preprint":false},{"year":2016,"finding":"AKAP220 (AKAP11, product of the Akap11 gene) controls apical actin networks in kidney collecting duct principal cells. CRISPR/Cas9 knockout of AKAP220 disrupts apical actin networks in organoid cultures and in vivo, reduces active RhoA GTPase levels, causes AQP2 and RhoA accumulation at the apical surface, and prevents appropriate urine dilution in response to overhydration.","method":"CRISPR/Cas9 gene editing (knockout mice and organoids), fluorescence imaging of kidney sections, biochemical measurement of active RhoA (GTPase pull-down), urine concentration assays in vivo","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with multiple orthogonal readouts (organoid imaging, tissue sections, biochemical RhoA activity, in vivo physiology) in a single rigorous study","pmids":["27402760"],"is_preprint":false},{"year":2021,"finding":"AKAP11 acts as an autophagy receptor that recruits the PKA regulatory subunit RI to autophagosomes via a LC3-interacting region (LIR motif). Glucose starvation induces AKAP11-dependent selective autophagic degradation of RI, leading to PKA catalytic subunit activation, enhanced CREB signaling, mitochondrial respiration, ATP production, and mitochondrial elongation. AKAP11 deficiency blocks PKA activation and impairs cell survival under glucose deprivation.","method":"Co-immunoprecipitation (AKAP11–LC3 interaction), autophagy flux assays, PKA activity measurements, AKAP11 knockdown/knockout, mitochondrial respiration (Seahorse), cell viability assays under glucose starvation","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, autophagy assays, functional PKA activity, metabolic readouts, genetic KO) in a single rigorous study","pmids":["33785595"],"is_preprint":false},{"year":2024,"finding":"The Cα-RIα-AKAP11 holocomplex is identified as a prominent autophagy-associated protein kinase complex by proteomic analysis of immunopurified lysosomes. AKAP11 scaffolds Cα-RIα to the autophagic machinery via its LIR motif. Ser83 on the RIα linker-hinge region is an AKAP11-dependent phosphorylation site that modulates RIα-Cα binding to the autophagosome and cAMP-induced PKA activation. Decoupling AKAP11-PKA from autophagy alters Ser83 phosphorylation and downstream PKA signaling in iPSC-derived neurons.","method":"Lysosome immunopurification with proteomics (LysoIP-MS), LIR motif mutagenesis, phosphoproteomics (Ser83 identification), AKAP11 ablation in iPSC-derived neurons","journal":"The EMBO Journal (published 2025) / bioRxiv preprint 2024","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — proteomic reconstitution of complex on autophagosomes, LIR mutagenesis, phosphorylation site mapping, validated in neurons; multiple orthogonal methods","pmids":["40263600","39211170"],"is_preprint":false},{"year":2025,"finding":"AKAP11 interacts with the PKA-RI adaptor SPHKAP and the ER-resident autophagy-related proteins VAPA/B through interactions identified by multi-omics; these proteins co-adapt to mediate PKA-RI complex degradation in neurons. Loss of AKAP11 distorts compartment-specific PKA and GSK3α/β activities and impairs neurotransmission in mouse models and human induced neurons.","method":"Multi-omics (proteomics, phosphoproteomics), co-immunoprecipitation (AKAP11–SPHKAP, AKAP11–VAPA/B), electrophysiology in mouse models and human induced neurons, AKAP11 knockout","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, multi-omics, electrophysiology, and genetic KO across multiple model systems with multiple orthogonal readouts","pmids":["41315293","39803523","40162211"],"is_preprint":false},{"year":2025,"finding":"Loss of AKAP11 in mouse brain leads to dramatically increased levels of PKA subunits (RI and catalytic) and phosphorylated PKA substrates, especially in synapses, establishing AKAP11 as a key regulator of PKA proteostasis. Real-time PKA activity measurements reveal elevated basal PKA activity in the striatum of Akap11−/− mice with exaggerated responses to dopamine receptor antagonists.","method":"Multi-omic analysis of Akap11 mutant mouse brains, real-time PKA activity measurements (FRET biosensors or equivalent), quantitative proteomics/phosphoproteomics of synaptic fractions, behavioral assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative proteomics plus real-time PKA activity measurements plus genetic KO, multiple orthogonal methods in one study","pmids":["41315276"],"is_preprint":false},{"year":2025,"finding":"Immunoprecipitation mass spectrometry in Akap11-deficient mice identified 222 high-confidence AKAP11 interaction proteins, including synaptic proteins (Exoc4, Ncam1, Picalm, Vapb) and actin-related proteins (Actb, Diaph1). Akap11 deficiency reduces dendritic spine density (particularly thin spines), decreases synapse density and synaptic vesicle density, and reduces PSD length as assessed by electron microscopy.","method":"Immunoprecipitation mass spectrometry (IP-MS), neuronal sparse labeling assays, electron microscopy, behavioral evaluation (prepulse inhibition)","journal":"Schizophrenia Bulletin","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — IP-MS interactome plus ultrastructural electron microscopy, single lab, two orthogonal methods","pmids":["40408419"],"is_preprint":false},{"year":2025,"finding":"In Akap11 mutant astrocytes, loss of AKAP11 leads to upregulation of cholesterol and fatty acid metabolic pathways, accumulation of lipid droplets, and elevated cAMP/PKA signaling. AKAP11 interacts with ER-resident VAPA and VAPB via an FFAT motif, linking its autophagy receptor function to lipid metabolism regulation. Co-culture experiments show that Akap11-deficient astrocytes increase excitatory neurotransmission and neuronal activity.","method":"Multi-omic analysis (transcriptomics, proteomics, metabolomics) of Akap11 mutant mouse astrocytes, lipid droplet staining, FFAT motif identification, co-culture electrophysiology with iPSC-derived neurons","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multi-omics plus functional co-culture assay, preprint not yet peer-reviewed, single lab","pmids":[],"is_preprint":true}],"current_model":"AKAP11 (AKAP220) is a multivalent A-kinase anchoring protein that scaffolds PKA, PP1, and GSK-3β into a signaling complex, inhibits PP1 catalytic activity through distinct binding and inhibitory domains, and serves as an autophagy receptor that recruits the PKA-RIα regulatory subunit to autophagosomes via an LC3-interacting region (LIR motif)—enabling selective autophagic degradation of RIα to activate PKA, modulate mitochondrial metabolism, and maintain PKA proteostasis; in neurons, this AKAP11-autophagy-PKA axis controls compartment-specific PKA and GSK-3α/β activities to regulate synaptic transmission, while in the kidney AKAP11 controls RhoA-dependent apical actin dynamics and AQP2 trafficking to maintain water homeostasis."},"narrative":{"mechanistic_narrative":"AKAP11 (AKAP220) is a multivalent A-kinase anchoring protein that assembles a signaling complex containing PKA, the type 1 protein phosphatase catalytic subunit (PP1c), and GSK-3β, coordinating kinase and phosphatase activities on a single scaffold [PMID:10209101, PMID:12147701]. It binds PP1c with high affinity through a consensus KVQF targeting motif while a distinct C-terminal region competitively inhibits PP1 catalytic activity, and assembly with the PKA RII subunit synergistically enhances this inhibition [PMID:11152471]. Within this quaternary complex, PKA activation selectively suppresses the AKAP11-bound pool of GSK-3β, allowing the scaffold to exert compartmentalized control over substrate phosphorylation [PMID:12147701]. Beyond scaffolding, AKAP11 functions as a selective autophagy receptor: through an LC3-interacting (LIR) region it recruits the PKA regulatory subunit RIα to autophagosomes for degradation, releasing active PKA catalytic subunit to drive CREB signaling, mitochondrial respiration, and cell survival under glucose starvation [PMID:33785595]. The Cα–RIα–AKAP11 holocomplex is delivered to lysosomes via the LIR motif, with an AKAP11-dependent phosphorylation site (RIα Ser83) tuning RIα–Cα binding and cAMP-induced PKA output, and AKAP11 engages SPHKAP and ER-resident VAPA/B to couple this degradative route to PKA-RI proteostasis [PMID:40263600, PMID:39211170, PMID:41315293, PMID:39803523, PMID:40162211]. Loss of AKAP11 elevates PKA subunit levels and substrate phosphorylation, raises basal PKA activity in brain, and disrupts compartment-specific PKA and GSK3α/β activities, impairing synaptic transmission and reducing dendritic spine and synapse density [PMID:41315293, PMID:39803523, PMID:40162211, PMID:41315276, PMID:40408419]. In the kidney, AKAP11 controls RhoA-dependent apical actin networks and AQP2 trafficking to maintain water homeostasis, with its knockout reducing active RhoA, causing apical AQP2 accumulation, and preventing appropriate urine dilution [PMID:19008911, PMID:27402760].","teleology":[{"year":1999,"claim":"Established that AKAP11 is not merely a PKA anchor but a multivalent scaffold capable of simultaneously binding a phosphatase, raising the question of how it integrates opposing enzymatic activities.","evidence":"In vitro KD measurement, microcystin-Sepharose affinity chromatography, and reciprocal co-IP with immunocytochemistry in rat hippocampal neurons","pmids":["10209101"],"confidence":"High","gaps":["Did not define how PP1 binding affects phosphatase activity","Physiological substrates of the scaffolded enzymes not identified"]},{"year":2001,"claim":"Resolved how AKAP11 engages PP1 by separating binding from inhibition, showing it both targets and competitively inhibits PP1 with synergistic enhancement upon PKA subunit recruitment.","evidence":"In vitro PP1 phosphatase assays with truncation/deletion mapping and chimeric PP1/PP2A catalytic subunit analysis","pmids":["11152471"],"confidence":"High","gaps":["Structural basis of the inhibitory region undefined","Cellular consequences of PP1 inhibition not tested"]},{"year":2002,"claim":"Extended the scaffold to a quaternary PKA–PP1–GSK-3β complex and showed that anchoring enables preferential, compartmentalized PKA-dependent inhibition of GSK-3β.","evidence":"Yeast two-hybrid, endogenous co-IP from COS cells, and GSK-3β kinase activity assays after PKA activation","pmids":["12147701"],"confidence":"High","gaps":["GSK-3β substrates regulated within the complex not identified","Spatial organization in intact cells not resolved"]},{"year":2011,"claim":"Connected AKAP11 scaffolding to cytoskeletal dynamics, showing localized GSK-3β suppression at cell leading edges controls microtubule behavior and migration.","evidence":"Co-IP with IQGAP1, siRNA silencing, live-cell microtubule imaging, and migration assays in metastatic cancer cells","pmids":["21890631"],"confidence":"Medium","gaps":["Single-lab functional data","Direct vs indirect AKAP11–CLASP2 link not established"]},{"year":2014,"claim":"Placed AKAP11 at endothelial adherens junctions, where PKA anchoring maintains barrier integrity and Rac1 activity.","evidence":"Co-IP with VE-cadherin/β-catenin, siRNA depletion, transendothelial resistance, and in vivo microvessel conductivity with AKAP-disrupting peptide","pmids":["25188285"],"confidence":"Medium","gaps":["Peptide disruption affects all AKAPs, not AKAP11 selectively","Direct VE-cadherin binding interface undefined"]},{"year":2008,"claim":"Identified AKAP11 as an AQP2-binding scaffold that promotes PKA phosphorylation of AQP2, linking it to collecting duct water handling.","evidence":"Yeast two-hybrid, immunofluorescence and immunoelectron microscopy in inner medullary collecting ducts, and co-expression phosphorylation assay","pmids":["19008911"],"confidence":"Medium","gaps":["In vivo physiological role not yet tested","Single lab, heterologous phosphorylation readout"]},{"year":2016,"claim":"Established the in vivo renal function of AKAP11, showing it controls RhoA-dependent apical actin and AQP2 trafficking required for urine dilution.","evidence":"CRISPR/Cas9 knockout mice and organoids, RhoA GTPase pull-downs, fluorescence imaging, and in vivo urine concentration assays","pmids":["27402760"],"confidence":"High","gaps":["Mechanism linking PKA/PP1 scaffolding to RhoA regulation not detailed","Connection to earlier AQP2-binding data not directly bridged"]},{"year":2021,"claim":"Reframed AKAP11 as a selective autophagy receptor, showing its LIR motif targets PKA-RIα for autophagic degradation to activate PKA and support metabolism under starvation.","evidence":"Co-IP of AKAP11–LC3, autophagy flux and PKA activity assays, KO under glucose deprivation, and Seahorse respirometry","pmids":["33785595"],"confidence":"High","gaps":["Signal triggering AKAP11-mediated RIα capture not defined","Tissue-specific relevance beyond cultured cells not addressed here"]},{"year":2024,"claim":"Defined the autophagy-associated Cα–RIα–AKAP11 holocomplex on lysosomes and identified RIα Ser83 as an AKAP11-dependent regulatory phosphosite tuning PKA activation.","evidence":"LysoIP proteomics, LIR motif mutagenesis, phosphoproteomic mapping of Ser83, and AKAP11 ablation in iPSC-derived neurons","pmids":["40263600","39211170"],"confidence":"High","gaps":["Kinase responsible for Ser83 phosphorylation not identified","Quantitative contribution of Ser83 to overall PKA output unresolved"]},{"year":2025,"claim":"Mapped AKAP11 partners (SPHKAP, VAPA/B) and demonstrated that AKAP11 loss disrupts compartment-specific PKA and GSK3α/β activity, elevates PKA proteostasis, and impairs neurotransmission, linking the autophagy-PKA axis to synaptic and astrocytic dysfunction.","evidence":"Multi-omics, reciprocal co-IP (SPHKAP, VAPA/B), real-time PKA activity measurements, electrophysiology, electron microscopy, and behavioral assays across mouse and human induced-neuron models","pmids":["41315293","39803523","40162211","41315276","40408419"],"confidence":"High","gaps":["Causal chain from PKA dysregulation to specific behavioral phenotypes incomplete","Astrocytic lipid-metabolism arm rests on preprint evidence"]},{"year":null,"claim":"How the distinct AKAP11 functions — PP1 inhibition, GSK-3β suppression, autophagy-receptor RIα degradation, and RhoA/actin control — are coordinated within a single protein across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model integrating the multiple binding/inhibitory domains","Mechanism coupling scaffolding to RhoA regulation in kidney undefined","Whether autophagy-receptor and scaffold functions operate simultaneously or context-dependently is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[9,12]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[9,10,11]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[6]}],"complexes":["PKA–PP1–GSK-3β quaternary scaffold complex","Cα–RIα–AKAP11 autophagy-associated PKA holocomplex"],"partners":["PP1C","GSK-3Β","AQP2","IQGAP1","VE-CADHERIN","SPHKAP","VAPB","MAP1LC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKA4","full_name":"A-kinase anchor protein 11","aliases":["A-kinase anchor protein 220 kDa","AKAP 220","hAKAP220","Protein kinase A-anchoring protein 11","PRKA11"],"length_aa":1901,"mass_kda":210.5,"function":"Binds to type II regulatory subunits of protein kinase A and anchors/targets them","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q9UKA4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AKAP11","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":"GSK3B","stoichiometry":0.2},{"gene":"PRKACA","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"VAPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/AKAP11","total_profiled":1310},"omim":[{"mim_id":"612110","title":"BONE MINERAL DENSITY QUANTITATIVE TRAIT LOCUS 9; BMND9","url":"https://www.omim.org/entry/612110"},{"mim_id":"611646","title":"SPHK1-INTERACTING PROTEIN; SPHKAP","url":"https://www.omim.org/entry/611646"},{"mim_id":"610170","title":"KYPHOSCOLIOSIS 1; KYPSC1","url":"https://www.omim.org/entry/610170"},{"mim_id":"604696","title":"A-KINASE ANCHOR PROTEIN 11; AKAP11","url":"https://www.omim.org/entry/604696"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AKAP11"},"hgnc":{"alias_symbol":["KIAA0629","AKAP220","PRKA11","FLJ11304","DKFZp781I12161","PPP1R44"],"prev_symbol":[]},"alphafold":{"accession":"Q9UKA4","domains":[{"cath_id":"3.40.50","chopping":"12-108_119-166_1810-1901","consensus_level":"medium","plddt":73.9219,"start":12,"end":1901}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKA4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKA4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKA4-F1-predicted_aligned_error_v6.png","plddt_mean":45.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AKAP11","jax_strain_url":"https://www.jax.org/strain/search?query=AKAP11"},"sequence":{"accession":"Q9UKA4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKA4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKA4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKA4"}},"corpus_meta":[{"pmid":"35410376","id":"PMC_35410376","title":"Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia.","date":"2022","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35410376","citation_count":149,"is_preprint":false},{"pmid":"12147701","id":"PMC_12147701","title":"A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta ) and mediates protein kinase A-dependent inhibition of GSK-3beta.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12147701","citation_count":111,"is_preprint":false},{"pmid":"10209101","id":"PMC_10209101","title":"Association of the type 1 protein phosphatase PP1 with the A-kinase anchoring protein AKAP220.","date":"1999","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/10209101","citation_count":102,"is_preprint":false},{"pmid":"36914641","id":"PMC_36914641","title":"Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients.","date":"2023","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36914641","citation_count":50,"is_preprint":false},{"pmid":"11152471","id":"PMC_11152471","title":"Multiple interactions within the AKAP220 signaling complex contribute to protein phosphatase 1 regulation.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11152471","citation_count":50,"is_preprint":false},{"pmid":"27402760","id":"PMC_27402760","title":"AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27402760","citation_count":48,"is_preprint":false},{"pmid":"33785595","id":"PMC_33785595","title":"Selective autophagy of AKAP11 activates cAMP/PKA to fuel mitochondrial metabolism and tumor cell 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\"method\": \"In vitro binding assay (KD measurement), affinity chromatography on microcystin-Sepharose, co-immunoprecipitation from cell extracts, immunocytochemistry in rat hippocampal neurons\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution with KD measurement plus reciprocal co-IP and affinity chromatography, multiple orthogonal methods\",\n      \"pmids\": [\"10209101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"AKAP220 (AKAP11) acts as a competitive inhibitor of PP1c activity (Ki = 2.9 µM); a consensus targeting motif (residues 1195–1198, KVQF) mediates PP1 binding without inhibiting it, while a distinct region (residues 1711–1901) is required for inhibition. Addition of PKA regulatory subunit (RII) to the complex further enhances PP1 inhibition, indicating synergistic intra- and inter-molecular regulation.\",\n      \"method\": \"In vitro PP1 phosphatase activity assay with AKAP220 fragments, deletion/truncation mapping, chimeric PP1/PP2A catalytic subunit analysis\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with mutagenesis/truncation mapping and multiple orthogonal approaches in a single rigorous study\",\n      \"pmids\": [\"11152471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AKAP220 (AKAP11) binds GSK-3β via yeast two-hybrid and forms a quaternary complex with GSK-3β, PKA, and PP1 in intact cells. PKA activation (via dibutyryl-cAMP) reduces GSK-3β activity within the AKAP220-bound pool more markedly than total cellular GSK-3β activity, demonstrating that the scaffold enables efficient PKA-dependent inhibition of GSK-3β.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation from COS cells at endogenous level, GSK-3β kinase activity assay after PKA activation, calyculin A (phosphatase inhibitor) treatment\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus functional kinase assay, two orthogonal methods confirming complex and functional consequence\",\n      \"pmids\": [\"12147701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"AKAP220 (AKAP11) binds AQP2 (aquaporin-2) identified by yeast two-hybrid, co-localizes with AQP2 in the cytosol of inner medullary collecting ducts by immunofluorescence and immunoelectron microscopy, and its co-expression in COS cells increases forskolin-stimulated PKA phosphorylation of AQP2 at Ser256.\",\n      \"method\": \"Yeast two-hybrid, double immunofluorescence, immunoelectron microscopy, co-expression phosphorylation assay in COS cells\",\n      \"journal\": \"Kidney International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus localization plus functional phosphorylation assay, single lab\",\n      \"pmids\": [\"19008911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AKAP220 (AKAP11) interacts with the cytoskeletal scaffolding protein IQGAP1, and this complex positions signaling enzymes (including GSK-3β suppression) at leading edges of migrating cells. AKAP220 suppresses GSK-3β activity locally to allow CLASP2 (a plus-end microtubule tracking protein) recruitment. Gene silencing of AKAP220 alters microtubule polymerization rate, lateral microtubule tracking, and retards cell migration in metastatic human cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (AKAP220–IQGAP1 interaction), gene silencing (siRNA), live-cell imaging of microtubule dynamics, cell migration assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus siRNA knockdown with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"21890631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AKAP220 (AKAP11) localizes to endothelial junctions and immunoprecipitation shows it interacts not only with PKA but also with VE-cadherin and β-catenin. Depletion of AKAP220 impairs endothelial barrier function, and displacement of PKA from AKAPs with a competing peptide (TAT-Ahx-AKAPis) disrupts adherens junctions, actin cytoskeleton, and causes Rac1 inactivation.\",\n      \"method\": \"Co-immunoprecipitation (AKAP220 with VE-cadherin/β-catenin), siRNA depletion, transendothelial electrical resistance measurement, immunofluorescence, in vivo microvessel hydraulic conductivity\",\n      \"journal\": \"PLOS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus functional KD phenotype, multiple cell/tissue systems, single lab\",\n      \"pmids\": [\"25188285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AKAP220 (AKAP11, product of the Akap11 gene) controls apical actin networks in kidney collecting duct principal cells. CRISPR/Cas9 knockout of AKAP220 disrupts apical actin networks in organoid cultures and in vivo, reduces active RhoA GTPase levels, causes AQP2 and RhoA accumulation at the apical surface, and prevents appropriate urine dilution in response to overhydration.\",\n      \"method\": \"CRISPR/Cas9 gene editing (knockout mice and organoids), fluorescence imaging of kidney sections, biochemical measurement of active RhoA (GTPase pull-down), urine concentration assays in vivo\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with multiple orthogonal readouts (organoid imaging, tissue sections, biochemical RhoA activity, in vivo physiology) in a single rigorous study\",\n      \"pmids\": [\"27402760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AKAP11 acts as an autophagy receptor that recruits the PKA regulatory subunit RI to autophagosomes via a LC3-interacting region (LIR motif). Glucose starvation induces AKAP11-dependent selective autophagic degradation of RI, leading to PKA catalytic subunit activation, enhanced CREB signaling, mitochondrial respiration, ATP production, and mitochondrial elongation. AKAP11 deficiency blocks PKA activation and impairs cell survival under glucose deprivation.\",\n      \"method\": \"Co-immunoprecipitation (AKAP11–LC3 interaction), autophagy flux assays, PKA activity measurements, AKAP11 knockdown/knockout, mitochondrial respiration (Seahorse), cell viability assays under glucose starvation\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, autophagy assays, functional PKA activity, metabolic readouts, genetic KO) in a single rigorous study\",\n      \"pmids\": [\"33785595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The Cα-RIα-AKAP11 holocomplex is identified as a prominent autophagy-associated protein kinase complex by proteomic analysis of immunopurified lysosomes. AKAP11 scaffolds Cα-RIα to the autophagic machinery via its LIR motif. Ser83 on the RIα linker-hinge region is an AKAP11-dependent phosphorylation site that modulates RIα-Cα binding to the autophagosome and cAMP-induced PKA activation. Decoupling AKAP11-PKA from autophagy alters Ser83 phosphorylation and downstream PKA signaling in iPSC-derived neurons.\",\n      \"method\": \"Lysosome immunopurification with proteomics (LysoIP-MS), LIR motif mutagenesis, phosphoproteomics (Ser83 identification), AKAP11 ablation in iPSC-derived neurons\",\n      \"journal\": \"The EMBO Journal (published 2025) / bioRxiv preprint 2024\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — proteomic reconstitution of complex on autophagosomes, LIR mutagenesis, phosphorylation site mapping, validated in neurons; multiple orthogonal methods\",\n      \"pmids\": [\"40263600\", \"39211170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AKAP11 interacts with the PKA-RI adaptor SPHKAP and the ER-resident autophagy-related proteins VAPA/B through interactions identified by multi-omics; these proteins co-adapt to mediate PKA-RI complex degradation in neurons. Loss of AKAP11 distorts compartment-specific PKA and GSK3α/β activities and impairs neurotransmission in mouse models and human induced neurons.\",\n      \"method\": \"Multi-omics (proteomics, phosphoproteomics), co-immunoprecipitation (AKAP11–SPHKAP, AKAP11–VAPA/B), electrophysiology in mouse models and human induced neurons, AKAP11 knockout\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, multi-omics, electrophysiology, and genetic KO across multiple model systems with multiple orthogonal readouts\",\n      \"pmids\": [\"41315293\", \"39803523\", \"40162211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of AKAP11 in mouse brain leads to dramatically increased levels of PKA subunits (RI and catalytic) and phosphorylated PKA substrates, especially in synapses, establishing AKAP11 as a key regulator of PKA proteostasis. Real-time PKA activity measurements reveal elevated basal PKA activity in the striatum of Akap11−/− mice with exaggerated responses to dopamine receptor antagonists.\",\n      \"method\": \"Multi-omic analysis of Akap11 mutant mouse brains, real-time PKA activity measurements (FRET biosensors or equivalent), quantitative proteomics/phosphoproteomics of synaptic fractions, behavioral assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative proteomics plus real-time PKA activity measurements plus genetic KO, multiple orthogonal methods in one study\",\n      \"pmids\": [\"41315276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Immunoprecipitation mass spectrometry in Akap11-deficient mice identified 222 high-confidence AKAP11 interaction proteins, including synaptic proteins (Exoc4, Ncam1, Picalm, Vapb) and actin-related proteins (Actb, Diaph1). Akap11 deficiency reduces dendritic spine density (particularly thin spines), decreases synapse density and synaptic vesicle density, and reduces PSD length as assessed by electron microscopy.\",\n      \"method\": \"Immunoprecipitation mass spectrometry (IP-MS), neuronal sparse labeling assays, electron microscopy, behavioral evaluation (prepulse inhibition)\",\n      \"journal\": \"Schizophrenia Bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — IP-MS interactome plus ultrastructural electron microscopy, single lab, two orthogonal methods\",\n      \"pmids\": [\"40408419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Akap11 mutant astrocytes, loss of AKAP11 leads to upregulation of cholesterol and fatty acid metabolic pathways, accumulation of lipid droplets, and elevated cAMP/PKA signaling. AKAP11 interacts with ER-resident VAPA and VAPB via an FFAT motif, linking its autophagy receptor function to lipid metabolism regulation. Co-culture experiments show that Akap11-deficient astrocytes increase excitatory neurotransmission and neuronal activity.\",\n      \"method\": \"Multi-omic analysis (transcriptomics, proteomics, metabolomics) of Akap11 mutant mouse astrocytes, lipid droplet staining, FFAT motif identification, co-culture electrophysiology with iPSC-derived neurons\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multi-omics plus functional co-culture assay, preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"AKAP11 (AKAP220) is a multivalent A-kinase anchoring protein that scaffolds PKA, PP1, and GSK-3β into a signaling complex, inhibits PP1 catalytic activity through distinct binding and inhibitory domains, and serves as an autophagy receptor that recruits the PKA-RIα regulatory subunit to autophagosomes via an LC3-interacting region (LIR motif)—enabling selective autophagic degradation of RIα to activate PKA, modulate mitochondrial metabolism, and maintain PKA proteostasis; in neurons, this AKAP11-autophagy-PKA axis controls compartment-specific PKA and GSK-3α/β activities to regulate synaptic transmission, while in the kidney AKAP11 controls RhoA-dependent apical actin dynamics and AQP2 trafficking to maintain water homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AKAP11 (AKAP220) is a multivalent A-kinase anchoring protein that assembles a signaling complex containing PKA, the type 1 protein phosphatase catalytic subunit (PP1c), and GSK-3\\u03b2, coordinating kinase and phosphatase activities on a single scaffold [#0, #2]. It binds PP1c with high affinity through a consensus KVQF targeting motif while a distinct C-terminal region competitively inhibits PP1 catalytic activity, and assembly with the PKA RII subunit synergistically enhances this inhibition [#1]. Within this quaternary complex, PKA activation selectively suppresses the AKAP11-bound pool of GSK-3\\u03b2, allowing the scaffold to exert compartmentalized control over substrate phosphorylation [#2]. Beyond scaffolding, AKAP11 functions as a selective autophagy receptor: through an LC3-interacting (LIR) region it recruits the PKA regulatory subunit RI\\u03b1 to autophagosomes for degradation, releasing active PKA catalytic subunit to drive CREB signaling, mitochondrial respiration, and cell survival under glucose starvation [#7]. The C\\u03b1\\u2013RI\\u03b1\\u2013AKAP11 holocomplex is delivered to lysosomes via the LIR motif, with an AKAP11-dependent phosphorylation site (RI\\u03b1 Ser83) tuning RI\\u03b1\\u2013C\\u03b1 binding and cAMP-induced PKA output, and AKAP11 engages SPHKAP and ER-resident VAPA/B to couple this degradative route to PKA-RI proteostasis [#8, #9]. Loss of AKAP11 elevates PKA subunit levels and substrate phosphorylation, raises basal PKA activity in brain, and disrupts compartment-specific PKA and GSK3\\u03b1/\\u03b2 activities, impairing synaptic transmission and reducing dendritic spine and synapse density [#9, #10, #11]. In the kidney, AKAP11 controls RhoA-dependent apical actin networks and AQP2 trafficking to maintain water homeostasis, with its knockout reducing active RhoA, causing apical AQP2 accumulation, and preventing appropriate urine dilution [#3, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that AKAP11 is not merely a PKA anchor but a multivalent scaffold capable of simultaneously binding a phosphatase, raising the question of how it integrates opposing enzymatic activities.\",\n      \"evidence\": \"In vitro KD measurement, microcystin-Sepharose affinity chromatography, and reciprocal co-IP with immunocytochemistry in rat hippocampal neurons\",\n      \"pmids\": [\"10209101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how PP1 binding affects phosphatase activity\", \"Physiological substrates of the scaffolded enzymes not identified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved how AKAP11 engages PP1 by separating binding from inhibition, showing it both targets and competitively inhibits PP1 with synergistic enhancement upon PKA subunit recruitment.\",\n      \"evidence\": \"In vitro PP1 phosphatase assays with truncation/deletion mapping and chimeric PP1/PP2A catalytic subunit analysis\",\n      \"pmids\": [\"11152471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the inhibitory region undefined\", \"Cellular consequences of PP1 inhibition not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended the scaffold to a quaternary PKA\\u2013PP1\\u2013GSK-3\\u03b2 complex and showed that anchoring enables preferential, compartmentalized PKA-dependent inhibition of GSK-3\\u03b2.\",\n      \"evidence\": \"Yeast two-hybrid, endogenous co-IP from COS cells, and GSK-3\\u03b2 kinase activity assays after PKA activation\",\n      \"pmids\": [\"12147701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GSK-3\\u03b2 substrates regulated within the complex not identified\", \"Spatial organization in intact cells not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected AKAP11 scaffolding to cytoskeletal dynamics, showing localized GSK-3\\u03b2 suppression at cell leading edges controls microtubule behavior and migration.\",\n      \"evidence\": \"Co-IP with IQGAP1, siRNA silencing, live-cell microtubule imaging, and migration assays in metastatic cancer cells\",\n      \"pmids\": [\"21890631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional data\", \"Direct vs indirect AKAP11\\u2013CLASP2 link not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed AKAP11 at endothelial adherens junctions, where PKA anchoring maintains barrier integrity and Rac1 activity.\",\n      \"evidence\": \"Co-IP with VE-cadherin/\\u03b2-catenin, siRNA depletion, transendothelial resistance, and in vivo microvessel conductivity with AKAP-disrupting peptide\",\n      \"pmids\": [\"25188285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peptide disruption affects all AKAPs, not AKAP11 selectively\", \"Direct VE-cadherin binding interface undefined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified AKAP11 as an AQP2-binding scaffold that promotes PKA phosphorylation of AQP2, linking it to collecting duct water handling.\",\n      \"evidence\": \"Yeast two-hybrid, immunofluorescence and immunoelectron microscopy in inner medullary collecting ducts, and co-expression phosphorylation assay\",\n      \"pmids\": [\"19008911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo physiological role not yet tested\", \"Single lab, heterologous phosphorylation readout\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the in vivo renal function of AKAP11, showing it controls RhoA-dependent apical actin and AQP2 trafficking required for urine dilution.\",\n      \"evidence\": \"CRISPR/Cas9 knockout mice and organoids, RhoA GTPase pull-downs, fluorescence imaging, and in vivo urine concentration assays\",\n      \"pmids\": [\"27402760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking PKA/PP1 scaffolding to RhoA regulation not detailed\", \"Connection to earlier AQP2-binding data not directly bridged\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reframed AKAP11 as a selective autophagy receptor, showing its LIR motif targets PKA-RI\\u03b1 for autophagic degradation to activate PKA and support metabolism under starvation.\",\n      \"evidence\": \"Co-IP of AKAP11\\u2013LC3, autophagy flux and PKA activity assays, KO under glucose deprivation, and Seahorse respirometry\",\n      \"pmids\": [\"33785595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering AKAP11-mediated RI\\u03b1 capture not defined\", \"Tissue-specific relevance beyond cultured cells not addressed here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the autophagy-associated C\\u03b1\\u2013RI\\u03b1\\u2013AKAP11 holocomplex on lysosomes and identified RI\\u03b1 Ser83 as an AKAP11-dependent regulatory phosphosite tuning PKA activation.\",\n      \"evidence\": \"LysoIP proteomics, LIR motif mutagenesis, phosphoproteomic mapping of Ser83, and AKAP11 ablation in iPSC-derived neurons\",\n      \"pmids\": [\"40263600\", \"39211170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for Ser83 phosphorylation not identified\", \"Quantitative contribution of Ser83 to overall PKA output unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped AKAP11 partners (SPHKAP, VAPA/B) and demonstrated that AKAP11 loss disrupts compartment-specific PKA and GSK3\\u03b1/\\u03b2 activity, elevates PKA proteostasis, and impairs neurotransmission, linking the autophagy-PKA axis to synaptic and astrocytic dysfunction.\",\n      \"evidence\": \"Multi-omics, reciprocal co-IP (SPHKAP, VAPA/B), real-time PKA activity measurements, electrophysiology, electron microscopy, and behavioral assays across mouse and human induced-neuron models\",\n      \"pmids\": [\"41315293\", \"39803523\", \"40162211\", \"41315276\", \"40408419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal chain from PKA dysregulation to specific behavioral phenotypes incomplete\", \"Astrocytic lipid-metabolism arm rests on preprint evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct AKAP11 functions \\u2014 PP1 inhibition, GSK-3\\u03b2 suppression, autophagy-receptor RI\\u03b1 degradation, and RhoA/actin control \\u2014 are coordinated within a single protein across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model integrating the multiple binding/inhibitory domains\", \"Mechanism coupling scaffolding to RhoA regulation in kidney undefined\", \"Whether autophagy-receptor and scaffold functions operate simultaneously or context-dependently is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [9, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [9, 10, 11]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"PKA\\u2013PP1\\u2013GSK-3\\u03b2 quaternary scaffold complex\",\n      \"C\\u03b1\\u2013RI\\u03b1\\u2013AKAP11 autophagy-associated PKA holocomplex\"\n    ],\n    \"partners\": [\n      \"PP1c\",\n      \"GSK-3\\u03b2\",\n      \"AQP2\",\n      \"IQGAP1\",\n      \"VE-cadherin\",\n      \"SPHKAP\",\n      \"VAPB\",\n      \"MAP1LC3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}