{"gene":"AKAP8L","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2000,"finding":"HAP95 (AKAP8L) was identified as a novel nuclear protein that specifically binds to the carboxyl terminus (nuclear transport domain) of RNA helicase A (RHA). Overexpression of HAP95 significantly increases CTE-dependent gene expression and HAP95 shuttles between the nucleus and cytoplasm.","method":"Yeast two-hybrid, co-immunoprecipitation, nuclear export assay, reporter gene assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding mapped with domain deletions, functional CTE reporter assay, nuclear shuttling confirmed; replicated in follow-up study (PMID:11402034)","pmids":["10748171"],"is_preprint":false},{"year":2001,"finding":"HAP95 (AKAP8L) domains required for RNA helicase A (RHA) binding and nuclear localization are both necessary for CTE transactivation; a novel nuclear export signal was identified in HAP95; HAP95 synergizes with RHA to promote nuclear export of unspliced mRNA.","method":"Truncation/deletion mutagenesis, reporter gene assay, nuclear export assay, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — systematic domain mapping with mutagenesis plus functional validation, follows up foundational paper with orthogonal methods","pmids":["11402034"],"is_preprint":false},{"year":2000,"finding":"NAKAP95 (AKAP8L) was mapped to chromosome 19p13.11-p13.12, found to reside tandemly ~250 bp from AKAP95, shares 40% similarity with AKAP95 including potential nuclear localization signal and two C2H2 zinc finger motifs, but lacks the canonical PKA RII binding motif.","method":"PCR-based chromosomal mapping, radiation hybrid panel, sequence alignment, RT-PCR","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct chromosomal mapping and sequence/structural characterization; single lab","pmids":["10697960"],"is_preprint":false},{"year":2008,"finding":"HAP95 (AKAP8L) was identified as an interacting partner of RNF43 by yeast two-hybrid and confirmed by co-immunoprecipitation; HAP95 is ubiquitylated and subjected to proteasome-dependent degradation, but is unlikely to be a direct substrate of RNF43 ubiquitin ligase activity.","method":"Yeast two-hybrid, co-immunoprecipitation, proteasome inhibitor treatment","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal co-IP confirmed interaction; ubiquitylation shown but substrate relationship not fully resolved","pmids":["18313049"],"is_preprint":false},{"year":2014,"finding":"HAP95 (AKAP8L) associates with the reverse transcriptase region of HIV-1 Pol protein; siRNA knockdown of HAP95 reduces tRNALys3 annealing to viral RNA; purified GST-HAP95 inhibits RHA activity in vitro; HAP95 and RHA have cooperative effects on tRNA annealing, suggesting HAP95 transiently blocks RHA to protect annealed tRNALys3 during packaging.","method":"Co-immunoprecipitation, siRNA knockdown, in vitro biochemical assay with purified GST-tagged HAP95","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro reconstitution with purified protein plus cellular knockdown; single lab, moderate mechanistic follow-up","pmids":["25034436"],"is_preprint":false},{"year":2018,"finding":"AKAP8L interacts with core subunits of H3K4 histone methyltransferase (HMT) complexes (including DPY30), analogous to its paralog AKAP8, suggesting a role as a potential regulator of these chromatin-modifying complexes.","method":"Co-immunoprecipitation","journal":"The FEBS journal","confidence":"Low","confidence_rationale":"Tier 3 — single co-IP for AKAP8L specifically; primary focus of paper is AKAP8, AKAP8L interaction is secondary finding","pmids":["29288530"],"is_preprint":false},{"year":2018,"finding":"SARNAclust computational analysis of eCLIP data identified novel RNA sequence/structure binding motifs for AKAP8L, indicating it functions as an RNA-binding protein with specific sequence/structure preferences.","method":"eCLIP data analysis, computational motif discovery (SARNAclust)","journal":"PLoS computational biology","confidence":"Low","confidence_rationale":"Tier 4 — computational analysis of existing CLIP data; no direct biochemical validation of AKAP8L binding","pmids":["29596423"],"is_preprint":false},{"year":2020,"finding":"AKAP8L binds to mTORC1 via its N-terminal region in the cytoplasm; loss of AKAP8L decreases mTORC1-mediated translation, cell growth, and proliferation; AKAP8L anchors PKA through regulatory subunit Iα; reintroduction of full-length but not N-terminal-deleted AKAP8L restores mTORC1-regulated processes.","method":"Co-immunoprecipitation, domain deletion mutagenesis, rescue experiments, cell growth/proliferation assays, translation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, domain mapping with mutagenesis, functional rescue experiments with specific deletion mutant, multiple orthogonal functional readouts","pmids":["32312749"],"is_preprint":false},{"year":2020,"finding":"Knockdown of AKAP8L suppressed the commitment of hematopoietic stem cells to erythroid lineage, inhibited cell proliferation, and delayed differentiation from CFU-E to proerythroblast stage.","method":"siRNA/shRNA knockdown, flow cytometry-based differentiation assay, colony-forming assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific cellular differentiation phenotype quantified; single lab","pmids":["32457162"],"is_preprint":false},{"year":2022,"finding":"AKAP8L interacts with SCD1 mRNA and IGF2BP1 protein, regulating SCD1 mRNA stability in an IGF2BP1-dependent manner, thereby promoting gastric cancer cell stemness and chemoresistance.","method":"Co-immunoprecipitation, RNA immunoprecipitation, overexpression/knockdown with in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus RNA-IP demonstrated interactions; IGF2BP1-dependency shown by combinatorial manipulation; single lab","pmids":["36522343"],"is_preprint":false},{"year":2024,"finding":"In high-glucose-treated microglia, elevated AKAP8L interacts with mTORC1 (confirmed by co-immunoprecipitation and proximity ligation assay); AKAP8L knockdown suppressed mTORC1 signaling, normalized autophagic flux, reduced neuroinflammation, and improved cognitive function in STZ-diabetic mice.","method":"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown, Morris water maze, proteomics","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 — two orthogonal methods (co-IP and PLA) confirm AKAP8L-mTORC1 interaction; in vivo knockdown with functional readouts; single lab, consistent with prior mTORC1 interaction paper","pmids":["39033121"],"is_preprint":false},{"year":2023,"finding":"AKAP8L interacts with PTEN in human induced neurons (iPSC-derived excitatory neurons), and this interaction influences neuronal growth.","method":"Protein-protein interaction network (AP-MS), functional follow-up in neurons","journal":"Cell genomics","confidence":"Low","confidence_rationale":"Tier 3 — interaction identified in interactome network; mechanistic follow-up for AKAP8L-PTEN is limited","pmids":["36950384"],"is_preprint":false}],"current_model":"AKAP8L (HAP95/NAKAP95) is a nuclear/cytoplasmic shuttling protein that binds RNA helicase A (RHA) via its C-terminal nuclear transport domain to promote CTE-mediated nuclear export of unspliced retroviral mRNA, anchors PKA regulatory subunit Iα, interacts with mTORC1 through its N-terminal region to promote cell growth and translation, functions as an RNA-binding protein that stabilizes target mRNAs (e.g., SCD1) in an IGF2BP1-dependent manner, and plays roles in erythroid differentiation, neuronal growth (via PTEN interaction), and microglial autophagy regulation."},"narrative":{"teleology":[{"year":2000,"claim":"The identification of AKAP8L (HAP95/NAKAP95) as a nuclear shuttling protein that binds RNA helicase A and promotes CTE-dependent gene expression established it as a participant in unspliced mRNA nuclear export, a function previously attributed only to RHA and its known cofactors.","evidence":"Yeast two-hybrid, co-immunoprecipitation, CTE reporter assay, and nuclear export assay in mammalian cells","pmids":["10748171","10697960"],"confidence":"High","gaps":["Endogenous mRNA targets of AKAP8L-dependent export were not identified","No structural basis for the HAP95–RHA interaction","Whether AKAP8L functions independently of RHA was untested"]},{"year":2001,"claim":"Systematic domain mapping revealed that both the RHA-binding domain and a novel nuclear export signal are required for CTE transactivation, establishing the minimal functional architecture of AKAP8L in mRNA export.","evidence":"Truncation/deletion mutagenesis with CTE reporter assays and co-immunoprecipitation","pmids":["11402034"],"confidence":"High","gaps":["Whether the NES is recognized by CRM1 or another export receptor was not determined","Physiological mRNA cargo beyond CTE-containing reporters remained unknown"]},{"year":2014,"claim":"Demonstrating that AKAP8L associates with HIV-1 Pol and modulates tRNALys3 annealing by transiently inhibiting RHA expanded the functional picture from mRNA export to viral RNA packaging.","evidence":"Co-immunoprecipitation, siRNA knockdown, and in vitro reconstitution with purified GST-HAP95","pmids":["25034436"],"confidence":"Medium","gaps":["In vivo relevance for HIV replication was not established with infectious virus","Whether this reflects a broader RNA chaperoning function of AKAP8L is unclear"]},{"year":2020,"claim":"Discovery that AKAP8L binds mTORC1 through its N-terminal domain to promote translation, cell growth, and proliferation — and anchors PKA RIα — revealed a cytoplasmic signaling scaffold function distinct from its nuclear RNA export role.","evidence":"Co-immunoprecipitation, domain deletion mutagenesis with rescue, translation and proliferation assays in mammalian cells","pmids":["32312749"],"confidence":"High","gaps":["How AKAP8L partitioning between nucleus and cytoplasm is regulated remains unknown","Whether PKA anchoring and mTORC1 binding are coordinated or independent functions was not resolved","Direct PKA phosphorylation of mTORC1 components via AKAP8L scaffolding was not tested"]},{"year":2020,"claim":"Loss-of-function studies showing that AKAP8L knockdown blocks erythroid commitment of hematopoietic stem cells linked its growth-promoting functions to a specific developmental context.","evidence":"shRNA/siRNA knockdown with flow cytometry-based differentiation and colony-forming assays in primary human hematopoietic cells","pmids":["32457162"],"confidence":"Medium","gaps":["The molecular pathway through which AKAP8L promotes erythroid commitment was not delineated","Whether mTORC1 or PKA signaling mediates this differentiation phenotype is unknown"]},{"year":2022,"claim":"Identification of AKAP8L as an RNA-binding protein that stabilizes SCD1 mRNA through IGF2BP1 established a post-transcriptional gene regulation function with implications for cancer cell stemness.","evidence":"RNA immunoprecipitation, co-immunoprecipitation, combinatorial knockdown/overexpression in gastric cancer cells with in vivo xenograft validation","pmids":["36522343"],"confidence":"Medium","gaps":["The full repertoire of AKAP8L-bound mRNAs beyond SCD1 is uncharacterized","Whether AKAP8L directly contacts RNA or acts solely through IGF2BP1 was not resolved","Relationship between mRNA stabilization and mTORC1 scaffolding functions is unexplored"]},{"year":2024,"claim":"Confirmation of the AKAP8L–mTORC1 interaction in microglia by proximity ligation assay, together with in vivo knockdown rescuing autophagic flux and cognitive deficits in diabetic mice, validated the mTORC1 scaffolding role in a disease-relevant physiological setting.","evidence":"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown in microglia, Morris water maze in STZ-diabetic mice","pmids":["39033121"],"confidence":"Medium","gaps":["Whether AKAP8L regulation of mTORC1 in microglia involves PKA anchoring was not addressed","Mechanism by which high glucose upregulates AKAP8L is unknown"]},{"year":null,"claim":"How AKAP8L coordinates its nuclear (RNA export, chromatin interaction) and cytoplasmic (mTORC1 scaffolding, PKA anchoring, mRNA stabilization) functions, and what signals regulate its nucleocytoplasmic distribution, remain central open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of AKAP8L or its complexes exists","The complete RNA-binding specificity and transcriptome-wide target set are undefined","Whether chromatin-modifying complex interactions (DPY30/H3K4 HMT) have functional consequences is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10]}],"complexes":["mTORC1-AKAP8L signaling complex"],"partners":["DHX9","MTOR","PRKAR1A","IGF2BP1","DPY30","RNF43","PTEN"],"other_free_text":[]},"mechanistic_narrative":"AKAP8L is a nuclear–cytoplasmic shuttling protein that integrates RNA export, mRNA stability, mTORC1 signaling, and PKA anchoring to regulate cell growth, proliferation, and differentiation. It binds RNA helicase A (RHA) through its C-terminal nuclear transport domain and synergizes with RHA to promote constitutive transport element (CTE)-dependent nuclear export of unspliced retroviral mRNA, with a nuclear export signal required for this activity [PMID:10748171, PMID:11402034]. AKAP8L interacts with mTORC1 via its N-terminal region in the cytoplasm to promote mTORC1-dependent translation and cell growth, while anchoring PKA regulatory subunit Iα; loss of AKAP8L impairs proliferation and mTORC1-regulated processes, an interaction independently validated in microglia where it modulates autophagic flux and neuroinflammation [PMID:32312749, PMID:39033121]. AKAP8L also functions as an RNA-binding protein that stabilizes SCD1 mRNA in an IGF2BP1-dependent manner and is required for commitment of hematopoietic stem cells to the erythroid lineage [PMID:36522343, PMID:32457162]."},"prefetch_data":{"uniprot":{"accession":"Q9ULX6","full_name":"A-kinase anchor protein 8-like","aliases":["Helicase A-binding protein 95","HAP95","Homologous to AKAP95 protein","HA95","Neighbor of A-kinase-anchoring protein 95","Neighbor of AKAP95"],"length_aa":646,"mass_kda":71.6,"function":"Could play a role in constitutive transport element (CTE)-mediated gene expression by association with DHX9. Increases CTE-dependent nuclear unspliced mRNA export (PubMed:10748171, PubMed:11402034). Proposed to target PRKACA to the nucleus but does not seem to be implicated in the binding of regulatory subunit II of PKA (PubMed:10761695, PubMed:11884601). May be involved in nuclear envelope breakdown and chromatin condensation. May be involved in anchoring nuclear membranes to chromatin in interphase and in releasing membranes from chromating at mitosis (PubMed:11034899). May regulate the initiation phase of DNA replication when associated with TMPO isoform Beta (PubMed:12538639). Required for cell cycle G2/M transition and histone deacetylation during mitosis. In mitotic cells recruits HDAC3 to the vicinity of chromatin leading to deacetylation and subsequent phosphorylation at 'Ser-10' of histone H3; in this function seems to act redundantly with AKAP8 (PubMed:16980585). May be involved in regulation of pre-mRNA splicing (PubMed:17594903) (Microbial infection) In case of EBV infection, may target PRKACA to EBNA-LP-containing nuclear sites to modulate transcription from specific promoters (Microbial infection) Can synergize with DHX9 to activate the CTE-mediated gene expression of type D retroviruses (Microbial infection) In case of HIV-1 infection, involved in the DHX9-promoted annealing of host tRNA(Lys3) to viral genomic RNA as a primer in reverse transcription; in vitro negatively regulates DHX9 annealing activity","subcellular_location":"Nucleus; Nucleus matrix; Nucleus speckle; Nucleus, PML body; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9ULX6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AKAP8L","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000011243","cell_line_id":"CID001543","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nuclear_punctae","grade":2}],"interactors":[{"gene":"HSPD1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DNAJB6","stoichiometry":0.2},{"gene":"DNAJC7","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001543","total_profiled":1310},"omim":[{"mim_id":"612941","title":"PRE-mRNA-PROCESSING FACTOR 40 HOMOLOG A; PRPF40A","url":"https://www.omim.org/entry/612941"},{"mim_id":"612482","title":"RING FINGER PROTEIN 43; RNF43","url":"https://www.omim.org/entry/612482"},{"mim_id":"609475","title":"A-KINASE ANCHOR PROTEIN 8-LIKE PROTEIN; AKAP8L","url":"https://www.omim.org/entry/609475"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AKAP8L"},"hgnc":{"alias_symbol":["NAKAP95","HAP95"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULX6","domains":[{"cath_id":"-","chopping":"365-559","consensus_level":"medium","plddt":84.6029,"start":365,"end":559}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX6-F1-predicted_aligned_error_v6.png","plddt_mean":54.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AKAP8L","jax_strain_url":"https://www.jax.org/strain/search?query=AKAP8L"},"sequence":{"accession":"Q9ULX6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULX6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULX6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX6"}},"corpus_meta":[{"pmid":"23633038","id":"PMC_23633038","title":"Ginseng saponin metabolite 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Overexpression of HAP95 significantly increases CTE-dependent gene expression and HAP95 shuttles between the nucleus and cytoplasm.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, nuclear export assay, reporter gene assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding mapped with domain deletions, functional CTE reporter assay, nuclear shuttling confirmed; replicated in follow-up study (PMID:11402034)\",\n      \"pmids\": [\"10748171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HAP95 (AKAP8L) domains required for RNA helicase A (RHA) binding and nuclear localization are both necessary for CTE transactivation; a novel nuclear export signal was identified in HAP95; HAP95 synergizes with RHA to promote nuclear export of unspliced mRNA.\",\n      \"method\": \"Truncation/deletion mutagenesis, reporter gene assay, nuclear export assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic domain mapping with mutagenesis plus functional validation, follows up foundational paper with orthogonal methods\",\n      \"pmids\": [\"11402034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"NAKAP95 (AKAP8L) was mapped to chromosome 19p13.11-p13.12, found to reside tandemly ~250 bp from AKAP95, shares 40% similarity with AKAP95 including potential nuclear localization signal and two C2H2 zinc finger motifs, but lacks the canonical PKA RII binding motif.\",\n      \"method\": \"PCR-based chromosomal mapping, radiation hybrid panel, sequence alignment, RT-PCR\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal mapping and sequence/structural characterization; single lab\",\n      \"pmids\": [\"10697960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HAP95 (AKAP8L) was identified as an interacting partner of RNF43 by yeast two-hybrid and confirmed by co-immunoprecipitation; HAP95 is ubiquitylated and subjected to proteasome-dependent degradation, but is unlikely to be a direct substrate of RNF43 ubiquitin ligase activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, proteasome inhibitor treatment\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal co-IP confirmed interaction; ubiquitylation shown but substrate relationship not fully resolved\",\n      \"pmids\": [\"18313049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HAP95 (AKAP8L) associates with the reverse transcriptase region of HIV-1 Pol protein; siRNA knockdown of HAP95 reduces tRNALys3 annealing to viral RNA; purified GST-HAP95 inhibits RHA activity in vitro; HAP95 and RHA have cooperative effects on tRNA annealing, suggesting HAP95 transiently blocks RHA to protect annealed tRNALys3 during packaging.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, in vitro biochemical assay with purified GST-tagged HAP95\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with purified protein plus cellular knockdown; single lab, moderate mechanistic follow-up\",\n      \"pmids\": [\"25034436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AKAP8L interacts with core subunits of H3K4 histone methyltransferase (HMT) complexes (including DPY30), analogous to its paralog AKAP8, suggesting a role as a potential regulator of these chromatin-modifying complexes.\",\n      \"method\": \"Co-immunoprecipitation\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP for AKAP8L specifically; primary focus of paper is AKAP8, AKAP8L interaction is secondary finding\",\n      \"pmids\": [\"29288530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SARNAclust computational analysis of eCLIP data identified novel RNA sequence/structure binding motifs for AKAP8L, indicating it functions as an RNA-binding protein with specific sequence/structure preferences.\",\n      \"method\": \"eCLIP data analysis, computational motif discovery (SARNAclust)\",\n      \"journal\": \"PLoS computational biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational analysis of existing CLIP data; no direct biochemical validation of AKAP8L binding\",\n      \"pmids\": [\"29596423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AKAP8L binds to mTORC1 via its N-terminal region in the cytoplasm; loss of AKAP8L decreases mTORC1-mediated translation, cell growth, and proliferation; AKAP8L anchors PKA through regulatory subunit Iα; reintroduction of full-length but not N-terminal-deleted AKAP8L restores mTORC1-regulated processes.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutagenesis, rescue experiments, cell growth/proliferation assays, translation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, domain mapping with mutagenesis, functional rescue experiments with specific deletion mutant, multiple orthogonal functional readouts\",\n      \"pmids\": [\"32312749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of AKAP8L suppressed the commitment of hematopoietic stem cells to erythroid lineage, inhibited cell proliferation, and delayed differentiation from CFU-E to proerythroblast stage.\",\n      \"method\": \"siRNA/shRNA knockdown, flow cytometry-based differentiation assay, colony-forming assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific cellular differentiation phenotype quantified; single lab\",\n      \"pmids\": [\"32457162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AKAP8L interacts with SCD1 mRNA and IGF2BP1 protein, regulating SCD1 mRNA stability in an IGF2BP1-dependent manner, thereby promoting gastric cancer cell stemness and chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, overexpression/knockdown with in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus RNA-IP demonstrated interactions; IGF2BP1-dependency shown by combinatorial manipulation; single lab\",\n      \"pmids\": [\"36522343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In high-glucose-treated microglia, elevated AKAP8L interacts with mTORC1 (confirmed by co-immunoprecipitation and proximity ligation assay); AKAP8L knockdown suppressed mTORC1 signaling, normalized autophagic flux, reduced neuroinflammation, and improved cognitive function in STZ-diabetic mice.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown, Morris water maze, proteomics\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal methods (co-IP and PLA) confirm AKAP8L-mTORC1 interaction; in vivo knockdown with functional readouts; single lab, consistent with prior mTORC1 interaction paper\",\n      \"pmids\": [\"39033121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AKAP8L interacts with PTEN in human induced neurons (iPSC-derived excitatory neurons), and this interaction influences neuronal growth.\",\n      \"method\": \"Protein-protein interaction network (AP-MS), functional follow-up in neurons\",\n      \"journal\": \"Cell genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — interaction identified in interactome network; mechanistic follow-up for AKAP8L-PTEN is limited\",\n      \"pmids\": [\"36950384\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AKAP8L (HAP95/NAKAP95) is a nuclear/cytoplasmic shuttling protein that binds RNA helicase A (RHA) via its C-terminal nuclear transport domain to promote CTE-mediated nuclear export of unspliced retroviral mRNA, anchors PKA regulatory subunit Iα, interacts with mTORC1 through its N-terminal region to promote cell growth and translation, functions as an RNA-binding protein that stabilizes target mRNAs (e.g., SCD1) in an IGF2BP1-dependent manner, and plays roles in erythroid differentiation, neuronal growth (via PTEN interaction), and microglial autophagy regulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AKAP8L is a nuclear–cytoplasmic shuttling protein that integrates RNA export, mRNA stability, mTORC1 signaling, and PKA anchoring to regulate cell growth, proliferation, and differentiation. It binds RNA helicase A (RHA) through its C-terminal nuclear transport domain and synergizes with RHA to promote constitutive transport element (CTE)-dependent nuclear export of unspliced retroviral mRNA, with a nuclear export signal required for this activity [PMID:10748171, PMID:11402034]. AKAP8L interacts with mTORC1 via its N-terminal region in the cytoplasm to promote mTORC1-dependent translation and cell growth, while anchoring PKA regulatory subunit Iα; loss of AKAP8L impairs proliferation and mTORC1-regulated processes, an interaction independently validated in microglia where it modulates autophagic flux and neuroinflammation [PMID:32312749, PMID:39033121]. AKAP8L also functions as an RNA-binding protein that stabilizes SCD1 mRNA in an IGF2BP1-dependent manner and is required for commitment of hematopoietic stem cells to the erythroid lineage [PMID:36522343, PMID:32457162].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The identification of AKAP8L (HAP95/NAKAP95) as a nuclear shuttling protein that binds RNA helicase A and promotes CTE-dependent gene expression established it as a participant in unspliced mRNA nuclear export, a function previously attributed only to RHA and its known cofactors.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, CTE reporter assay, and nuclear export assay in mammalian cells\",\n      \"pmids\": [\"10748171\", \"10697960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous mRNA targets of AKAP8L-dependent export were not identified\",\n        \"No structural basis for the HAP95–RHA interaction\",\n        \"Whether AKAP8L functions independently of RHA was untested\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Systematic domain mapping revealed that both the RHA-binding domain and a novel nuclear export signal are required for CTE transactivation, establishing the minimal functional architecture of AKAP8L in mRNA export.\",\n      \"evidence\": \"Truncation/deletion mutagenesis with CTE reporter assays and co-immunoprecipitation\",\n      \"pmids\": [\"11402034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the NES is recognized by CRM1 or another export receptor was not determined\",\n        \"Physiological mRNA cargo beyond CTE-containing reporters remained unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that AKAP8L associates with HIV-1 Pol and modulates tRNALys3 annealing by transiently inhibiting RHA expanded the functional picture from mRNA export to viral RNA packaging.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, and in vitro reconstitution with purified GST-HAP95\",\n      \"pmids\": [\"25034436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo relevance for HIV replication was not established with infectious virus\",\n        \"Whether this reflects a broader RNA chaperoning function of AKAP8L is unclear\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that AKAP8L binds mTORC1 through its N-terminal domain to promote translation, cell growth, and proliferation — and anchors PKA RIα — revealed a cytoplasmic signaling scaffold function distinct from its nuclear RNA export role.\",\n      \"evidence\": \"Co-immunoprecipitation, domain deletion mutagenesis with rescue, translation and proliferation assays in mammalian cells\",\n      \"pmids\": [\"32312749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How AKAP8L partitioning between nucleus and cytoplasm is regulated remains unknown\",\n        \"Whether PKA anchoring and mTORC1 binding are coordinated or independent functions was not resolved\",\n        \"Direct PKA phosphorylation of mTORC1 components via AKAP8L scaffolding was not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Loss-of-function studies showing that AKAP8L knockdown blocks erythroid commitment of hematopoietic stem cells linked its growth-promoting functions to a specific developmental context.\",\n      \"evidence\": \"shRNA/siRNA knockdown with flow cytometry-based differentiation and colony-forming assays in primary human hematopoietic cells\",\n      \"pmids\": [\"32457162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular pathway through which AKAP8L promotes erythroid commitment was not delineated\",\n        \"Whether mTORC1 or PKA signaling mediates this differentiation phenotype is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of AKAP8L as an RNA-binding protein that stabilizes SCD1 mRNA through IGF2BP1 established a post-transcriptional gene regulation function with implications for cancer cell stemness.\",\n      \"evidence\": \"RNA immunoprecipitation, co-immunoprecipitation, combinatorial knockdown/overexpression in gastric cancer cells with in vivo xenograft validation\",\n      \"pmids\": [\"36522343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The full repertoire of AKAP8L-bound mRNAs beyond SCD1 is uncharacterized\",\n        \"Whether AKAP8L directly contacts RNA or acts solely through IGF2BP1 was not resolved\",\n        \"Relationship between mRNA stabilization and mTORC1 scaffolding functions is unexplored\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmation of the AKAP8L–mTORC1 interaction in microglia by proximity ligation assay, together with in vivo knockdown rescuing autophagic flux and cognitive deficits in diabetic mice, validated the mTORC1 scaffolding role in a disease-relevant physiological setting.\",\n      \"evidence\": \"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown in microglia, Morris water maze in STZ-diabetic mice\",\n      \"pmids\": [\"39033121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether AKAP8L regulation of mTORC1 in microglia involves PKA anchoring was not addressed\",\n        \"Mechanism by which high glucose upregulates AKAP8L is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AKAP8L coordinates its nuclear (RNA export, chromatin interaction) and cytoplasmic (mTORC1 scaffolding, PKA anchoring, mRNA stabilization) functions, and what signals regulate its nucleocytoplasmic distribution, remain central open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of AKAP8L or its complexes exists\",\n        \"The complete RNA-binding specificity and transcriptome-wide target set are undefined\",\n        \"Whether chromatin-modifying complex interactions (DPY30/H3K4 HMT) have functional consequences is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"mTORC1-AKAP8L signaling complex\"\n    ],\n    \"partners\": [\n      \"DHX9\",\n      \"MTOR\",\n      \"PRKAR1A\",\n      \"IGF2BP1\",\n      \"DPY30\",\n      \"RNF43\",\n      \"PTEN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}