{"gene":"PDE6D","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":1998,"finding":"PDE6D (delta subunit) can detach the photoreceptor cGMP phosphodiesterase PDE6 (alpha-beta-gamma2) partially from bovine rod outer segment membranes under physiological conditions, acting as a membrane-dissociation factor for the PDE6 complex.","method":"Biochemical fractionation of bovine rod outer segments; cDNA cloning and sequence analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical fractionation experiment in native tissue, single lab","pmids":["9570951"],"is_preprint":false},{"year":2012,"finding":"PDE6D is required for ciliary targeting of farnesylated INPP5E; ARL13B (but not ARL2 or ARL3) facilitates this process, and ARL13B, INPP5E, PDE6D, and CEP164 form a distinct functional network involved in Joubert syndrome and nephronophthisis.","method":"Co-immunoprecipitation, cell-based ciliary targeting assays, genetic epistasis in ciliopathy patient cells and model systems","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, functional rescue, multiple orthogonal methods, replicated across labs","pmids":["23150559"],"is_preprint":false},{"year":2014,"finding":"A splice-site mutation in PDE6D reduces its binding to INPP5E (a prenylated cargo) and prevents INPP5E localization to primary cilia in patient fibroblasts; mutant PDE6D also fails to bind GTP-bound ARL3, which normally acts as a cargo-release factor for PDE6D-bound INPP5E.","method":"Exome sequencing, proteomic cargo identification, Co-IP binding assays with mutant PDE6D, immunofluorescence in patient fibroblasts, zebrafish pde6d knockdown rescue","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (proteomics, Co-IP, cell imaging, in vivo rescue), moderate-strong evidence","pmids":["24166846"],"is_preprint":false},{"year":2014,"finding":"PDE6D (PrBP/δ) is required for trafficking of isoprenylated proteins PDE6 and GRK1 from photoreceptor inner segments to outer segments; knockout of Unc119 in Pde6d-null mice partially reverses the GRK1 transport defect in cones, indicating interdependence of isoprenylated and acylated protein transport pathways.","method":"Pde6d knockout mouse, Pde6d/Unc119 double knockout mouse, ERG recordings, immunofluorescence localization","journal":"Advances in experimental medicine and biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (double KO), in vivo functional readout (ERG), localization assays","pmids":["24664735"],"is_preprint":false},{"year":2015,"finding":"PDE6D binds preferentially to the C-terminal prenyl moiety (rather than the N-terminal RCC1-like domain) of RPGR, and the amino acid adjacent to the prenylation motif determines specificity of the PDE6D–RPGR interaction in mammalian cells.","method":"Co-immunoprecipitation in mammalian cells, domain mapping with prenylation mutants","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP/domain mapping study, single lab","pmids":["26553938"],"is_preprint":false},{"year":2016,"finding":"Prenylated RPGR (constitutive isoform) requires both prenylation and PDE6D for its ciliary localization; ablation of PDE6D blocks ciliary targeting of RPGR, identifying RPGR as a cargo of PDE6D for ciliary trafficking.","method":"PDE6D knockdown, prenylation mutant analysis, immunofluorescence localization in mammalian cells","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific localization phenotype, but single lab","pmids":["27493202"],"is_preprint":false},{"year":2013,"finding":"PDE6D was identified as the direct molecular binding partner of anecortave acetate (a glaucoma/angiostatic drug) via yeast three-hybrid screen, confirmed by competitive Y3H, co-immunoprecipitation, and SPR; overexpression of PDE6D in mouse eyes caused elevated intraocular pressure reversed by anecortave acetate.","method":"Yeast three-hybrid screen, competitive Y3H, co-immunoprecipitation, surface plasmon resonance, in vivo mouse IOP measurement","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal binding methods (Y3H, Co-IP, SPR) plus in vivo functional validation","pmids":["23301619"],"is_preprint":false},{"year":2022,"finding":"Stabilizing the RAS:PDE6D complex by rationally designed RAS point mutations that increase RAS affinity for PDE6D redirects RAS to the cytoplasm and primary cilium and inhibits oncogenic RAS/ERK signaling; fragment screening identified molecules binding at the KRAS:PDE6D interface confirmed by co-crystal structures.","method":"RAS point mutant affinity engineering, SPR fragment screening, co-crystal structure determination, cell-based RAS localization and ERK signaling assays","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structures, in vitro SPR, and cell-based functional validation in single study","pmids":["35104933"],"is_preprint":false},{"year":2022,"finding":"Inhibition of PDE6D (by compound DW0254) blocks RAS localization to the plasma membrane and inhibits RAC activation through a PI3K/AKT-dependent mechanism, linking PDE6D-mediated RAS transport to RAC signaling in leukemia cells.","method":"Chemical proteomics, biophysical binding assays, RAS/RAC localization assays, PI3K/AKT pathway inhibitor epistasis","journal":"Blood cancer journal","confidence":"Medium","confidence_rationale":"Tier 2 — chemical proteomics target ID plus mechanistic epistasis, single lab","pmids":["35422065"],"is_preprint":false},{"year":2019,"finding":"PDE6D depletion in HCC cells reduces proliferation, clonogenicity, migration, and ERK activation; overexpression confers sorafenib resistance, placing PDE6D upstream of ERK signaling via its role in RAS trafficking to the plasma membrane.","method":"siRNA knockdown, overexpression, cell proliferation/migration assays, ERK phosphorylation western blot","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD/OE with defined cellular phenotypes and pathway readout, single lab","pmids":["30901922"],"is_preprint":false},{"year":2023,"finding":"Affinity proteomics of PDE6D identified novel prenylated cargo proteins including NIM1K and UBL3; both localize inside the cilium in a prenylation-dependent manner, and UBL3 associates with proteins regulating small extracellular vesicles and ciliogenesis, suggesting a role in sorting proteins toward the photoreceptor outer segment.","method":"Affinity proteomics (pulldown of PDE6D-interacting proteins), immunofluorescence localization with prenylation mutants, UBL3 affinity proteomics","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 — affinity proteomics plus localization with prenylation mutants, single lab","pmids":["36672247"],"is_preprint":false},{"year":2024,"finding":"PKG2-mediated phosphorylation of Ser181 on K-Ras lowers its binding affinity for PDE6D, providing a post-translational mechanism that modulates the K-Ras/PDE6D interaction; combining a PDE6D inhibitor (Deltaflexin3) with the PKG2 activator Sildenafil more potently inhibits PDE6D/K-Ras binding and cancer cell proliferation.","method":"In cellulo binding assays with Ser181 phosphorylation-mimetic mutants, pharmacological combination assays, proliferation assays","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — phosphomutant binding assays and functional combination data, single lab","pmids":["38758695"],"is_preprint":false}],"current_model":"PDE6D is a prenyl-binding chaperone that shields the farnesyl/geranylgeranyl moiety of diverse prenylated cargo proteins (including KRAS, INPP5E, RPGR, GRK1, NIM1K, UBL3, and photoreceptor PDE6) to maintain them in a soluble, cytosolic pool; ARL3-GTP acts as a cargo-release factor that dissociates cargo from PDE6D at the target membrane (e.g., primary cilia or plasma membrane), while ARL13B facilitates ciliary delivery of specific cargo such as INPP5E; loss of PDE6D function causes mislocalization of prenylated cargos, impaired RAS/ERK signaling, and ciliopathy phenotypes including Joubert syndrome."},"narrative":{"teleology":[{"year":1998,"claim":"The initial question of what PDE6D does biochemically was answered: it acts as a membrane-dissociation factor that can extract the prenylated PDE6 holoenzyme from rod outer segment membranes, establishing its identity as a solubilizing chaperone for lipidated proteins.","evidence":"Biochemical fractionation of bovine rod outer segments with recombinant PDE6D","pmids":["9570951"],"confidence":"Medium","gaps":["Single biochemical system (bovine rods); generality to other prenylated cargos not yet tested","No structural basis for prenyl recognition"]},{"year":2012,"claim":"The question of whether PDE6D functions beyond photoreceptors was resolved by showing it is required for ciliary targeting of farnesylated INPP5E, with ARL13B acting as a facilitator, linking PDE6D to a broader ciliopathy network involving Joubert syndrome and nephronophthisis.","evidence":"Co-immunoprecipitation, ciliary targeting assays, and genetic epistasis in ciliopathy patient cells","pmids":["23150559"],"confidence":"High","gaps":["Mechanism by which ARL13B promotes PDE6D-dependent ciliary delivery not molecularly defined","Full extent of PDE6D ciliary cargo repertoire unknown"]},{"year":2013,"claim":"A pharmacological angle was opened when PDE6D was identified as the direct molecular target of anecortave acetate, and its overexpression in mouse eyes elevated intraocular pressure, revealing a potential non-canonical role in ocular physiology.","evidence":"Yeast three-hybrid screen, competitive Y3H, Co-IP, SPR, and in vivo mouse IOP measurement","pmids":["23301619"],"confidence":"High","gaps":["Which prenylated cargo mediates the IOP phenotype is unknown","Mechanism linking PDE6D to aqueous humor dynamics not established"]},{"year":2014,"claim":"Causative disease mutations were defined: a PDE6D splice-site mutation reduces binding to both INPP5E and ARL3-GTP, establishing ARL3-GTP as the cargo-release factor for PDE6D and providing a molecular mechanism for Joubert syndrome pathogenesis.","evidence":"Exome sequencing, Co-IP with mutant PDE6D, immunofluorescence in patient fibroblasts, zebrafish pde6d knockdown rescue","pmids":["24166846"],"confidence":"High","gaps":["Whether residual PDE6D activity modifies disease severity not tested","No structural model of how the splice mutation disrupts ARL3 binding"]},{"year":2014,"claim":"Genetic epistasis in mice demonstrated that PDE6D is essential for trafficking both PDE6 and GRK1 to photoreceptor outer segments, and revealed interdependence with the acylated-protein chaperone UNC119, showing that prenylated and myristoylated trafficking pathways are coupled.","evidence":"Pde6d knockout and Pde6d/Unc119 double knockout mice, ERG recordings, immunofluorescence","pmids":["24664735"],"confidence":"High","gaps":["Molecular basis of UNC119–PDE6D crosstalk not defined","Whether the double-KO rescue extends to rods not shown"]},{"year":2015,"claim":"The determinants of cargo specificity were clarified: PDE6D binds the C-terminal prenyl moiety of RPGR, with the amino acid adjacent to the prenylation CAAX motif dictating selectivity, expanding the cargo list to include a key retinal ciliopathy protein.","evidence":"Co-IP in mammalian cells with prenylation-site mutants and domain mapping","pmids":["26553938","27493202"],"confidence":"Medium","gaps":["No structural data for RPGR–PDE6D complex","Single-lab finding without independent replication of the specificity determinant"]},{"year":2019,"claim":"Functional consequences of PDE6D for oncogenic signaling were established: PDE6D depletion blocks KRAS plasma-membrane localization, reduces ERK activation, and suppresses proliferation in hepatocellular carcinoma cells, positioning PDE6D as an enabler of RAS pathway output.","evidence":"siRNA knockdown, overexpression, cell proliferation/migration assays, ERK phosphorylation western blot in HCC cells","pmids":["30901922"],"confidence":"Medium","gaps":["Single cancer type; breadth across RAS-driven cancers not tested","No in vivo tumor model"]},{"year":2022,"claim":"Structural and chemical biology approaches validated PDE6D as a druggable node: co-crystal structures of fragments at the KRAS–PDE6D interface were obtained, and stabilizing the RAS–PDE6D complex by affinity-enhancing RAS mutations redirected RAS to the cytoplasm and cilium, proving that modulating complex lifetime controls RAS signaling output.","evidence":"RAS affinity-engineered mutants, SPR fragment screening, co-crystal structures, cell-based RAS localization and ERK assays","pmids":["35104933"],"confidence":"High","gaps":["No drug-like inhibitor with in vivo efficacy reported from these fragments","Effect on non-KRAS prenylated cargos not assessed"]},{"year":2022,"claim":"The signaling reach of PDE6D-mediated RAS transport was extended to RAC activation through PI3K/AKT: chemical inhibition of PDE6D with DW0254 blocked both RAS membrane localization and downstream RAC activation in leukemia cells.","evidence":"Chemical proteomics, biophysical binding assays, RAS/RAC localization, PI3K/AKT inhibitor epistasis in leukemia cells","pmids":["35422065"],"confidence":"Medium","gaps":["DW0254 selectivity for PDE6D over UNC119 not fully characterized","In vivo antileukemic activity not demonstrated"]},{"year":2023,"claim":"The prenylated cargo repertoire of PDE6D was substantially broadened by affinity proteomics, identifying NIM1K and UBL3 as novel ciliary cargos, with UBL3 linking PDE6D to extracellular vesicle biogenesis and ciliogenesis.","evidence":"Affinity proteomics pulldown of PDE6D interactors, immunofluorescence with prenylation mutants, UBL3 interactome analysis","pmids":["36672247"],"confidence":"Medium","gaps":["Functional consequence of NIM1K or UBL3 mislocalization not tested","Single-lab proteomics without independent validation of novel cargos"]},{"year":2024,"claim":"Post-translational regulation of the KRAS–PDE6D interaction was uncovered: PKG2-mediated phosphorylation of K-Ras Ser181 weakens PDE6D binding, and combining a PDE6D inhibitor with PKG2 activation synergistically blocks KRAS–PDE6D association and cancer cell proliferation.","evidence":"Phosphomimetic mutant binding assays, pharmacological combination of Deltaflexin3 and Sildenafil, proliferation assays","pmids":["38758695"],"confidence":"Medium","gaps":["Ser181 phosphorylation not confirmed with endogenous PKG2 signaling","Synergy not tested in vivo or in primary patient samples"]},{"year":null,"claim":"Key unresolved questions include: how PDE6D achieves cargo selectivity among the many prenylated proteins in the cell; the precise membrane-proximal mechanism by which ARL3-GTP releases cargo at target compartments; and whether therapeutic modulation of PDE6D can selectively disrupt oncogenic RAS signaling without impairing ciliary and photoreceptor functions.","evidence":"","pmids":[],"confidence":"High","gaps":["No complete structural model of the ARL3-GTP/PDE6D/cargo ternary release complex","In vivo therapeutic window for PDE6D inhibition not established","Selectivity mechanism for individual prenylated cargos not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,2,4,7]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,2,5,7,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,7,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,9,11]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,2,3,5,10]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,8]}],"complexes":[],"partners":["KRAS","INPP5E","ARL3","ARL13B","RPGR","GRK1","UBL3","NIM1K"],"other_free_text":[]},"mechanistic_narrative":"PDE6D is a prenyl-binding chaperone that solubilizes farnesylated and geranylgeranylated cargo proteins by shielding their lipid moiety, enabling their cytosolic transport and correct subcellular delivery to primary cilia or the plasma membrane. Its cargo repertoire includes photoreceptor PDE6 and GRK1, the ciliary proteins INPP5E and RPGR, the oncogene KRAS, and additional prenylated proteins such as NIM1K and UBL3 [PMID:9570951, PMID:24664735, PMID:23150559, PMID:27493202, PMID:35104933, PMID:36672247]. Cargo release at target membranes is triggered by ARL3-GTP, while ARL13B facilitates ciliary delivery of specific cargos such as INPP5E; loss-of-function mutations in PDE6D cause mislocalization of INPP5E from cilia and underlie Joubert syndrome [PMID:24166846, PMID:23150559]. PDE6D-dependent transport of KRAS to the plasma membrane sustains RAS/ERK signaling, and pharmacological or genetic disruption of the KRAS–PDE6D interaction redirects RAS to the cytoplasm, attenuating oncogenic ERK and PI3K/AKT-RAC signaling in cancer cells [PMID:35104933, PMID:35422065, PMID:30901922]."},"prefetch_data":{"uniprot":{"accession":"O43924","full_name":"Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta","aliases":["Protein p17"],"length_aa":150,"mass_kda":17.4,"function":"Promotes the release of prenylated target proteins from cellular membranes (PubMed:9712853). Modulates the activity of prenylated or palmitoylated Ras family members by regulating their subcellular location (PubMed:22002721, PubMed:23698361). Required for normal ciliary targeting of farnesylated target proteins, such as INPP5E (PubMed:24166846). Required for RAB28 localization to the cone cell outer segments in the retina (By similarity). Modulates the subcellular location of target proteins by acting as a GTP specific dissociation inhibitor (GDI) (By similarity). Increases the affinity of ARL3 for GTP by several orders of magnitude. Stabilizes ARL3-GTP by decreasing the nucleotide dissociation rate (By similarity)","subcellular_location":"Cytoplasm, cytosol; Cytoplasmic vesicle membrane; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/O43924/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDE6D","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ARL3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PDE6D","total_profiled":1310},"omim":[{"mim_id":"620513","title":"UNC119 LIPID-BINDING CHAPERONE B; UNC119B","url":"https://www.omim.org/entry/620513"},{"mim_id":"615665","title":"JOUBERT SYNDROME 22; JBTS22","url":"https://www.omim.org/entry/615665"},{"mim_id":"614848","title":"CENTROSOMAL PROTEIN, 164-KD; CEP164","url":"https://www.omim.org/entry/614848"},{"mim_id":"613037","title":"INOSITOL POLYPHOSPHATE-5-PHOSPHATASE, 72-KD; INPP5E","url":"https://www.omim.org/entry/613037"},{"mim_id":"608922","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 13B; ARL13B","url":"https://www.omim.org/entry/608922"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PDE6D"},"hgnc":{"alias_symbol":["JBTS22"],"prev_symbol":[]},"alphafold":{"accession":"O43924","domains":[{"cath_id":"2.70.50.40","chopping":"2-148","consensus_level":"high","plddt":96.4923,"start":2,"end":148}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43924","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43924-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43924-F1-predicted_aligned_error_v6.png","plddt_mean":96.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDE6D","jax_strain_url":"https://www.jax.org/strain/search?query=PDE6D"},"sequence":{"accession":"O43924","fasta_url":"https://rest.uniprot.org/uniprotkb/O43924.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43924/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43924"}},"corpus_meta":[{"pmid":"23150559","id":"PMC_23150559","title":"ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23150559","citation_count":196,"is_preprint":false},{"pmid":"24166846","id":"PMC_24166846","title":"A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium.","date":"2014","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/24166846","citation_count":108,"is_preprint":false},{"pmid":"31956834","id":"PMC_31956834","title":"PDE6D Inhibitors with a New Design Principle Selectively Block K-Ras Activity.","date":"2019","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/31956834","citation_count":35,"is_preprint":false},{"pmid":"9570951","id":"PMC_9570951","title":"Characterization of human and mouse rod cGMP phosphodiesterase delta subunit (PDE6D) and chromosomal localization of the human gene.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9570951","citation_count":29,"is_preprint":false},{"pmid":"27493202","id":"PMC_27493202","title":"RPGR, a prenylated retinal ciliopathy protein, is targeted to cilia in a prenylation- and PDE6D-dependent manner.","date":"2016","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/27493202","citation_count":18,"is_preprint":false},{"pmid":"26553938","id":"PMC_26553938","title":"PDE6D binds to the C-terminus of RPGR in a prenylation-dependent manner.","date":"2015","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/26553938","citation_count":18,"is_preprint":false},{"pmid":"35104933","id":"PMC_35104933","title":"Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling.","date":"2022","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35104933","citation_count":17,"is_preprint":false},{"pmid":"38758695","id":"PMC_38758695","title":"An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth.","date":"2024","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38758695","citation_count":15,"is_preprint":false},{"pmid":"30901922","id":"PMC_30901922","title":"The Delta Subunit of Rod-Specific Photoreceptor cGMP Phosphodiesterase (PDE6D) Contributes to Hepatocellular Carcinoma Progression.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/30901922","citation_count":11,"is_preprint":false},{"pmid":"23301619","id":"PMC_23301619","title":"Identification of PDE6D as a molecular target of anecortave acetate via a methotrexate-anchored yeast three-hybrid screen.","date":"2013","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/23301619","citation_count":11,"is_preprint":false},{"pmid":"35422065","id":"PMC_35422065","title":"Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects.","date":"2022","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/35422065","citation_count":10,"is_preprint":false},{"pmid":"40216151","id":"PMC_40216151","title":"Metformin inhibits the progression of castration-resistant prostate cancer by regulating PDE6D induced purine metabolic alternation and cGMP / PKG pathway activation.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/40216151","citation_count":7,"is_preprint":false},{"pmid":"36672247","id":"PMC_36672247","title":"PDE6D Mediates Trafficking of Prenylated Proteins NIM1K and UBL3 to Primary Cilia.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36672247","citation_count":7,"is_preprint":false},{"pmid":"30423442","id":"PMC_30423442","title":"A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22).","date":"2018","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30423442","citation_count":6,"is_preprint":false},{"pmid":"12927076","id":"PMC_12927076","title":"Analysis of PDE6D and PDE6G genes for generalised progressive retinal atrophy (gPRA) mutations in dogs.","date":"2003","source":"Genetics, selection, evolution : GSE","url":"https://pubmed.ncbi.nlm.nih.gov/12927076","citation_count":5,"is_preprint":false},{"pmid":"10452952","id":"PMC_10452952","title":"Molecular characterization and mapping of canine cGMP-phosphodiesterase delta subunit (PDE6D).","date":"1999","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10452952","citation_count":5,"is_preprint":false},{"pmid":"24664735","id":"PMC_24664735","title":"Unc119 gene deletion partially rescues the GRK1 transport defect of Pde6d (- /-) cones.","date":"2014","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/24664735","citation_count":4,"is_preprint":false},{"pmid":"41611882","id":"PMC_41611882","title":"Computational identification and mechanistic characterization of natural product binders targeting the PDE6D prenyl binding tunnel.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41611882","citation_count":1,"is_preprint":false},{"pmid":"42034571","id":"PMC_42034571","title":"The role of PDE6D in trafficking KRAS.","date":"2026","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42034571","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.29.679187","title":"Development of a genetically encoded and potent PDE6D inhibitor","date":"2025-09-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.29.679187","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9697,"output_tokens":2774,"usd":0.03535},"stage2":{"model":"claude-opus-4-6","input_tokens":6129,"output_tokens":3049,"usd":0.160305},"total_usd":0.195655,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"PDE6D (delta subunit) can detach the photoreceptor cGMP phosphodiesterase PDE6 (alpha-beta-gamma2) partially from bovine rod outer segment membranes under physiological conditions, acting as a membrane-dissociation factor for the PDE6 complex.\",\n      \"method\": \"Biochemical fractionation of bovine rod outer segments; cDNA cloning and sequence analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical fractionation experiment in native tissue, single lab\",\n      \"pmids\": [\"9570951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PDE6D is required for ciliary targeting of farnesylated INPP5E; ARL13B (but not ARL2 or ARL3) facilitates this process, and ARL13B, INPP5E, PDE6D, and CEP164 form a distinct functional network involved in Joubert syndrome and nephronophthisis.\",\n      \"method\": \"Co-immunoprecipitation, cell-based ciliary targeting assays, genetic epistasis in ciliopathy patient cells and model systems\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, functional rescue, multiple orthogonal methods, replicated across labs\",\n      \"pmids\": [\"23150559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A splice-site mutation in PDE6D reduces its binding to INPP5E (a prenylated cargo) and prevents INPP5E localization to primary cilia in patient fibroblasts; mutant PDE6D also fails to bind GTP-bound ARL3, which normally acts as a cargo-release factor for PDE6D-bound INPP5E.\",\n      \"method\": \"Exome sequencing, proteomic cargo identification, Co-IP binding assays with mutant PDE6D, immunofluorescence in patient fibroblasts, zebrafish pde6d knockdown rescue\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (proteomics, Co-IP, cell imaging, in vivo rescue), moderate-strong evidence\",\n      \"pmids\": [\"24166846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDE6D (PrBP/δ) is required for trafficking of isoprenylated proteins PDE6 and GRK1 from photoreceptor inner segments to outer segments; knockout of Unc119 in Pde6d-null mice partially reverses the GRK1 transport defect in cones, indicating interdependence of isoprenylated and acylated protein transport pathways.\",\n      \"method\": \"Pde6d knockout mouse, Pde6d/Unc119 double knockout mouse, ERG recordings, immunofluorescence localization\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (double KO), in vivo functional readout (ERG), localization assays\",\n      \"pmids\": [\"24664735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PDE6D binds preferentially to the C-terminal prenyl moiety (rather than the N-terminal RCC1-like domain) of RPGR, and the amino acid adjacent to the prenylation motif determines specificity of the PDE6D–RPGR interaction in mammalian cells.\",\n      \"method\": \"Co-immunoprecipitation in mammalian cells, domain mapping with prenylation mutants\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/domain mapping study, single lab\",\n      \"pmids\": [\"26553938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Prenylated RPGR (constitutive isoform) requires both prenylation and PDE6D for its ciliary localization; ablation of PDE6D blocks ciliary targeting of RPGR, identifying RPGR as a cargo of PDE6D for ciliary trafficking.\",\n      \"method\": \"PDE6D knockdown, prenylation mutant analysis, immunofluorescence localization in mammalian cells\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific localization phenotype, but single lab\",\n      \"pmids\": [\"27493202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PDE6D was identified as the direct molecular binding partner of anecortave acetate (a glaucoma/angiostatic drug) via yeast three-hybrid screen, confirmed by competitive Y3H, co-immunoprecipitation, and SPR; overexpression of PDE6D in mouse eyes caused elevated intraocular pressure reversed by anecortave acetate.\",\n      \"method\": \"Yeast three-hybrid screen, competitive Y3H, co-immunoprecipitation, surface plasmon resonance, in vivo mouse IOP measurement\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal binding methods (Y3H, Co-IP, SPR) plus in vivo functional validation\",\n      \"pmids\": [\"23301619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Stabilizing the RAS:PDE6D complex by rationally designed RAS point mutations that increase RAS affinity for PDE6D redirects RAS to the cytoplasm and primary cilium and inhibits oncogenic RAS/ERK signaling; fragment screening identified molecules binding at the KRAS:PDE6D interface confirmed by co-crystal structures.\",\n      \"method\": \"RAS point mutant affinity engineering, SPR fragment screening, co-crystal structure determination, cell-based RAS localization and ERK signaling assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures, in vitro SPR, and cell-based functional validation in single study\",\n      \"pmids\": [\"35104933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Inhibition of PDE6D (by compound DW0254) blocks RAS localization to the plasma membrane and inhibits RAC activation through a PI3K/AKT-dependent mechanism, linking PDE6D-mediated RAS transport to RAC signaling in leukemia cells.\",\n      \"method\": \"Chemical proteomics, biophysical binding assays, RAS/RAC localization assays, PI3K/AKT pathway inhibitor epistasis\",\n      \"journal\": \"Blood cancer journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chemical proteomics target ID plus mechanistic epistasis, single lab\",\n      \"pmids\": [\"35422065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDE6D depletion in HCC cells reduces proliferation, clonogenicity, migration, and ERK activation; overexpression confers sorafenib resistance, placing PDE6D upstream of ERK signaling via its role in RAS trafficking to the plasma membrane.\",\n      \"method\": \"siRNA knockdown, overexpression, cell proliferation/migration assays, ERK phosphorylation western blot\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD/OE with defined cellular phenotypes and pathway readout, single lab\",\n      \"pmids\": [\"30901922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Affinity proteomics of PDE6D identified novel prenylated cargo proteins including NIM1K and UBL3; both localize inside the cilium in a prenylation-dependent manner, and UBL3 associates with proteins regulating small extracellular vesicles and ciliogenesis, suggesting a role in sorting proteins toward the photoreceptor outer segment.\",\n      \"method\": \"Affinity proteomics (pulldown of PDE6D-interacting proteins), immunofluorescence localization with prenylation mutants, UBL3 affinity proteomics\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — affinity proteomics plus localization with prenylation mutants, single lab\",\n      \"pmids\": [\"36672247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PKG2-mediated phosphorylation of Ser181 on K-Ras lowers its binding affinity for PDE6D, providing a post-translational mechanism that modulates the K-Ras/PDE6D interaction; combining a PDE6D inhibitor (Deltaflexin3) with the PKG2 activator Sildenafil more potently inhibits PDE6D/K-Ras binding and cancer cell proliferation.\",\n      \"method\": \"In cellulo binding assays with Ser181 phosphorylation-mimetic mutants, pharmacological combination assays, proliferation assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — phosphomutant binding assays and functional combination data, single lab\",\n      \"pmids\": [\"38758695\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDE6D is a prenyl-binding chaperone that shields the farnesyl/geranylgeranyl moiety of diverse prenylated cargo proteins (including KRAS, INPP5E, RPGR, GRK1, NIM1K, UBL3, and photoreceptor PDE6) to maintain them in a soluble, cytosolic pool; ARL3-GTP acts as a cargo-release factor that dissociates cargo from PDE6D at the target membrane (e.g., primary cilia or plasma membrane), while ARL13B facilitates ciliary delivery of specific cargo such as INPP5E; loss of PDE6D function causes mislocalization of prenylated cargos, impaired RAS/ERK signaling, and ciliopathy phenotypes including Joubert syndrome.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PDE6D is a prenyl-binding chaperone that solubilizes farnesylated and geranylgeranylated cargo proteins by shielding their lipid moiety, enabling their cytosolic transport and correct subcellular delivery to primary cilia or the plasma membrane. Its cargo repertoire includes photoreceptor PDE6 and GRK1, the ciliary proteins INPP5E and RPGR, the oncogene KRAS, and additional prenylated proteins such as NIM1K and UBL3 [PMID:9570951, PMID:24664735, PMID:23150559, PMID:27493202, PMID:35104933, PMID:36672247]. Cargo release at target membranes is triggered by ARL3-GTP, while ARL13B facilitates ciliary delivery of specific cargos such as INPP5E; loss-of-function mutations in PDE6D cause mislocalization of INPP5E from cilia and underlie Joubert syndrome [PMID:24166846, PMID:23150559]. PDE6D-dependent transport of KRAS to the plasma membrane sustains RAS/ERK signaling, and pharmacological or genetic disruption of the KRAS–PDE6D interaction redirects RAS to the cytoplasm, attenuating oncogenic ERK and PI3K/AKT-RAC signaling in cancer cells [PMID:35104933, PMID:35422065, PMID:30901922].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"The initial question of what PDE6D does biochemically was answered: it acts as a membrane-dissociation factor that can extract the prenylated PDE6 holoenzyme from rod outer segment membranes, establishing its identity as a solubilizing chaperone for lipidated proteins.\",\n      \"evidence\": \"Biochemical fractionation of bovine rod outer segments with recombinant PDE6D\",\n      \"pmids\": [\"9570951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single biochemical system (bovine rods); generality to other prenylated cargos not yet tested\", \"No structural basis for prenyl recognition\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The question of whether PDE6D functions beyond photoreceptors was resolved by showing it is required for ciliary targeting of farnesylated INPP5E, with ARL13B acting as a facilitator, linking PDE6D to a broader ciliopathy network involving Joubert syndrome and nephronophthisis.\",\n      \"evidence\": \"Co-immunoprecipitation, ciliary targeting assays, and genetic epistasis in ciliopathy patient cells\",\n      \"pmids\": [\"23150559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ARL13B promotes PDE6D-dependent ciliary delivery not molecularly defined\", \"Full extent of PDE6D ciliary cargo repertoire unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A pharmacological angle was opened when PDE6D was identified as the direct molecular target of anecortave acetate, and its overexpression in mouse eyes elevated intraocular pressure, revealing a potential non-canonical role in ocular physiology.\",\n      \"evidence\": \"Yeast three-hybrid screen, competitive Y3H, Co-IP, SPR, and in vivo mouse IOP measurement\",\n      \"pmids\": [\"23301619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which prenylated cargo mediates the IOP phenotype is unknown\", \"Mechanism linking PDE6D to aqueous humor dynamics not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Causative disease mutations were defined: a PDE6D splice-site mutation reduces binding to both INPP5E and ARL3-GTP, establishing ARL3-GTP as the cargo-release factor for PDE6D and providing a molecular mechanism for Joubert syndrome pathogenesis.\",\n      \"evidence\": \"Exome sequencing, Co-IP with mutant PDE6D, immunofluorescence in patient fibroblasts, zebrafish pde6d knockdown rescue\",\n      \"pmids\": [\"24166846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether residual PDE6D activity modifies disease severity not tested\", \"No structural model of how the splice mutation disrupts ARL3 binding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic epistasis in mice demonstrated that PDE6D is essential for trafficking both PDE6 and GRK1 to photoreceptor outer segments, and revealed interdependence with the acylated-protein chaperone UNC119, showing that prenylated and myristoylated trafficking pathways are coupled.\",\n      \"evidence\": \"Pde6d knockout and Pde6d/Unc119 double knockout mice, ERG recordings, immunofluorescence\",\n      \"pmids\": [\"24664735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of UNC119–PDE6D crosstalk not defined\", \"Whether the double-KO rescue extends to rods not shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The determinants of cargo specificity were clarified: PDE6D binds the C-terminal prenyl moiety of RPGR, with the amino acid adjacent to the prenylation CAAX motif dictating selectivity, expanding the cargo list to include a key retinal ciliopathy protein.\",\n      \"evidence\": \"Co-IP in mammalian cells with prenylation-site mutants and domain mapping\",\n      \"pmids\": [\"26553938\", \"27493202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural data for RPGR–PDE6D complex\", \"Single-lab finding without independent replication of the specificity determinant\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Functional consequences of PDE6D for oncogenic signaling were established: PDE6D depletion blocks KRAS plasma-membrane localization, reduces ERK activation, and suppresses proliferation in hepatocellular carcinoma cells, positioning PDE6D as an enabler of RAS pathway output.\",\n      \"evidence\": \"siRNA knockdown, overexpression, cell proliferation/migration assays, ERK phosphorylation western blot in HCC cells\",\n      \"pmids\": [\"30901922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cancer type; breadth across RAS-driven cancers not tested\", \"No in vivo tumor model\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural and chemical biology approaches validated PDE6D as a druggable node: co-crystal structures of fragments at the KRAS–PDE6D interface were obtained, and stabilizing the RAS–PDE6D complex by affinity-enhancing RAS mutations redirected RAS to the cytoplasm and cilium, proving that modulating complex lifetime controls RAS signaling output.\",\n      \"evidence\": \"RAS affinity-engineered mutants, SPR fragment screening, co-crystal structures, cell-based RAS localization and ERK assays\",\n      \"pmids\": [\"35104933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No drug-like inhibitor with in vivo efficacy reported from these fragments\", \"Effect on non-KRAS prenylated cargos not assessed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The signaling reach of PDE6D-mediated RAS transport was extended to RAC activation through PI3K/AKT: chemical inhibition of PDE6D with DW0254 blocked both RAS membrane localization and downstream RAC activation in leukemia cells.\",\n      \"evidence\": \"Chemical proteomics, biophysical binding assays, RAS/RAC localization, PI3K/AKT inhibitor epistasis in leukemia cells\",\n      \"pmids\": [\"35422065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DW0254 selectivity for PDE6D over UNC119 not fully characterized\", \"In vivo antileukemic activity not demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The prenylated cargo repertoire of PDE6D was substantially broadened by affinity proteomics, identifying NIM1K and UBL3 as novel ciliary cargos, with UBL3 linking PDE6D to extracellular vesicle biogenesis and ciliogenesis.\",\n      \"evidence\": \"Affinity proteomics pulldown of PDE6D interactors, immunofluorescence with prenylation mutants, UBL3 interactome analysis\",\n      \"pmids\": [\"36672247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of NIM1K or UBL3 mislocalization not tested\", \"Single-lab proteomics without independent validation of novel cargos\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Post-translational regulation of the KRAS–PDE6D interaction was uncovered: PKG2-mediated phosphorylation of K-Ras Ser181 weakens PDE6D binding, and combining a PDE6D inhibitor with PKG2 activation synergistically blocks KRAS–PDE6D association and cancer cell proliferation.\",\n      \"evidence\": \"Phosphomimetic mutant binding assays, pharmacological combination of Deltaflexin3 and Sildenafil, proliferation assays\",\n      \"pmids\": [\"38758695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ser181 phosphorylation not confirmed with endogenous PKG2 signaling\", \"Synergy not tested in vivo or in primary patient samples\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how PDE6D achieves cargo selectivity among the many prenylated proteins in the cell; the precise membrane-proximal mechanism by which ARL3-GTP releases cargo at target compartments; and whether therapeutic modulation of PDE6D can selectively disrupt oncogenic RAS signaling without impairing ciliary and photoreceptor functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No complete structural model of the ARL3-GTP/PDE6D/cargo ternary release complex\", \"In vivo therapeutic window for PDE6D inhibition not established\", \"Selectivity mechanism for individual prenylated cargos not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 2, 4, 7]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 2, 5, 7, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 9, 11]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 2, 3, 5, 10]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KRAS\",\n      \"INPP5E\",\n      \"ARL3\",\n      \"ARL13B\",\n      \"RPGR\",\n      \"GRK1\",\n      \"UBL3\",\n      \"NIM1K\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}