{"gene":"PSD","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1999,"finding":"EFA6A (PSD/EFA6) contains Sec7 and pleckstrin homology (PH) domains and functions as a guanine nucleotide exchange factor (GEF) that promotes efficient GDP/GTP exchange specifically on ARF6 (not ARF1). EFA6A localizes to the cytoplasmic face of plasma membrane invaginations, regulates endosomal membrane recycling and transferrin receptor redistribution to the cell surface, and induces actin-based membrane ruffles dependent on ARF6 and Rac1 activation.","method":"GEF nucleotide exchange assays, subcellular localization by immunofluorescence, dominant-negative ARF6 and Rac1 co-expression, transferrin recycling assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro GEF assay, multiple orthogonal functional readouts (actin ruffles, receptor recycling), dominant-negative epistasis","pmids":["10075920"],"is_preprint":false},{"year":2001,"finding":"In vitro, EFA6A (PSD) Sec7 domain activates ARF6 exclusively and does not activate ARF1, whereas ARNO activates ARF1 preferentially. Selectivity is determined by the Sec7 domain alone and by the ARF core domains, independent of the myristoylated N-terminal helix.","method":"In vitro GEF activity assay on phospholipid membranes with isolated Sec7 domains and ARF core domains; ARF1/ARF6 specificity mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro biochemical assay with domain dissection and mutagenesis-equivalent domain swaps","pmids":["11342560"],"is_preprint":false},{"year":2002,"finding":"EFA6A (PSD/EFA6) and its paralog EFA6B share a conserved C-terminal ~150 aa region with a predicted coiled-coil motif. Overexpression of the PH domain/C-terminal region of EFA6A or EFA6B (without the Sec7 domain) promotes lengthening of dorsal microvilli-like membrane protrusions, an effect requiring integrity of the coiled-coil motif. Association with membrane ruffles depends on the PH domain, which interacts with PI(4,5)P2.","method":"Deletion/domain-swap overexpression in BHK cells, immunofluorescence localization, coiled-coil motif mutagenesis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — domain deletion experiments with clear morphological readout, single lab, multiple constructs","pmids":["12082148"],"is_preprint":false},{"year":2003,"finding":"EFA6 (PSD) regulates actin cytoskeleton dynamics and tight junction (TJ) formation in epithelial MDCK cells in response to E-cadherin engagement. EFA6 is recruited to a Triton X-100-insoluble fraction upon calcium-triggered E-cadherin adhesion, selectively stabilizes the apical actin ring to retain occludin at the cell surface and exclude TJ proteins from endocytosis. These effects require both the catalytic Sec7 exchange activity and the actin-remodeling C-terminal domain.","method":"Calcium switch assay, Triton X-100 fractionation, immunofluorescence, overexpression of catalytic-dead Sec7 mutant, C-terminal domain deletion constructs","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — domain-specific mutants, fractionation, functional TJ readout; single lab","pmids":["14668475"],"is_preprint":false},{"year":2004,"finding":"EFA6 (PSD) interacts with TWIK1 K+ channel only when EFA6 is bound to ARF6 (ARF6-dependent interaction). TWIK1 is expressed in a subapical recycling endosomal compartment in renal proximal tubules and polarized MDCK cells; the ARF6/EFA6/TWIK1 complex is proposed to regulate channel internalization and recycling.","method":"Co-immunoprecipitation, yeast two-hybrid, subcellular localization by immunofluorescence","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and yeast two-hybrid, multiple methods but single lab, ARF6-dependency is a novel mechanistic detail","pmids":["15540117"],"is_preprint":false},{"year":2004,"finding":"EFA6A (PSD) promotes dendritic spine formation in hippocampal neurons in an ARF6 activation-dependent manner. Active ARF6 promotes conversion of filopodia to spines. Knockdown of ARF6 and EFA6A by siRNA decreases spine formation and reduces filopodia-to-spine conversion. ARF6 and EFA6A protect mature spines from inactivity-induced destabilization. The spine-promoting effect of ARF6 is partially blocked by Rac1.","method":"siRNA knockdown, dominant-negative ARF6, live-imaging of spine dynamics, overexpression in hippocampal neurons","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA loss-of-function, dominant-negative epistasis, live imaging with defined cellular phenotype; multiple orthogonal methods","pmids":["16672654"],"is_preprint":false},{"year":2004,"finding":"EFA6A (PSD) mRNA is somatodendritically localized in hippocampal neurons in vivo and in vitro, with peak dendritic expression between P7 and P14 in rats. Overexpression of a GEP-defective (catalytically dead) mutant of EFA6A enhances dendritic formation, implicating EFA6A in regulation of hippocampal dendritic development.","method":"Non-radioactive in situ hybridization, overexpression of catalytic-dead EFA6A mutant, morphometric analysis of dendrites","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in situ hybridization for localization plus dominant-negative overexpression for function; single lab","pmids":["15009133"],"is_preprint":false},{"year":2006,"finding":"EFA6A (PSD) enhances glioma cell invasion through an ARF6/ERK signaling cascade. Overexpression of EFA6A significantly increases cell motility and invasiveness; these effects are abolished by the catalytic-dead EFA6A(E242K) mutant, dominant-negative ARF6(T27N), or the MEK inhibitor U0126, indicating that EFA6A acts upstream of ARF6 to activate ERK-dependent invasion.","method":"Conditional overexpression, wound healing and Matrigel invasion assays, dominant-negative EFA6A and ARF6, pharmacological MEK inhibition, phospho-ERK western blot","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — catalytic-dead mutant + dominant-negative epistasis + kinase inhibitor convergence; single lab","pmids":["16452216"],"is_preprint":false},{"year":2006,"finding":"EFA6D (a family member of EFA6/PSD) shows preferential GEF activity toward ARF6 in ARF pull-down assays and is highly concentrated in the postsynaptic density fraction of mouse brain, with a distinct spatiotemporal expression pattern from EFA6A and EFA6C.","method":"ARF pull-down GEF activity assay, subcellular fractionation, RT-PCR, in situ hybridization","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GEF activity assay plus fractionation, but for paralog EFA6D not EFA6A specifically; included as family-level finding","pmids":["16707115"],"is_preprint":false},{"year":2007,"finding":"EFA6A (PSD) protein localizes to dendritic spines of hippocampal neurons and can interact with alpha-actinin-1. Yeast two-hybrid and immunofluorescence co-localization show partial overlap of EFA6A and alpha-actinin at dendritic spines in vivo and in culture. The central region of alpha-actinin-1 (spectrin repeats) mediates the interaction with EFA6A's C-terminal region.","method":"Yeast two-hybrid screening, immunofluorescence co-localization in hippocampal neurons, subcellular fractionation","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus co-localization; interaction domain identified but direct binding not confirmed by in vitro pulldown","pmids":["17298598"],"is_preprint":false},{"year":2008,"finding":"EFA6A (PSD) and three other EFA6 family members (EFA6A, EFA6C, EFA6D) are abundantly expressed in mouse brain and enriched in the postsynaptic density fraction, establishing that EFA6 family GEFs for ARF6 are concentrated at neuronal synapses.","method":"Subcellular fractionation, immunoblot, RT-PCR, in situ hybridization (review/summary of experimental findings from multiple prior studies)","journal":"The Tohoku journal of experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper summarizing prior fractionation data; no new experiment reported in this abstract","pmids":["18323689"],"is_preprint":false},{"year":2010,"finding":"USP9x-mediated deubiquitination of EFA6 (PSD) is required for tight junction biogenesis. At steady state, EFA6 is constitutively ubiquitinated and degraded by the proteasome. At newly forming epithelial contacts, USP9x deubiquitinates EFA6, leading to a transient increase in EFA6 levels that facilitates TJ formation. Knockdown of either EFA6 or USP9x impairs TJ biogenesis; EFA6 overexpression rescues TJ biogenesis in USP9x-knockdown cells.","method":"Knockdown by siRNA, co-immunoprecipitation, overexpression rescue, immunofluorescence co-localization at primordial junctions","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal knockdown/rescue experiments, co-IP identifying USP9x as EFA6 deubiquitinase, functional TJ readout; multiple orthogonal methods","pmids":["20339350"],"is_preprint":false},{"year":2014,"finding":"EFA6 (PSD) directly interacts with endophilin via the endophilin N-BAR domain (identified by two-hybrid and confirmed with purified proteins). Endophilin stimulates the catalytic GEF activity of EFA6A on ARF6. The Sec7 domain of EFA6A competes with flat (but not highly curved) lipid membranes for N-BAR binding. In cells, EFA6A recruits endophilin to EFA6A-positive plasma membrane ruffles, and endophilin expression rescues EFA6A-mediated inhibition of transferrin internalization, placing EFA6/ARF6 upstream of clathrin-mediated endocytosis.","method":"Yeast two-hybrid, in vitro pulldown with purified proteins, GEF activity assay, lipid competition assay, co-localization, transferrin internalization rescue assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct interaction confirmed with purified proteins, in vitro GEF stimulation assay, functional cellular rescue; multiple orthogonal methods","pmids":["24979773"],"is_preprint":false},{"year":2017,"finding":"EFA6 (PSD) localizes within the axon initial segment (AIS) of mature CNS cortical neurons and acts as an intrinsic regulator of selective axon transport. EFA6 at the AIS restricts Rab11 vesicle (and integrin) transport into axons. Depleting EFA6 from cortical neurons permits endosomal integrin transport and enhances axon regeneration after laser axotomy; overexpressing EFA6 prevents DRG neuron regeneration. EFA6 does not localize at the AIS in DRG axons, correlating with their regenerative capacity.","method":"siRNA/shRNA knockdown, laser axotomy, live imaging of Rab11/integrin transport, overexpression, localization by immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss- and gain-of-function with defined transport and regeneration readouts, AIS localization directly established; multiple orthogonal approaches","pmids":["28935671"],"is_preprint":false},{"year":2019,"finding":"CD13 tethers EFA6 (PSD) to the plasma membrane at the leading edge of migrating cells, forming a complex with IQGAP1 and active ARF6. This complex promotes ARF6 GTPase cycling, β1 integrin recycling to the surface (preventing its trafficking to late endosomes and degradation), and cell migration. Loss of CD13 impairs EFA6 membrane positioning and reduces ARF6 activity.","method":"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown, β1 integrin trafficking assay, migration assays, immunofluorescence","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP identifying complex, knockdown phenotypes with defined trafficking readout; single lab","pmids":["31040262"],"is_preprint":false},{"year":2019,"finding":"EFA6 (PSD/Drosophila Efa6) can directly inhibit microtubule polymerization at the plasma membrane via an N-terminal 18 amino acid motif (MT elimination domain, MTED) that binds tubulin and inhibits microtubule growth in vitro and in cells, independent of ARF GEF activity. Full-length membrane-anchored Efa6 blocks explorative MTs in axon shafts and growth cones; loss of Efa6 increases explorative MTs leading to increased axon branching and growth, while overexpression causes axon atrophy.","method":"In vitro microtubule polymerization assay, MTED peptide binding to tubulin, Drosophila neuron overexpression/loss-of-function, live imaging of MT dynamics, morphometric analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified tubulin, domain-specific mutant (MTED), genetic loss-of-function in neurons with clear phenotype; multiple orthogonal methods","pmids":["31718774"],"is_preprint":false}],"current_model":"PSD (EFA6A) is a plasma membrane-localized ARF6-specific guanine nucleotide exchange factor (GEF) whose Sec7 domain catalyzes GDP/GTP exchange exclusively on ARF6; it coordinates endosomal membrane recycling, actin cytoskeletal reorganization (via ARF6→Rac1), tight junction formation (regulated by USP9x-mediated deubiquitination), and dendritic spine development in neurons; additionally, EFA6/PSD localizes to the axon initial segment where it restricts integrin/Rab11 vesicle transport into axons to limit regeneration, and in Drosophila its N-terminal MT elimination domain (MTED) directly inhibits cortical microtubule polymerization to regulate axon growth and branching."},"narrative":{"mechanistic_narrative":"PSD (EFA6A) is a plasma membrane-associated guanine nucleotide exchange factor that, through its Sec7 domain, catalyzes GDP/GTP exchange exclusively on the small GTPase ARF6 and not ARF1, with selectivity dictated by the Sec7 and ARF core domains independent of the myristoylated N-terminal helix [PMID:10075920, PMID:11342560]. Its PH domain targets it to PI(4,5)P2-rich plasma membrane invaginations and ruffles while a conserved coiled-coil-containing C-terminal region drives actin-based membrane protrusions [PMID:10075920, PMID:12082148]. Through ARF6 activation it governs endosomal membrane recycling and clathrin-mediated endocytosis—activity stimulated by direct binding to the endophilin N-BAR domain, which it recruits to membrane ruffles to control transferrin internalization [PMID:10075920, PMID:24979773]. PSD couples this GEF activity and its actin-remodeling C-terminus to epithelial tight junction biogenesis, stabilizing the apical actin ring and retaining occludin upon E-cadherin engagement, a function gated by USP9x-mediated deubiquitination that transiently stabilizes PSD at nascent junctions [PMID:14668475, PMID:20339350]. In neurons, PSD promotes ARF6-dependent filopodium-to-spine conversion and dendritic spine maturation [PMID:16672654], and at the axon initial segment it restricts Rab11/integrin vesicle entry into axons to limit regeneration [PMID:28935671]. Beyond its GEF function, the EFA6/Drosophila Efa6 N-terminal microtubule elimination domain (MTED) directly binds tubulin and inhibits cortical microtubule polymerization, independent of ARF GEF activity, to regulate axon growth and branching [PMID:31718774]. PSD also acts upstream of ARF6/ERK signaling to drive glioma invasion [PMID:16452216] and is positioned at the leading edge of migrating cells via CD13 within an IQGAP1/ARF6 complex that promotes β1 integrin recycling [PMID:31040262].","teleology":[{"year":1999,"claim":"Established PSD/EFA6A as an ARF6-specific GEF and linked it to membrane recycling and actin remodeling, defining its core molecular activity.","evidence":"In vitro GEF nucleotide exchange assays, immunofluorescence localization, dominant-negative ARF6/Rac1, transferrin recycling assay","pmids":["10075920"],"confidence":"High","gaps":["Did not resolve structural basis of ARF6 selectivity","Upstream membrane recruitment cues undefined"]},{"year":2001,"claim":"Mapped the determinants of ARF6 versus ARF1 selectivity to the Sec7 and ARF core domains, showing the myristoylated helix is dispensable.","evidence":"Reconstituted in vitro GEF assay on phospholipid membranes with isolated Sec7 and ARF core domains, specificity mapping","pmids":["11342560"],"confidence":"High","gaps":["Atomic-resolution contacts not defined","In-cell relevance of selectivity not tested"]},{"year":2002,"claim":"Identified the PH domain (PI(4,5)P2 binding) and a conserved C-terminal coiled-coil as separable membrane-targeting and protrusion-promoting modules distinct from catalysis.","evidence":"Domain deletion/swap overexpression in BHK cells, coiled-coil mutagenesis, immunofluorescence","pmids":["12082148"],"confidence":"Medium","gaps":["Direct lipid-binding affinity not quantified","Coiled-coil partner not identified"]},{"year":2003,"claim":"Connected PSD to epithelial tight junction formation, showing both Sec7 catalysis and the actin-remodeling C-terminus are required to stabilize the apical actin ring and retain occludin.","evidence":"Calcium switch assay, Triton X-100 fractionation, catalytic-dead and C-terminal deletion constructs, immunofluorescence in MDCK cells","pmids":["14668475"],"confidence":"Medium","gaps":["Direct effectors linking actin ring to occludin retention unresolved","Single cell-type evidence"]},{"year":2004,"claim":"Demonstrated ARF6-dependent partner interactions (TWIK1 channel) and a neuronal role in dendritic spine formation, broadening PSD function from epithelia to neurons.","evidence":"Co-IP, yeast two-hybrid, siRNA knockdown, dominant-negative ARF6, live spine imaging, in situ hybridization, catalytic-dead overexpression in hippocampal neurons","pmids":["15540117","16672654","15009133"],"confidence":"High","gaps":["Opposing dendritic effects of catalytic-dead mutant versus spine phenotype not reconciled","TWIK1 interaction lacks reciprocal validation"]},{"year":2006,"claim":"Extended PSD/ARF6 signaling to disease (glioma invasion via ERK) and confirmed family-wide postsynaptic enrichment of EFA6 ARF6-GEFs.","evidence":"Matrigel invasion assays, catalytic-dead and dominant-negative epistasis, MEK inhibitor, ARF pull-down GEF assay, subcellular fractionation","pmids":["16452216","16707115"],"confidence":"Medium","gaps":["In vivo tumor relevance not established","Mechanism coupling ARF6 to ERK undefined"]},{"year":2007,"claim":"Identified alpha-actinin-1 as a C-terminal interactor at dendritic spines, providing a candidate link between PSD and the spine actin cytoskeleton.","evidence":"Yeast two-hybrid, immunofluorescence co-localization, subcellular fractionation in hippocampal neurons","pmids":["17298598"],"confidence":"Medium","gaps":["Direct binding not confirmed by in vitro pulldown","Functional consequence of interaction untested"]},{"year":2010,"claim":"Revealed PSD is regulated post-translationally by USP9x deubiquitination, stabilizing it transiently at nascent junctions to enable tight junction biogenesis.","evidence":"Reciprocal siRNA knockdown, co-IP, overexpression rescue, immunofluorescence at primordial junctions","pmids":["20339350"],"confidence":"High","gaps":["E3 ligase that ubiquitinates PSD unidentified","Ubiquitination site(s) not mapped"]},{"year":2014,"claim":"Defined endophilin as a direct activator of PSD GEF activity, integrating ARF6 activation with clathrin-mediated endocytosis.","evidence":"Yeast two-hybrid, in vitro pulldown with purified proteins, GEF stimulation assay, lipid competition, transferrin internalization rescue","pmids":["24979773"],"confidence":"High","gaps":["Structural basis of Sec7/N-BAR competition unresolved","Physiological setting of endophilin stimulation in vivo not shown"]},{"year":2017,"claim":"Localized PSD to the axon initial segment as an intrinsic gatekeeper of selective axon transport, restricting Rab11/integrin entry to limit axon regeneration.","evidence":"shRNA/siRNA knockdown, laser axotomy, live imaging of Rab11/integrin transport, overexpression, immunofluorescence in cortical and DRG neurons","pmids":["28935671"],"confidence":"High","gaps":["Molecular mechanism by which PSD blocks vesicle entry unresolved","Role of ARF6 GEF activity in this function not dissected"]},{"year":2019,"claim":"Uncovered a GEF-independent activity—the N-terminal MTED directly inhibits microtubule polymerization—and a CD13/IQGAP1-anchored ARF6 complex promoting integrin recycling and migration.","evidence":"In vitro MT polymerization assay, MTED tubulin binding, Drosophila gain/loss-of-function with live MT imaging; co-IP, PLA, knockdown, β1 integrin trafficking and migration assays","pmids":["31718774","31040262"],"confidence":"High","gaps":["Conservation of mammalian MTED function not fully established","Integration of MTED and GEF activities in a single cell context unresolved"]},{"year":null,"claim":"How PSD's distinct activities—ARF6 GEF catalysis, MTED-mediated microtubule inhibition, and actin remodeling—are coordinated and selectively deployed across epithelial, migratory, and neuronal contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating Sec7, PH, MTED, and C-terminal modules","Spatial/temporal switching between GEF and microtubule functions undefined","In vivo mammalian knockout phenotype not characterized in corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,8,12]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,9,15]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,14,15]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,15]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,12,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[13]}],"complexes":[],"partners":["ARF6","ENDOPHILIN","USP9X","ALPHA-ACTININ-1","TWIK1","CD13","IQGAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A5PKW4","full_name":"PH and SEC7 domain-containing protein 1","aliases":["Exchange factor for ADP-ribosylation factor guanine nucleotide factor 6","Exchange factor for ARF6","Exchange factor for ARF6 A","Pleckstrin homology and SEC7 domain-containing protein 1"],"length_aa":1024,"mass_kda":109.5,"function":"Guanine nucleotide exchange factor for ARF6 (PubMed:23603394). Induces cytoskeletal remodeling (By similarity)","subcellular_location":"Cell membrane; Cell projection, ruffle membrane; Cleavage furrow","url":"https://www.uniprot.org/uniprotkb/A5PKW4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSD","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":[],"url":"https://opencell.sf.czbiohub.org/search/PSD","total_profiled":1310},"omim":[{"mim_id":"621329","title":"FAMILY WITH SEQUENCE SIMILARITY 81, MEMBER A; FAM81A","url":"https://www.omim.org/entry/621329"},{"mim_id":"621028","title":"ANKYRIN REPEAT- AND BTB DOMAIN-CONTAINING PROTEIN 3; ABTB3","url":"https://www.omim.org/entry/621028"},{"mim_id":"620656","title":"PLECKSTRIN AND SEC7 DOMAINS-CONTAINING PROTEIN 2; PSD2","url":"https://www.omim.org/entry/620656"},{"mim_id":"618793","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 62; MRD62","url":"https://www.omim.org/entry/618793"},{"mim_id":"618597","title":"BRAIN-ENRICHED GUANYLATE KINASE-ASSOCIATED PROTEIN; BEGAIN","url":"https://www.omim.org/entry/618597"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":475.5},{"tissue":"intestine","ntpm":249.1}],"url":"https://www.proteinatlas.org/search/PSD"},"hgnc":{"alias_symbol":["KIAA2011","TYL","PSD1","EFA6A","EFA6"],"prev_symbol":[]},"alphafold":{"accession":"A5PKW4","domains":[{"cath_id":"1.10.1000.11","chopping":"553-723","consensus_level":"high","plddt":83.273,"start":553,"end":723},{"cath_id":"2.30.29.30","chopping":"759-804_811-874","consensus_level":"medium","plddt":90.0905,"start":759,"end":874},{"cath_id":"1.20.58","chopping":"899-981","consensus_level":"medium","plddt":86.3154,"start":899,"end":981}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A5PKW4","model_url":"https://alphafold.ebi.ac.uk/files/AF-A5PKW4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A5PKW4-F1-predicted_aligned_error_v6.png","plddt_mean":55.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSD","jax_strain_url":"https://www.jax.org/strain/search?query=PSD"},"sequence":{"accession":"A5PKW4","fasta_url":"https://rest.uniprot.org/uniprotkb/A5PKW4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A5PKW4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A5PKW4"}},"corpus_meta":[{"pmid":"7569905","id":"PMC_7569905","title":"Domain 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one","url":"https://pubmed.ncbi.nlm.nih.gov/23342049","citation_count":27,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46704,"output_tokens":4491,"usd":0.103738,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12446,"output_tokens":3900,"usd":0.079865,"stage2_stop_reason":"end_turn"},"total_usd":0.183603,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"EFA6A (PSD/EFA6) contains Sec7 and pleckstrin homology (PH) domains and functions as a guanine nucleotide exchange factor (GEF) that promotes efficient GDP/GTP exchange specifically on ARF6 (not ARF1). EFA6A localizes to the cytoplasmic face of plasma membrane invaginations, regulates endosomal membrane recycling and transferrin receptor redistribution to the cell surface, and induces actin-based membrane ruffles dependent on ARF6 and Rac1 activation.\",\n      \"method\": \"GEF nucleotide exchange assays, subcellular localization by immunofluorescence, dominant-negative ARF6 and Rac1 co-expression, transferrin recycling assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro GEF assay, multiple orthogonal functional readouts (actin ruffles, receptor recycling), dominant-negative epistasis\",\n      \"pmids\": [\"10075920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In vitro, EFA6A (PSD) Sec7 domain activates ARF6 exclusively and does not activate ARF1, whereas ARNO activates ARF1 preferentially. Selectivity is determined by the Sec7 domain alone and by the ARF core domains, independent of the myristoylated N-terminal helix.\",\n      \"method\": \"In vitro GEF activity assay on phospholipid membranes with isolated Sec7 domains and ARF core domains; ARF1/ARF6 specificity mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro biochemical assay with domain dissection and mutagenesis-equivalent domain swaps\",\n      \"pmids\": [\"11342560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EFA6A (PSD/EFA6) and its paralog EFA6B share a conserved C-terminal ~150 aa region with a predicted coiled-coil motif. Overexpression of the PH domain/C-terminal region of EFA6A or EFA6B (without the Sec7 domain) promotes lengthening of dorsal microvilli-like membrane protrusions, an effect requiring integrity of the coiled-coil motif. Association with membrane ruffles depends on the PH domain, which interacts with PI(4,5)P2.\",\n      \"method\": \"Deletion/domain-swap overexpression in BHK cells, immunofluorescence localization, coiled-coil motif mutagenesis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — domain deletion experiments with clear morphological readout, single lab, multiple constructs\",\n      \"pmids\": [\"12082148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EFA6 (PSD) regulates actin cytoskeleton dynamics and tight junction (TJ) formation in epithelial MDCK cells in response to E-cadherin engagement. EFA6 is recruited to a Triton X-100-insoluble fraction upon calcium-triggered E-cadherin adhesion, selectively stabilizes the apical actin ring to retain occludin at the cell surface and exclude TJ proteins from endocytosis. These effects require both the catalytic Sec7 exchange activity and the actin-remodeling C-terminal domain.\",\n      \"method\": \"Calcium switch assay, Triton X-100 fractionation, immunofluorescence, overexpression of catalytic-dead Sec7 mutant, C-terminal domain deletion constructs\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — domain-specific mutants, fractionation, functional TJ readout; single lab\",\n      \"pmids\": [\"14668475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EFA6 (PSD) interacts with TWIK1 K+ channel only when EFA6 is bound to ARF6 (ARF6-dependent interaction). TWIK1 is expressed in a subapical recycling endosomal compartment in renal proximal tubules and polarized MDCK cells; the ARF6/EFA6/TWIK1 complex is proposed to regulate channel internalization and recycling.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, subcellular localization by immunofluorescence\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and yeast two-hybrid, multiple methods but single lab, ARF6-dependency is a novel mechanistic detail\",\n      \"pmids\": [\"15540117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EFA6A (PSD) promotes dendritic spine formation in hippocampal neurons in an ARF6 activation-dependent manner. Active ARF6 promotes conversion of filopodia to spines. Knockdown of ARF6 and EFA6A by siRNA decreases spine formation and reduces filopodia-to-spine conversion. ARF6 and EFA6A protect mature spines from inactivity-induced destabilization. The spine-promoting effect of ARF6 is partially blocked by Rac1.\",\n      \"method\": \"siRNA knockdown, dominant-negative ARF6, live-imaging of spine dynamics, overexpression in hippocampal neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA loss-of-function, dominant-negative epistasis, live imaging with defined cellular phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"16672654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EFA6A (PSD) mRNA is somatodendritically localized in hippocampal neurons in vivo and in vitro, with peak dendritic expression between P7 and P14 in rats. Overexpression of a GEP-defective (catalytically dead) mutant of EFA6A enhances dendritic formation, implicating EFA6A in regulation of hippocampal dendritic development.\",\n      \"method\": \"Non-radioactive in situ hybridization, overexpression of catalytic-dead EFA6A mutant, morphometric analysis of dendrites\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in situ hybridization for localization plus dominant-negative overexpression for function; single lab\",\n      \"pmids\": [\"15009133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EFA6A (PSD) enhances glioma cell invasion through an ARF6/ERK signaling cascade. Overexpression of EFA6A significantly increases cell motility and invasiveness; these effects are abolished by the catalytic-dead EFA6A(E242K) mutant, dominant-negative ARF6(T27N), or the MEK inhibitor U0126, indicating that EFA6A acts upstream of ARF6 to activate ERK-dependent invasion.\",\n      \"method\": \"Conditional overexpression, wound healing and Matrigel invasion assays, dominant-negative EFA6A and ARF6, pharmacological MEK inhibition, phospho-ERK western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — catalytic-dead mutant + dominant-negative epistasis + kinase inhibitor convergence; single lab\",\n      \"pmids\": [\"16452216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EFA6D (a family member of EFA6/PSD) shows preferential GEF activity toward ARF6 in ARF pull-down assays and is highly concentrated in the postsynaptic density fraction of mouse brain, with a distinct spatiotemporal expression pattern from EFA6A and EFA6C.\",\n      \"method\": \"ARF pull-down GEF activity assay, subcellular fractionation, RT-PCR, in situ hybridization\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GEF activity assay plus fractionation, but for paralog EFA6D not EFA6A specifically; included as family-level finding\",\n      \"pmids\": [\"16707115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EFA6A (PSD) protein localizes to dendritic spines of hippocampal neurons and can interact with alpha-actinin-1. Yeast two-hybrid and immunofluorescence co-localization show partial overlap of EFA6A and alpha-actinin at dendritic spines in vivo and in culture. The central region of alpha-actinin-1 (spectrin repeats) mediates the interaction with EFA6A's C-terminal region.\",\n      \"method\": \"Yeast two-hybrid screening, immunofluorescence co-localization in hippocampal neurons, subcellular fractionation\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus co-localization; interaction domain identified but direct binding not confirmed by in vitro pulldown\",\n      \"pmids\": [\"17298598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EFA6A (PSD) and three other EFA6 family members (EFA6A, EFA6C, EFA6D) are abundantly expressed in mouse brain and enriched in the postsynaptic density fraction, establishing that EFA6 family GEFs for ARF6 are concentrated at neuronal synapses.\",\n      \"method\": \"Subcellular fractionation, immunoblot, RT-PCR, in situ hybridization (review/summary of experimental findings from multiple prior studies)\",\n      \"journal\": \"The Tohoku journal of experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper summarizing prior fractionation data; no new experiment reported in this abstract\",\n      \"pmids\": [\"18323689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"USP9x-mediated deubiquitination of EFA6 (PSD) is required for tight junction biogenesis. At steady state, EFA6 is constitutively ubiquitinated and degraded by the proteasome. At newly forming epithelial contacts, USP9x deubiquitinates EFA6, leading to a transient increase in EFA6 levels that facilitates TJ formation. Knockdown of either EFA6 or USP9x impairs TJ biogenesis; EFA6 overexpression rescues TJ biogenesis in USP9x-knockdown cells.\",\n      \"method\": \"Knockdown by siRNA, co-immunoprecipitation, overexpression rescue, immunofluorescence co-localization at primordial junctions\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal knockdown/rescue experiments, co-IP identifying USP9x as EFA6 deubiquitinase, functional TJ readout; multiple orthogonal methods\",\n      \"pmids\": [\"20339350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EFA6 (PSD) directly interacts with endophilin via the endophilin N-BAR domain (identified by two-hybrid and confirmed with purified proteins). Endophilin stimulates the catalytic GEF activity of EFA6A on ARF6. The Sec7 domain of EFA6A competes with flat (but not highly curved) lipid membranes for N-BAR binding. In cells, EFA6A recruits endophilin to EFA6A-positive plasma membrane ruffles, and endophilin expression rescues EFA6A-mediated inhibition of transferrin internalization, placing EFA6/ARF6 upstream of clathrin-mediated endocytosis.\",\n      \"method\": \"Yeast two-hybrid, in vitro pulldown with purified proteins, GEF activity assay, lipid competition assay, co-localization, transferrin internalization rescue assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct interaction confirmed with purified proteins, in vitro GEF stimulation assay, functional cellular rescue; multiple orthogonal methods\",\n      \"pmids\": [\"24979773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EFA6 (PSD) localizes within the axon initial segment (AIS) of mature CNS cortical neurons and acts as an intrinsic regulator of selective axon transport. EFA6 at the AIS restricts Rab11 vesicle (and integrin) transport into axons. Depleting EFA6 from cortical neurons permits endosomal integrin transport and enhances axon regeneration after laser axotomy; overexpressing EFA6 prevents DRG neuron regeneration. EFA6 does not localize at the AIS in DRG axons, correlating with their regenerative capacity.\",\n      \"method\": \"siRNA/shRNA knockdown, laser axotomy, live imaging of Rab11/integrin transport, overexpression, localization by immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss- and gain-of-function with defined transport and regeneration readouts, AIS localization directly established; multiple orthogonal approaches\",\n      \"pmids\": [\"28935671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD13 tethers EFA6 (PSD) to the plasma membrane at the leading edge of migrating cells, forming a complex with IQGAP1 and active ARF6. This complex promotes ARF6 GTPase cycling, β1 integrin recycling to the surface (preventing its trafficking to late endosomes and degradation), and cell migration. Loss of CD13 impairs EFA6 membrane positioning and reduces ARF6 activity.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown, β1 integrin trafficking assay, migration assays, immunofluorescence\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP identifying complex, knockdown phenotypes with defined trafficking readout; single lab\",\n      \"pmids\": [\"31040262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EFA6 (PSD/Drosophila Efa6) can directly inhibit microtubule polymerization at the plasma membrane via an N-terminal 18 amino acid motif (MT elimination domain, MTED) that binds tubulin and inhibits microtubule growth in vitro and in cells, independent of ARF GEF activity. Full-length membrane-anchored Efa6 blocks explorative MTs in axon shafts and growth cones; loss of Efa6 increases explorative MTs leading to increased axon branching and growth, while overexpression causes axon atrophy.\",\n      \"method\": \"In vitro microtubule polymerization assay, MTED peptide binding to tubulin, Drosophila neuron overexpression/loss-of-function, live imaging of MT dynamics, morphometric analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified tubulin, domain-specific mutant (MTED), genetic loss-of-function in neurons with clear phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"31718774\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSD (EFA6A) is a plasma membrane-localized ARF6-specific guanine nucleotide exchange factor (GEF) whose Sec7 domain catalyzes GDP/GTP exchange exclusively on ARF6; it coordinates endosomal membrane recycling, actin cytoskeletal reorganization (via ARF6→Rac1), tight junction formation (regulated by USP9x-mediated deubiquitination), and dendritic spine development in neurons; additionally, EFA6/PSD localizes to the axon initial segment where it restricts integrin/Rab11 vesicle transport into axons to limit regeneration, and in Drosophila its N-terminal MT elimination domain (MTED) directly inhibits cortical microtubule polymerization to regulate axon growth and branching.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSD (EFA6A) is a plasma membrane-associated guanine nucleotide exchange factor that, through its Sec7 domain, catalyzes GDP/GTP exchange exclusively on the small GTPase ARF6 and not ARF1, with selectivity dictated by the Sec7 and ARF core domains independent of the myristoylated N-terminal helix [#0, #1]. Its PH domain targets it to PI(4,5)P2-rich plasma membrane invaginations and ruffles while a conserved coiled-coil-containing C-terminal region drives actin-based membrane protrusions [#0, #2]. Through ARF6 activation it governs endosomal membrane recycling and clathrin-mediated endocytosis—activity stimulated by direct binding to the endophilin N-BAR domain, which it recruits to membrane ruffles to control transferrin internalization [#0, #12]. PSD couples this GEF activity and its actin-remodeling C-terminus to epithelial tight junction biogenesis, stabilizing the apical actin ring and retaining occludin upon E-cadherin engagement, a function gated by USP9x-mediated deubiquitination that transiently stabilizes PSD at nascent junctions [#3, #11]. In neurons, PSD promotes ARF6-dependent filopodium-to-spine conversion and dendritic spine maturation [#5], and at the axon initial segment it restricts Rab11/integrin vesicle entry into axons to limit regeneration [#13]. Beyond its GEF function, the EFA6/Drosophila Efa6 N-terminal microtubule elimination domain (MTED) directly binds tubulin and inhibits cortical microtubule polymerization, independent of ARF GEF activity, to regulate axon growth and branching [#15]. PSD also acts upstream of ARF6/ERK signaling to drive glioma invasion [#7] and is positioned at the leading edge of migrating cells via CD13 within an IQGAP1/ARF6 complex that promotes β1 integrin recycling [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established PSD/EFA6A as an ARF6-specific GEF and linked it to membrane recycling and actin remodeling, defining its core molecular activity.\",\n      \"evidence\": \"In vitro GEF nucleotide exchange assays, immunofluorescence localization, dominant-negative ARF6/Rac1, transferrin recycling assay\",\n      \"pmids\": [\"10075920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve structural basis of ARF6 selectivity\", \"Upstream membrane recruitment cues undefined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapped the determinants of ARF6 versus ARF1 selectivity to the Sec7 and ARF core domains, showing the myristoylated helix is dispensable.\",\n      \"evidence\": \"Reconstituted in vitro GEF assay on phospholipid membranes with isolated Sec7 and ARF core domains, specificity mapping\",\n      \"pmids\": [\"11342560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution contacts not defined\", \"In-cell relevance of selectivity not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the PH domain (PI(4,5)P2 binding) and a conserved C-terminal coiled-coil as separable membrane-targeting and protrusion-promoting modules distinct from catalysis.\",\n      \"evidence\": \"Domain deletion/swap overexpression in BHK cells, coiled-coil mutagenesis, immunofluorescence\",\n      \"pmids\": [\"12082148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct lipid-binding affinity not quantified\", \"Coiled-coil partner not identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected PSD to epithelial tight junction formation, showing both Sec7 catalysis and the actin-remodeling C-terminus are required to stabilize the apical actin ring and retain occludin.\",\n      \"evidence\": \"Calcium switch assay, Triton X-100 fractionation, catalytic-dead and C-terminal deletion constructs, immunofluorescence in MDCK cells\",\n      \"pmids\": [\"14668475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effectors linking actin ring to occludin retention unresolved\", \"Single cell-type evidence\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated ARF6-dependent partner interactions (TWIK1 channel) and a neuronal role in dendritic spine formation, broadening PSD function from epithelia to neurons.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, siRNA knockdown, dominant-negative ARF6, live spine imaging, in situ hybridization, catalytic-dead overexpression in hippocampal neurons\",\n      \"pmids\": [\"15540117\", \"16672654\", \"15009133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Opposing dendritic effects of catalytic-dead mutant versus spine phenotype not reconciled\", \"TWIK1 interaction lacks reciprocal validation\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended PSD/ARF6 signaling to disease (glioma invasion via ERK) and confirmed family-wide postsynaptic enrichment of EFA6 ARF6-GEFs.\",\n      \"evidence\": \"Matrigel invasion assays, catalytic-dead and dominant-negative epistasis, MEK inhibitor, ARF pull-down GEF assay, subcellular fractionation\",\n      \"pmids\": [\"16452216\", \"16707115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo tumor relevance not established\", \"Mechanism coupling ARF6 to ERK undefined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified alpha-actinin-1 as a C-terminal interactor at dendritic spines, providing a candidate link between PSD and the spine actin cytoskeleton.\",\n      \"evidence\": \"Yeast two-hybrid, immunofluorescence co-localization, subcellular fractionation in hippocampal neurons\",\n      \"pmids\": [\"17298598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding not confirmed by in vitro pulldown\", \"Functional consequence of interaction untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed PSD is regulated post-translationally by USP9x deubiquitination, stabilizing it transiently at nascent junctions to enable tight junction biogenesis.\",\n      \"evidence\": \"Reciprocal siRNA knockdown, co-IP, overexpression rescue, immunofluorescence at primordial junctions\",\n      \"pmids\": [\"20339350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase that ubiquitinates PSD unidentified\", \"Ubiquitination site(s) not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined endophilin as a direct activator of PSD GEF activity, integrating ARF6 activation with clathrin-mediated endocytosis.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro pulldown with purified proteins, GEF stimulation assay, lipid competition, transferrin internalization rescue\",\n      \"pmids\": [\"24979773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Sec7/N-BAR competition unresolved\", \"Physiological setting of endophilin stimulation in vivo not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localized PSD to the axon initial segment as an intrinsic gatekeeper of selective axon transport, restricting Rab11/integrin entry to limit axon regeneration.\",\n      \"evidence\": \"shRNA/siRNA knockdown, laser axotomy, live imaging of Rab11/integrin transport, overexpression, immunofluorescence in cortical and DRG neurons\",\n      \"pmids\": [\"28935671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which PSD blocks vesicle entry unresolved\", \"Role of ARF6 GEF activity in this function not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Uncovered a GEF-independent activity—the N-terminal MTED directly inhibits microtubule polymerization—and a CD13/IQGAP1-anchored ARF6 complex promoting integrin recycling and migration.\",\n      \"evidence\": \"In vitro MT polymerization assay, MTED tubulin binding, Drosophila gain/loss-of-function with live MT imaging; co-IP, PLA, knockdown, β1 integrin trafficking and migration assays\",\n      \"pmids\": [\"31718774\", \"31040262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of mammalian MTED function not fully established\", \"Integration of MTED and GEF activities in a single cell context unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSD's distinct activities—ARF6 GEF catalysis, MTED-mediated microtubule inhibition, and actin remodeling—are coordinated and selectively deployed across epithelial, migratory, and neuronal contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating Sec7, PH, MTED, and C-terminal modules\", \"Spatial/temporal switching between GEF and microtubule functions undefined\", \"In vivo mammalian knockout phenotype not characterized in corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005085\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 8, 12]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 9, 15]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 14, 15]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 12, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ARF6\", \"endophilin\", \"USP9x\", \"alpha-actinin-1\", \"TWIK1\", \"CD13\", \"IQGAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}