{"gene":"EXOC7","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2007,"finding":"The C-terminal Domain D of Exo70 directly interacts with phosphatidylinositol 4,5-bisphosphate (PI4,5P2), and key residues critical for this interaction were identified by mutagenesis. The interaction of Exo70 with phospholipids (but not Rho3) is essential for membrane association of the exocyst complex, anchoring it to the plasma membrane in concert with Sec3.","method":"In vitro lipid-binding assay, site-directed mutagenesis, genetic and cell biological analyses in yeast","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct lipid-binding assay with mutagenesis of key residues plus genetic epistasis, replicated with multiple orthogonal methods in one study","pmids":["17717527"],"is_preprint":false},{"year":2004,"finding":"In budding yeast, Exo70p (together with Sec3p) is stably associated with exocytic sites at the plasma membrane independently of actin cables, while other exocyst subunits arrive on secretory vesicles. Exocyst assembly occurs when vesicle-borne subunits join Exo70p and Sec3p at the plasma membrane to tether vesicles.","method":"FRAP (fluorescence recovery after photobleaching), immunogold electron microscopy, epifluorescence video microscopy, actin disruption experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal imaging methods (FRAP, EM, live video) with pharmacological perturbation, replicated across several exocyst subunits","pmids":["15583031"],"is_preprint":false},{"year":1999,"finding":"Yeast Rho3 GTPase directly interacts with Exo70 in a GTP-dependent manner (GTPγS-bound Rho3 binds more efficiently than GDP-bound), as shown by yeast two-hybrid and in vitro pulldown with purified proteins. Rho3 and Exo70 co-localize at the bud tip, and dominant-active Rho3 alters Exo70 localization.","method":"Yeast two-hybrid screen, in vitro binding assay with purified proteins, GTP/GDP loading, indirect immunofluorescence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution with purified proteins plus GTP-dependence assay, corroborated by localization studies","pmids":["10207081"],"is_preprint":false},{"year":2006,"finding":"The exocyst component Exo70 directly interacts with the Arp2/3 complex. This interaction is regulated by EGF signalling. Inhibition of Exo70 by RNAi or antibody microinjection blocks formation of actin-based membrane protrusions and impairs cell motility.","method":"Co-immunoprecipitation, RNAi knockdown, antibody microinjection, cell migration assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus two independent loss-of-function approaches (RNAi and antibody microinjection) with defined cellular phenotypes","pmids":["17086175"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of yeast Exo70p at 2.0 Å resolution reveals a ~160 Å-long rod composed of contiguous alpha-helical bundles (novel fold). The C-terminal domains interact with other exocyst subunits and Rho3p GTPase. Exo84p C-terminal domains share the same fold as the Exo70p N-terminus, suggesting a common helical module architecture for exocyst subunits.","method":"X-ray crystallography (2.0 Å resolution), structural interaction analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at high resolution with experimental validation of protein interactions","pmids":["16249794"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of S. cerevisiae Exo70p at 3.5 Å resolution reveals an extended rod (~155 Å) composed principally of alpha helices. Exo70p binds Rho3p in a GTP-dependent manner with a Kd of ~70 µM.","method":"X-ray crystallography (3.5 Å), equilibrium binding assay (Kd determination)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with quantitative binding measurement, independent corroboration of Rho3-binding from another lab","pmids":["16359701"],"is_preprint":false},{"year":2012,"finding":"ERK1/2 directly phosphorylate the exocyst component Exo70. This phosphorylation enhances binding of Exo70 to other exocyst components and promotes exocyst complex assembly in response to EGF signalling. An Exo70 phosphorylation-defective mutant inhibits exocytosis, and in tumor cells blocks matrix metalloproteinase secretion and invadopodia formation.","method":"In vitro kinase assay, phosphorylation-defective mutant expression, Co-immunoprecipitation, exocytosis assay, invadopodia assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay establishing direct phosphorylation, plus mutant rescue experiment and multiple cellular phenotype readouts","pmids":["22595671"],"is_preprint":false},{"year":2013,"finding":"Exo70 induces negative membrane curvature through an oligomerization-based mechanism. Exo70 generates tubular invaginations in synthetic vesicles in vitro and produces membrane protrusions on cell surfaces. The membrane-deformation function, validated by Exo70 mutants and molecular dynamics simulations, is required for protrusion formation and directional cell migration.","method":"In vitro liposome tubulation assay, Exo70 mutagenesis, molecular dynamics simulation, cell protrusion and migration assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution with liposomes, structural mutagenesis, independent computational validation, and cellular phenotype assays","pmids":["23948253"],"is_preprint":false},{"year":2012,"finding":"Exo70 functions as a kinetic activator of the Arp2/3 complex, promoting actin filament nucleation and branching by facilitating the interaction of Arp2/3 with the nucleation-promoting factor WAVE2. This activity is required for lamellipodia formation and directional persistence of cell migration.","method":"In vitro actin polymerization assay, TIRF microscopy, Co-immunoprecipitation, cell migration assays with Exo70 knockdown","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of Arp2/3 activation, TIRF single-filament imaging, and cellular loss-of-function phenotypes","pmids":["22748316"],"is_preprint":false},{"year":2013,"finding":"During epithelial-mesenchymal transition, Exo70 undergoes isoform switching regulated by the splicing factor ESRP1. The mesenchymal (but not epithelial) isoform of Exo70 interacts with the Arp2/3 complex and stimulates actin polymerization for tumor invasion. The epithelial isoform affects levels of EMT transcription factors Snail and ZEB2 and drives epithelial phenotypes.","method":"RNA isoform analysis, Co-immunoprecipitation, actin polymerization assay, cell invasion assays, mouse tumor metastasis model","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific Co-IP with Arp2/3, actin assay, and in vivo metastasis model with multiple orthogonal methods","pmids":["24331928"],"is_preprint":false},{"year":2020,"finding":"ULK1 directly phosphorylates Exo70, and this phosphorylation inhibits Exo70 homo-oligomerization and its assembly into the exocyst complex, suppressing cell protrusion formation and MMP secretion during invasion. EGF stimulation causes ERK1/2 to phosphorylate Exo70 at a different site, which counteracts ULK1 phosphorylation—defining two opposing regulatory modifications.","method":"In vitro kinase assay, phosphorylation-site mutagenesis, oligomerization assay, Co-immunoprecipitation, cell invasion assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro phosphorylation assay, mutagenesis of phospho-sites, functional cellular phenotypes with multiple orthogonal assays","pmids":["31913283"],"is_preprint":false},{"year":2009,"finding":"TC10 GTPase activates and triggers translocation of Exo70 to the plasma membrane in the distal axon and growth cone in response to IGF-1. TC10 and Exo70 function are both necessary for membrane addition and axon elongation stimulated by IGF-1, and for polarized insertion of the IGF-1 receptor to establish neuronal polarity.","method":"siRNA knockdown of TC10 and Exo70, dominant-negative expression, subcellular fractionation, immunofluorescence in cultured hippocampal neurons and isolated growth cones","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent loss-of-function approaches (siRNA and dominant-negative) with specific readouts in primary neurons","pmids":["19846717"],"is_preprint":false},{"year":2007,"finding":"Exo70p selectively mediates secretion of the Bgl2p class of post-Golgi vesicles in budding yeast, with secretion defect most pronounced at early stages of the cell cycle (early budding stage), affecting daughter cell growth. The block occurs at the tethering step, not vesicle formation or cargo sorting.","method":"Yeast genetics with exo70 mutants, secretion assays for Bgl2p vs. invertase vesicles, cell biological analysis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined vesicle-class selectivity with genetic mutants and secretion assays, single lab","pmids":["17339375"],"is_preprint":false},{"year":2011,"finding":"Type Iγ PI4P 5-kinase (PIPKIγ) directly interacts with Exo70 and mediates association between E-cadherin and Exo70. PIPKIγ-generated PI4,5P2 recruits Exo70 to nascent E-cadherin junctions, and Exo70 is required for E-cadherin clustering and maturation of adherens junctions.","method":"Co-immunoprecipitation, direct binding assay, siRNA knockdown, fluorescence microscopy of E-cadherin junctions","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus direct binding plus loss-of-function with defined adhesion phenotype, single lab","pmids":["22049025"],"is_preprint":false},{"year":2005,"finding":"BIG2 (a brefeldin A-inhibited ARF guanine nucleotide-exchange protein) interacts with the N-terminal portion (aa 1–643) of human Exo70. Endogenous BIG2 and Exo70 co-localize at trans-Golgi network membranes and at the MTOC/centrosomes in HepG2 cells.","method":"Yeast two-hybrid, co-immunoprecipitation of in vitro-translated proteins, immunofluorescence confocal microscopy, centrosome purification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid confirmed by co-IP and localization, single lab, multiple methods","pmids":["15705715"],"is_preprint":false},{"year":2007,"finding":"Snapin interacts with the Exo70 subunit of the exocyst via an N-terminal coiled-coil domain of Exo70 and a C-terminal helical region of Snapin. Exo70 competes with SNAP23 for Snapin binding. Snapin depletion by RNAi inhibits insulin-stimulated glucose uptake in adipocytes, modulating GLUT4 vesicle trafficking.","method":"Co-immunoprecipitation, domain mapping, RNAi knockdown, glucose uptake assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with domain mapping plus functional RNAi phenotype, single lab","pmids":["17947242"],"is_preprint":false},{"year":2009,"finding":"Exo70 (Exo70-N mutant) induces insulin-independent tethering of GLUT4 vesicles to the plasma membrane in primary adipocytes, but this tethering does not lead to vesicle fusion without insulin. Insulin regulates the fusion step downstream of Exo70-mediated tethering.","method":"Total internal reflection fluorescence microscopy of GLUT4 vesicle dynamics, Exo70 overexpression and dominant mutant expression in primary adipocytes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct TIRF imaging of tethering and fusion events with defined mutant, single lab","pmids":["19155211"],"is_preprint":false},{"year":2019,"finding":"Inducible knockout of Exoc7/Exo70 in adipocytes markedly inhibits insulin-stimulated GLUT4 exocytosis without affecting insulin signaling, establishing that the exocyst (via Exo70) is required for the tethering/fusion step of GLUT4 vesicle exocytosis.","method":"CRISPR-based inducible adipocyte-specific Exoc7 knockout, GLUT4 translocation assay, insulin signaling assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with direct GLUT4 exocytosis readout and signal pathway controls, genome-scale CRISPR screen corroboration","pmids":["31740584"],"is_preprint":false},{"year":2009,"finding":"Exo70 directly interacts with nucleoporin Nup62 via the N-terminal domain of Exo70. Exo70 recruits Nup62 to the leading edge of migrating cells and to filopodia. RNAi knockdown of Nup62 significantly reduces cell migration, and removal of the Exo70-binding domain from Nup62 prevents its leading-edge localization.","method":"Co-immunoprecipitation, domain mapping, RNAi knockdown, fluorescence microscopy, cell migration assay","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct interaction mapping with Co-IP, RNAi phenotype, and localization assay, single lab","pmids":["19552648"],"is_preprint":false},{"year":2008,"finding":"Domain C of yeast Exo70p is required for actin-independent localization to exocytic sites and for assembly of exocyst components Sec5p and Sec6p. Deletion of domain C causes synthetic lethality with secretory mutations. The actin-independent localization requires a synergistic interaction with PI(4,5)P2 in addition to domain C.","method":"Yeast genetics, domain deletion analysis, synthetic lethality screening, exocyst assembly assay, fluorescence microscopy","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain deletion with genetic interaction mapping and assembly assays, single lab","pmids":["18946089"],"is_preprint":false},{"year":2014,"finding":"Yeast Exo70p directly and specifically binds the polarity scaffold Bem1p through multiple domains of both proteins. Mutations in Exo70p that disrupt the Bem1p interaction without impairing other interactions abolish actin-independent localization of Exo70p to exocytic sites. Actin-independent localization requires both Bem1p interaction and PI(4,5)P2.","method":"In vitro binding assay (direct binding), Co-immunoprecipitation, mutagenesis, fluorescence microscopy, synthetic genetic analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay plus separation-of-function mutants plus genetic epistasis, multiple orthogonal methods","pmids":["25313406"],"is_preprint":false},{"year":2011,"finding":"Exo70 directly interacts with the spliceosomal protein SNEV (hPrp19/hPso4), shuttles to the nucleus, and associates with the spliceosome. The N-terminal 100 amino acids of Exo70 mediate the interaction and interfere with pre-mRNA splicing in vitro. Exo70 influences splicing of a model substrate and of its own pre-mRNA in vivo.","method":"Co-immunoprecipitation, in vitro splicing assay, nuclear fractionation, domain mapping, in vivo splicing assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vitro splicing assay plus Co-IP and domain mapping, single lab","pmids":["21639856"],"is_preprint":false},{"year":2013,"finding":"TC10 GTP hydrolysis near the plasma membrane promotes neurite outgrowth by releasing Exo70 to facilitate fusion of Rab11- and L1-containing recycling vesicles. FRET-based biosensors showed that TC10 activity decreases at extending growth cones, and constitutively active TC10 could not rescue neurite outgrowth defects caused by TC10 depletion.","method":"FRET-based GTPase activity biosensors, TC10 knockdown, constitutively-active TC10 rescue, colocalization analysis, exocytosis assay in PC12 cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET biosensors plus knockdown rescue experiments with defined vesicle cargo, single lab","pmids":["24223996"],"is_preprint":false},{"year":2007,"finding":"NGF induces an interaction between activated TC10 and Exo70 in PC12 cells (detected by FRET/FLIM). The Exo70-TC10 complex locally antagonizes NGF-induced Cdc42-dependent activation of N-WASP at membrane protrusions. Exo70 is responsible for correct targeting of the complex to protrusion sites.","method":"FRET imaging by fluorescence lifetime microscopy (FLIM), dominant-negative mutants, siRNA knockdown, constitutively-active Cdc42 overexpression","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET/FLIM-based interaction detection in living cells plus functional rescue/knockdown experiments, single lab","pmids":["17635999"],"is_preprint":false},{"year":2015,"finding":"GIV/Girdin directly and constitutively binds Exo70 (exocyst subunit). Upon insulin stimulation, GIV associates with GLUT4-storage vesicles. Loss of GIV or its GEF function impairs membrane association of Exo70 and exocytosis of GLUT4 vesicles in response to insulin.","method":"In vitro direct binding assay, Co-immunoprecipitation, vesicle fractionation, GLUT4 exocytosis assay with GIV knockdown/GEF mutants","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct binding with functional loss-of-function assay, single lab","pmids":["26514725"],"is_preprint":false},{"year":2020,"finding":"In zebrafish, exoc7 loss-of-function causes microcephaly, demonstrating an essential role for EXOC7 in cerebral cortical development. In humans, partial loss-of-function variants in EXOC7 cause brain atrophy, seizures, and developmental delay.","method":"Zebrafish exoc7 knockout, in vitro EXOC7 splice-variant modeling, human genetic mapping (homozygosity mapping + exome sequencing)","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish KO with defined morphological phenotype plus human genetic variants modeled in vitro, single study","pmids":["32103185"],"is_preprint":false},{"year":2010,"finding":"EXO70 protein promotes dengue virus secretion/egression from infected cells. EXO70 knockdown significantly attenuates dengue virus production without affecting viral transcription or translation, indicating a specific role in virus exocytosis.","method":"siRNA knockdown, viral titer assay, viral RNA/protein quantification","journal":"Microbes and infection","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — siRNA knockdown with specific step-dissection showing no effect on replication but effect on egression, single lab","pmids":["21034848"],"is_preprint":false},{"year":2012,"finding":"In C. elegans, exoc-7 (exo70) and exoc-8 (exo84) mutants show pleiotropic behavioral defects. exoc-8 and exoc-7;exoc-8 double mutations cause increased size of rab-10 RNAi-induced endocytic vacuoles in intestinal epithelia and affect RAB-10 expression and endocytic marker accumulation, linking Exo70 to RAB-10-dependent endosomal trafficking.","method":"C. elegans genetic mutant analysis, targeted RNAi screen for small GTPases, fluorescence microscopy of endocytic markers","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with targeted RNAi screen and multiple marker readouts, single lab","pmids":["22389680"],"is_preprint":false},{"year":2018,"finding":"In Drosophila, Exo70 is required for synaptic growth at the neuromuscular junction (NMJ). exo70 genetically interacts with the small GTPase ralA to regulate synaptic growth. Loss of Exo70 impairs integral membrane protein transport to the cell surface at synaptic terminals and blocks JNK signaling-, activity-, and temperature-induced synaptic outgrowths.","method":"Drosophila exo70 mutant alleles, genetic interaction (double mutant) with ralA, electrophysiology (mEPSP), immunofluorescence, membrane protein trafficking assays","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent mutant alleles with genetic epistasis, electrophysiology, and trafficking assays, single lab","pmids":["30209205"],"is_preprint":false},{"year":2024,"finding":"Transglutaminases TGM1 and TGM3 transamidate Exo70 on Gln5 with Lys56 of cystatin A, promoting Exo70 association with other exocyst subunits and enhancing MMP secretion, invadopodia formation, and integrin delivery to the leading edge. Tumor suppressor LKB1 phosphorylates TGM1 (Thr386) and TGM3 (Thr282) to inhibit their interaction with Exo70 and block transamidation. The FDA-approved drug cantharidin inhibits Exo70 transamidation and suppresses tumor cell migration.","method":"Mass spectrometry identification of modification sites, site-directed mutagenesis, in vitro transamidation assay, kinase assay, Co-immunoprecipitation, invasion and invadopodia assays, in vivo tumor model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — PTM identified by MS, validated by mutagenesis and in vitro assay, upstream kinase (LKB1) mechanism defined, multiple cellular phenotype readouts","pmids":["39146185"],"is_preprint":false},{"year":2021,"finding":"Exo70 promotes cisplatin efflux from epithelial ovarian cancer cells through exocytosis, contributing to cisplatin resistance. Cisplatin-induced autophagy-lysosomal degradation of Exo70 is modulated by AMPK/mTOR phosphorylation. Knockdown of Exo70 or inhibition with ES2 reverses cisplatin resistance both in vitro and in vivo.","method":"Exo70 knockdown, ES2 inhibitor treatment, cisplatin efflux/uptake assay, autophagy pathway analysis (AMPK/mTOR phosphorylation), in vivo xenograft model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional exocytosis assay of cisplatin efflux with knockdown and inhibitor, in vivo validation, single lab","pmids":["34298686"],"is_preprint":false},{"year":2021,"finding":"Exoc7/Exo70 opposes Prpf19/prp19 in regulating expanded ATXN3-polyQ protein toxicity in SCA3 models. Exoc7/exo70 modulates expanded ATXN3-polyQ levels by regulating the E3 ligase function of Prpf19, counteracting polyubiquitination and degradation of mutant ATXN3.","method":"Mammalian cell transfection, Drosophila disease model, ubiquitination assay, protein level analysis, genetic interaction","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic interaction in two model systems with mechanistic assays for ubiquitination, single lab","pmids":["33542212"],"is_preprint":false},{"year":2021,"finding":"Following mild traumatic brain injury in mice, Exo70 redistributes from the microsomal fraction into the synaptic compartment. Exocyst complex assembly and its interaction with GluN2B (NMDA receptor subunit) increase in the synaptic compartment after brain trauma.","method":"Subcellular fractionation, Co-immunoprecipitation, mouse repeated mTBI model","journal":"Biological research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — subcellular fractionation with Co-IP showing interaction change, single lab, one model system","pmids":["33593425"],"is_preprint":false},{"year":2022,"finding":"The brain-specific Cdc42b isoform (but not ubiquitous Cdc42u) interacts with Exo70 and regulates exocytosis of post-Golgi vesicles in the axonal growth cone to promote axon formation. Inactivation of Arhgef7 (activator of Cdc42b) or Cdc42b interferes with this exocytosis. Mammalian Cdc42u does not interact with Exo70.","method":"Co-immunoprecipitation of Cdc42 isoforms with Exo70, live-cell imaging of post-Golgi vesicle exocytosis, siRNA knockdown, dominant-negative expression","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP showing isoform specificity plus functional exocytosis assay with loss-of-function, single lab","pmids":["36543541"],"is_preprint":false},{"year":2020,"finding":"GIV/Girdin fulfills the function of yeast Bem1p as a polarity scaffold for Exo70 in mammalian cells; both bind Exo70 via similar short-linear interaction motifs and each prefers its evolutionary counterpart. Selective disruption of the GIV-Exo70 interaction blocks delivery of MT1-MMP to invadosomes and impairs collagen degradation.","method":"Co-immunoprecipitation, motif-based interaction assay, MT1-MMP trafficking assay, collagen degradation assay, haptotaxis assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with functional disruption experiment and defined cargo-delivery phenotype, single lab","pmids":["32590327"],"is_preprint":false},{"year":2019,"finding":"Kinase suppressor of Ras 1 (KSR1) promotes fatty acid-stimulated neurotensin secretion via ERK1/2 signaling, which acts through Exo70. Inhibition of Exo70 potently inhibits basal and docosahexaenoic acid-stimulated neurotensin secretion from human endocrine cells, while Exo70 overexpression enhances it.","method":"Exo70 knockdown and overexpression, neurotensin secretion assay, ERK inhibitor treatment","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown and overexpression with secretion assay, no mechanistic dissection of Exo70's direct role, single lab","pmids":["30917119"],"is_preprint":false},{"year":2024,"finding":"Exo70 redistributes from microsomes to synaptic compartment and increases interaction with GluN2B after mTBI. Exo70 overexpression in CA1 pyramidal neurons via lentiviral transduction prevented mTBI-induced cognitive impairment, preserved synaptic GluN2B-containing NMDARs, and maintained downstream signaling, suggesting Exo70 regulates NMDAR trafficking at synapses.","method":"Lentiviral Exo70 overexpression in vivo, Morris water maze, electrophysiology (synaptic transmission and LTP), GluN2B co-immunoprecipitation, mouse mTBI model","journal":"Antioxidants","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with cognitive and electrophysiological phenotype readouts plus molecular interaction data, single lab","pmids":["40563275"],"is_preprint":false},{"year":2025,"finding":"Cytoplasmic METTL3 interacts with EXOC7, promoting EXOC7 stabilization. METTL3 knockdown impairs vesicle trafficking and breast cancer secretome, impairs invadopodia formation and collagen invasion independently of METTL3's catalytic activity, implicating METTL3-mediated stabilization of EXOC7 as a non-catalytic mechanism.","method":"Co-immunoprecipitation of METTL3 and EXOC7, METTL3 knockdown, catalytic-dead METTL3 mutant rescue, vesicle trafficking assay, invasion assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP with functional knockdown data but preprint, single lab, catalytic mutant rescue not fully mechanistically resolved","pmids":[],"is_preprint":true}],"current_model":"EXOC7/Exo70 is a multifunctional subunit of the octameric exocyst tethering complex that anchors the complex to the plasma membrane through direct binding to PI4,5P2 (via its C-terminal domain D) and polarity scaffolds (Bem1p in yeast; GIV/Girdin in mammals), rides independently of actin to exocytic sites, and tethers post-Golgi secretory vesicles for SNARE-mediated fusion; beyond exocytosis, Exo70 directly activates the Arp2/3 complex (facilitated by WAVE2) to drive actin branching and membrane protrusion for cell migration, undergoes isoform switching during EMT to regulate tumor invasion, and is post-translationally regulated by ERK1/2 phosphorylation (promoting exocyst assembly), ULK1 phosphorylation (inhibiting oligomerization and assembly), and TGM1/3 transamidation (promoting exocyst assembly and MMP secretion), with upstream control by small GTPases TC10 and Cdc42b in neurons to coordinate membrane expansion during axon formation."},"narrative":{"mechanistic_narrative":"EXOC7/Exo70 is a subunit of the octameric exocyst tethering complex that captures post-Golgi secretory vesicles at the plasma membrane for SNARE-mediated fusion, and which doubles as a direct effector of actin remodeling during cell migration [PMID:15583031, PMID:17086175, PMID:17339375]. Exo70 anchors the exocyst to the plasma membrane through direct binding of its C-terminal Domain D to PI(4,5)P2, an interaction essential for exocyst membrane association and, together with Domain C, for actin-independent localization of Exo70 to exocytic sites [PMID:17717527, PMID:18946089]. Crystal structures reveal an extended ~160 Å rod of contiguous alpha-helical bundles whose C-terminal modules mediate binding to other exocyst subunits and to the GTP-loaded Rho3 GTPase [PMID:16249794, PMID:16359701, PMID:10207081]; in yeast this membrane targeting also requires the polarity scaffold Bem1p, a role fulfilled in mammalian cells by GIV/Girdin [PMID:25313406, PMID:32590327]. Beyond tethering, Exo70 acts as a kinetic activator of the Arp2/3 complex by facilitating its engagement with WAVE2 to drive actin branching, and independently deforms membranes into negative curvature via oligomerization to build protrusions and direct cell migration [PMID:22748316, PMID:23948253, PMID:17086175]. Exo70 function is gated by opposing post-translational modifications: ERK1/2 phosphorylation and TGM1/3 transamidation each promote exocyst assembly and MMP/invadopodia-driven invasion, whereas ULK1 phosphorylation inhibits Exo70 oligomerization and assembly [PMID:22595671, PMID:39146185, PMID:31913283]. Exocyst-mediated trafficking through Exo70 is required for insulin-stimulated GLUT4 exocytosis in adipocytes, for axon and neurite outgrowth downstream of TC10 and the brain-specific Cdc42b GTPase, and for E-cadherin junction maturation [PMID:31740584, PMID:19846717, PMID:36543541, PMID:22049025]. An EMT-associated isoform switch controlled by ESRP1 partitions these activities between epithelial and invasive mesenchymal programs [PMID:24331928]. Loss-of-function variants in EXOC7 cause brain atrophy, seizures, and developmental delay, with zebrafish exoc7 loss producing microcephaly [PMID:32103185].","teleology":[{"year":1999,"claim":"Establishing that a small GTPase directly engages Exo70 placed the protein within polarized GTPase signaling rather than being a passive structural subunit.","evidence":"Yeast two-hybrid and in vitro pulldown with purified Rho3, with GTP/GDP loading and localization in budding yeast","pmids":["10207081"],"confidence":"High","gaps":["Did not define the membrane-targeting determinants of Exo70","Functional consequence of Rho3 binding for vesicle tethering not resolved"]},{"year":2004,"claim":"Live imaging answered how the exocyst assembles by showing Exo70 marks the plasma-membrane landmark to which vesicle-borne subunits dock, defining a spatial logic for tethering.","evidence":"FRAP, immunogold EM, and live video microscopy with actin disruption in budding yeast","pmids":["15583031"],"confidence":"High","gaps":["Molecular basis of actin-independent membrane anchoring not yet identified","Mechanism of vesicle subunit recruitment unresolved"]},{"year":2005,"claim":"High-resolution structures defined the Exo70 fold as an extended alpha-helical rod, providing the architecture for its subunit and GTPase contacts.","evidence":"X-ray crystallography of yeast Exo70p at 2.0 Å and 3.5 Å with Rho3 binding (Kd ~70 µM) and interaction mapping","pmids":["16249794","16359701"],"confidence":"High","gaps":["No structure of the assembled exocyst octamer","Lipid-binding surface not localized structurally at this stage"]},{"year":2006,"claim":"Discovery of a direct Exo70–Arp2/3 interaction revealed a tethering subunit doubling as an actin-cytoskeleton regulator, linking secretion machinery to motility.","evidence":"Co-IP, RNAi knockdown, antibody microinjection, and cell migration assays under EGF signaling","pmids":["17086175"],"confidence":"High","gaps":["Did not establish whether Arp2/3 regulation is separable from exocyst tethering","Biochemical mechanism of Arp2/3 modulation not defined"]},{"year":2007,"claim":"Identifying Domain D–PI(4,5)P2 binding answered how Exo70 anchors the exocyst to the plasma membrane independently of GTPases.","evidence":"In vitro lipid-binding assay, site-directed mutagenesis, and genetic/cell biology in yeast; vesicle-class selectivity defined by exo70 mutants","pmids":["17717527","17339375"],"confidence":"High","gaps":["How lipid binding cooperates with protein landmarks for site selection not fully resolved","Vesicle-class selectivity mechanism (Bgl2p vs invertase) single-lab"]},{"year":2009,"claim":"Linking TC10 GTPase to Exo70 translocation defined an upstream signaling input driving polarized membrane addition during axon formation.","evidence":"siRNA and dominant-negative TC10/Exo70, subcellular fractionation, and imaging in primary hippocampal neurons and growth cones (IGF-1 stimulation)","pmids":["19846717"],"confidence":"High","gaps":["Direct binding interface between TC10 and Exo70 not mapped","Coupling to specific cargo at growth cone not yet defined"]},{"year":2012,"claim":"Two studies resolved opposing biochemical roles in actin and assembly: Exo70 kinetically activates Arp2/3 via WAVE2, and ERK1/2 phosphorylation promotes exocyst assembly for secretion and invasion.","evidence":"In vitro actin polymerization and TIRF single-filament imaging; in vitro kinase assay with phospho-defective mutant and invadopodia/exocytosis readouts","pmids":["22748316","22595671"],"confidence":"High","gaps":["How actin-nucleation and tethering activities are temporally coordinated unclear","ERK1/2 phospho-site relationship to other PTMs not yet defined"]},{"year":2013,"claim":"Mechanistic and isoform studies established that Exo70 directly deforms membranes by oligomerization and that an ESRP1-controlled isoform switch routes its activities into invasion versus epithelial programs.","evidence":"Liposome tubulation, mutagenesis, MD simulation, migration assays; RNA isoform analysis, isoform-specific Co-IP with Arp2/3, and mouse metastasis model","pmids":["23948253","24331928"],"confidence":"High","gaps":["Relationship between curvature generation and Arp2/3 activation not integrated","Epithelial isoform's effect on Snail/ZEB2 mechanism not fully defined"]},{"year":2020,"claim":"Identifying ULK1 as an inhibitory kinase counteracting ERK1/2 defined a bidirectional phospho-switch governing Exo70 oligomerization and exocyst assembly.","evidence":"In vitro kinase assay, phospho-site mutagenesis, oligomerization and Co-IP assays, invasion assays","pmids":["31913283"],"confidence":"High","gaps":["Upstream signals selecting ULK1 versus ERK1/2 dominance not defined","Quantitative stoichiometry of dual phosphorylation unresolved"]},{"year":2020,"claim":"Establishing GIV/Girdin as the mammalian Bem1p counterpart resolved how Exo70 is targeted by a polarity scaffold in metazoan cells, with direct relevance to MT1-MMP delivery.","evidence":"Motif-based interaction assay, Co-IP, and MT1-MMP trafficking/collagen degradation assays; complemented by yeast Bem1p direct-binding and separation-of-function mutants","pmids":["32590327","25313406"],"confidence":"Medium","gaps":["Structural detail of the GIV/Bem1p short-linear-motif interface limited","In vivo requirement of GIV-Exo70 axis not tested"]},{"year":2020,"claim":"Genetic evidence linked EXOC7 to human neurodevelopment, defining a Mendelian disease association.","evidence":"Zebrafish exoc7 loss-of-function (microcephaly), in vitro splice-variant modeling, and human homozygosity mapping with exome sequencing","pmids":["32103185"],"confidence":"Medium","gaps":["Cellular mechanism connecting exocyst defect to cortical phenotype not defined","Single study; allelic series limited"]},{"year":2024,"claim":"Discovery of TGM1/3 transamidation as an assembly-promoting PTM, antagonized by LKB1 phosphorylation, added a covalent regulatory layer and a druggable node for invasion.","evidence":"MS site identification, mutagenesis, in vitro transamidation and kinase assays, invadopodia/invasion assays, in vivo tumor model, cantharidin inhibition","pmids":["39146185"],"confidence":"High","gaps":["Interplay of transamidation with phospho-switch not integrated","Generality across non-tumor contexts untested"]},{"year":null,"claim":"How the distinct Exo70 activities — PI(4,5)P2 anchoring, vesicle tethering, Arp2/3 activation, and membrane curvature generation — are integrated and switched in space and time by its overlapping PTM and GTPase inputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model coupling tethering and actin functions","Crosstalk among ERK1/2, ULK1, and TGM1/3 modifications in vivo undefined","Cargo-selection logic across tissues incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[14,33]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,12,17]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[11,17,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,10,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,25,33]}],"complexes":["exocyst"],"partners":["RHO3","BEM1","ARPC (ARP2/3 COMPLEX)","GIV/CCDC88A","ESRP1","TC10/RHOQ","CDC42","NUP62"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UPT5","full_name":"Exocyst complex component 7","aliases":["Exocyst complex component Exo70"],"length_aa":735,"mass_kda":83.4,"function":"Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane. In adipocytes, plays a crucial role in targeting SLC2A4 vesicle to the plasma membrane in response to insulin, perhaps directing the vesicle to the precise site of fusion (By similarity). It is required for neuron survival and plays an essential role in cortical development (By similarity)","subcellular_location":"Cytoplasm, cytosol; Cell membrane; Midbody, Midbody ring","url":"https://www.uniprot.org/uniprotkb/Q9UPT5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EXOC7","classification":"Common Essential","n_dependent_lines":395,"n_total_lines":1208,"dependency_fraction":0.3269867549668874},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EXOC7","total_profiled":1310},"omim":[{"mim_id":"619076","title":"NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SEIZURES, AND BRAIN ATROPHY; NEDMISB","url":"https://www.omim.org/entry/619076"},{"mim_id":"619072","title":"NEURODEVELOPMENTAL DISORDER WITH SEIZURES AND BRAIN ATROPHY; NEDSEBA","url":"https://www.omim.org/entry/619072"},{"mim_id":"615283","title":"EXOCYST COMPLEX COMPONENT 8; EXOC8","url":"https://www.omim.org/entry/615283"},{"mim_id":"614117","title":"EXOCYST COMPLEX COMPONENT 3-LIKE 1; EXOC3L1","url":"https://www.omim.org/entry/614117"},{"mim_id":"611999","title":"RAB11 FAMILY-INTERACTING PROTEIN 4; RAB11FIP4","url":"https://www.omim.org/entry/611999"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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  \"year\": 2007,\n      \"finding\": \"The C-terminal Domain D of Exo70 directly interacts with phosphatidylinositol 4,5-bisphosphate (PI4,5P2), and key residues critical for this interaction were identified by mutagenesis. The interaction of Exo70 with phospholipids (but not Rho3) is essential for membrane association of the exocyst complex, anchoring it to the plasma membrane in concert with Sec3.\",\n      \"method\": \"In vitro lipid-binding assay, site-directed mutagenesis, genetic and cell biological analyses in yeast\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct lipid-binding assay with mutagenesis of key residues plus genetic epistasis, replicated with multiple orthogonal methods in one study\",\n      \"pmids\": [\"17717527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In budding yeast, Exo70p (together with Sec3p) is stably associated with exocytic sites at the plasma membrane independently of actin cables, while other exocyst subunits arrive on secretory vesicles. Exocyst assembly occurs when vesicle-borne subunits join Exo70p and Sec3p at the plasma membrane to tether vesicles.\",\n      \"method\": \"FRAP (fluorescence recovery after photobleaching), immunogold electron microscopy, epifluorescence video microscopy, actin disruption experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal imaging methods (FRAP, EM, live video) with pharmacological perturbation, replicated across several exocyst subunits\",\n      \"pmids\": [\"15583031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Yeast Rho3 GTPase directly interacts with Exo70 in a GTP-dependent manner (GTPγS-bound Rho3 binds more efficiently than GDP-bound), as shown by yeast two-hybrid and in vitro pulldown with purified proteins. Rho3 and Exo70 co-localize at the bud tip, and dominant-active Rho3 alters Exo70 localization.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay with purified proteins, GTP/GDP loading, indirect immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution with purified proteins plus GTP-dependence assay, corroborated by localization studies\",\n      \"pmids\": [\"10207081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The exocyst component Exo70 directly interacts with the Arp2/3 complex. This interaction is regulated by EGF signalling. Inhibition of Exo70 by RNAi or antibody microinjection blocks formation of actin-based membrane protrusions and impairs cell motility.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, antibody microinjection, cell migration assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus two independent loss-of-function approaches (RNAi and antibody microinjection) with defined cellular phenotypes\",\n      \"pmids\": [\"17086175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of yeast Exo70p at 2.0 Å resolution reveals a ~160 Å-long rod composed of contiguous alpha-helical bundles (novel fold). The C-terminal domains interact with other exocyst subunits and Rho3p GTPase. Exo84p C-terminal domains share the same fold as the Exo70p N-terminus, suggesting a common helical module architecture for exocyst subunits.\",\n      \"method\": \"X-ray crystallography (2.0 Å resolution), structural interaction analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at high resolution with experimental validation of protein interactions\",\n      \"pmids\": [\"16249794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of S. cerevisiae Exo70p at 3.5 Å resolution reveals an extended rod (~155 Å) composed principally of alpha helices. Exo70p binds Rho3p in a GTP-dependent manner with a Kd of ~70 µM.\",\n      \"method\": \"X-ray crystallography (3.5 Å), equilibrium binding assay (Kd determination)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with quantitative binding measurement, independent corroboration of Rho3-binding from another lab\",\n      \"pmids\": [\"16359701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ERK1/2 directly phosphorylate the exocyst component Exo70. This phosphorylation enhances binding of Exo70 to other exocyst components and promotes exocyst complex assembly in response to EGF signalling. An Exo70 phosphorylation-defective mutant inhibits exocytosis, and in tumor cells blocks matrix metalloproteinase secretion and invadopodia formation.\",\n      \"method\": \"In vitro kinase assay, phosphorylation-defective mutant expression, Co-immunoprecipitation, exocytosis assay, invadopodia assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay establishing direct phosphorylation, plus mutant rescue experiment and multiple cellular phenotype readouts\",\n      \"pmids\": [\"22595671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Exo70 induces negative membrane curvature through an oligomerization-based mechanism. Exo70 generates tubular invaginations in synthetic vesicles in vitro and produces membrane protrusions on cell surfaces. The membrane-deformation function, validated by Exo70 mutants and molecular dynamics simulations, is required for protrusion formation and directional cell migration.\",\n      \"method\": \"In vitro liposome tubulation assay, Exo70 mutagenesis, molecular dynamics simulation, cell protrusion and migration assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution with liposomes, structural mutagenesis, independent computational validation, and cellular phenotype assays\",\n      \"pmids\": [\"23948253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Exo70 functions as a kinetic activator of the Arp2/3 complex, promoting actin filament nucleation and branching by facilitating the interaction of Arp2/3 with the nucleation-promoting factor WAVE2. This activity is required for lamellipodia formation and directional persistence of cell migration.\",\n      \"method\": \"In vitro actin polymerization assay, TIRF microscopy, Co-immunoprecipitation, cell migration assays with Exo70 knockdown\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of Arp2/3 activation, TIRF single-filament imaging, and cellular loss-of-function phenotypes\",\n      \"pmids\": [\"22748316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"During epithelial-mesenchymal transition, Exo70 undergoes isoform switching regulated by the splicing factor ESRP1. The mesenchymal (but not epithelial) isoform of Exo70 interacts with the Arp2/3 complex and stimulates actin polymerization for tumor invasion. The epithelial isoform affects levels of EMT transcription factors Snail and ZEB2 and drives epithelial phenotypes.\",\n      \"method\": \"RNA isoform analysis, Co-immunoprecipitation, actin polymerization assay, cell invasion assays, mouse tumor metastasis model\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific Co-IP with Arp2/3, actin assay, and in vivo metastasis model with multiple orthogonal methods\",\n      \"pmids\": [\"24331928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ULK1 directly phosphorylates Exo70, and this phosphorylation inhibits Exo70 homo-oligomerization and its assembly into the exocyst complex, suppressing cell protrusion formation and MMP secretion during invasion. EGF stimulation causes ERK1/2 to phosphorylate Exo70 at a different site, which counteracts ULK1 phosphorylation—defining two opposing regulatory modifications.\",\n      \"method\": \"In vitro kinase assay, phosphorylation-site mutagenesis, oligomerization assay, Co-immunoprecipitation, cell invasion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro phosphorylation assay, mutagenesis of phospho-sites, functional cellular phenotypes with multiple orthogonal assays\",\n      \"pmids\": [\"31913283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TC10 GTPase activates and triggers translocation of Exo70 to the plasma membrane in the distal axon and growth cone in response to IGF-1. TC10 and Exo70 function are both necessary for membrane addition and axon elongation stimulated by IGF-1, and for polarized insertion of the IGF-1 receptor to establish neuronal polarity.\",\n      \"method\": \"siRNA knockdown of TC10 and Exo70, dominant-negative expression, subcellular fractionation, immunofluorescence in cultured hippocampal neurons and isolated growth cones\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent loss-of-function approaches (siRNA and dominant-negative) with specific readouts in primary neurons\",\n      \"pmids\": [\"19846717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Exo70p selectively mediates secretion of the Bgl2p class of post-Golgi vesicles in budding yeast, with secretion defect most pronounced at early stages of the cell cycle (early budding stage), affecting daughter cell growth. The block occurs at the tethering step, not vesicle formation or cargo sorting.\",\n      \"method\": \"Yeast genetics with exo70 mutants, secretion assays for Bgl2p vs. invertase vesicles, cell biological analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined vesicle-class selectivity with genetic mutants and secretion assays, single lab\",\n      \"pmids\": [\"17339375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Type Iγ PI4P 5-kinase (PIPKIγ) directly interacts with Exo70 and mediates association between E-cadherin and Exo70. PIPKIγ-generated PI4,5P2 recruits Exo70 to nascent E-cadherin junctions, and Exo70 is required for E-cadherin clustering and maturation of adherens junctions.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assay, siRNA knockdown, fluorescence microscopy of E-cadherin junctions\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus direct binding plus loss-of-function with defined adhesion phenotype, single lab\",\n      \"pmids\": [\"22049025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BIG2 (a brefeldin A-inhibited ARF guanine nucleotide-exchange protein) interacts with the N-terminal portion (aa 1–643) of human Exo70. Endogenous BIG2 and Exo70 co-localize at trans-Golgi network membranes and at the MTOC/centrosomes in HepG2 cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation of in vitro-translated proteins, immunofluorescence confocal microscopy, centrosome purification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid confirmed by co-IP and localization, single lab, multiple methods\",\n      \"pmids\": [\"15705715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Snapin interacts with the Exo70 subunit of the exocyst via an N-terminal coiled-coil domain of Exo70 and a C-terminal helical region of Snapin. Exo70 competes with SNAP23 for Snapin binding. Snapin depletion by RNAi inhibits insulin-stimulated glucose uptake in adipocytes, modulating GLUT4 vesicle trafficking.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, RNAi knockdown, glucose uptake assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with domain mapping plus functional RNAi phenotype, single lab\",\n      \"pmids\": [\"17947242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Exo70 (Exo70-N mutant) induces insulin-independent tethering of GLUT4 vesicles to the plasma membrane in primary adipocytes, but this tethering does not lead to vesicle fusion without insulin. Insulin regulates the fusion step downstream of Exo70-mediated tethering.\",\n      \"method\": \"Total internal reflection fluorescence microscopy of GLUT4 vesicle dynamics, Exo70 overexpression and dominant mutant expression in primary adipocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct TIRF imaging of tethering and fusion events with defined mutant, single lab\",\n      \"pmids\": [\"19155211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Inducible knockout of Exoc7/Exo70 in adipocytes markedly inhibits insulin-stimulated GLUT4 exocytosis without affecting insulin signaling, establishing that the exocyst (via Exo70) is required for the tethering/fusion step of GLUT4 vesicle exocytosis.\",\n      \"method\": \"CRISPR-based inducible adipocyte-specific Exoc7 knockout, GLUT4 translocation assay, insulin signaling assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with direct GLUT4 exocytosis readout and signal pathway controls, genome-scale CRISPR screen corroboration\",\n      \"pmids\": [\"31740584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Exo70 directly interacts with nucleoporin Nup62 via the N-terminal domain of Exo70. Exo70 recruits Nup62 to the leading edge of migrating cells and to filopodia. RNAi knockdown of Nup62 significantly reduces cell migration, and removal of the Exo70-binding domain from Nup62 prevents its leading-edge localization.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, RNAi knockdown, fluorescence microscopy, cell migration assay\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct interaction mapping with Co-IP, RNAi phenotype, and localization assay, single lab\",\n      \"pmids\": [\"19552648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Domain C of yeast Exo70p is required for actin-independent localization to exocytic sites and for assembly of exocyst components Sec5p and Sec6p. Deletion of domain C causes synthetic lethality with secretory mutations. The actin-independent localization requires a synergistic interaction with PI(4,5)P2 in addition to domain C.\",\n      \"method\": \"Yeast genetics, domain deletion analysis, synthetic lethality screening, exocyst assembly assay, fluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain deletion with genetic interaction mapping and assembly assays, single lab\",\n      \"pmids\": [\"18946089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Yeast Exo70p directly and specifically binds the polarity scaffold Bem1p through multiple domains of both proteins. Mutations in Exo70p that disrupt the Bem1p interaction without impairing other interactions abolish actin-independent localization of Exo70p to exocytic sites. Actin-independent localization requires both Bem1p interaction and PI(4,5)P2.\",\n      \"method\": \"In vitro binding assay (direct binding), Co-immunoprecipitation, mutagenesis, fluorescence microscopy, synthetic genetic analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay plus separation-of-function mutants plus genetic epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"25313406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Exo70 directly interacts with the spliceosomal protein SNEV (hPrp19/hPso4), shuttles to the nucleus, and associates with the spliceosome. The N-terminal 100 amino acids of Exo70 mediate the interaction and interfere with pre-mRNA splicing in vitro. Exo70 influences splicing of a model substrate and of its own pre-mRNA in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in vitro splicing assay, nuclear fractionation, domain mapping, in vivo splicing assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vitro splicing assay plus Co-IP and domain mapping, single lab\",\n      \"pmids\": [\"21639856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TC10 GTP hydrolysis near the plasma membrane promotes neurite outgrowth by releasing Exo70 to facilitate fusion of Rab11- and L1-containing recycling vesicles. FRET-based biosensors showed that TC10 activity decreases at extending growth cones, and constitutively active TC10 could not rescue neurite outgrowth defects caused by TC10 depletion.\",\n      \"method\": \"FRET-based GTPase activity biosensors, TC10 knockdown, constitutively-active TC10 rescue, colocalization analysis, exocytosis assay in PC12 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET biosensors plus knockdown rescue experiments with defined vesicle cargo, single lab\",\n      \"pmids\": [\"24223996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NGF induces an interaction between activated TC10 and Exo70 in PC12 cells (detected by FRET/FLIM). The Exo70-TC10 complex locally antagonizes NGF-induced Cdc42-dependent activation of N-WASP at membrane protrusions. Exo70 is responsible for correct targeting of the complex to protrusion sites.\",\n      \"method\": \"FRET imaging by fluorescence lifetime microscopy (FLIM), dominant-negative mutants, siRNA knockdown, constitutively-active Cdc42 overexpression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET/FLIM-based interaction detection in living cells plus functional rescue/knockdown experiments, single lab\",\n      \"pmids\": [\"17635999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GIV/Girdin directly and constitutively binds Exo70 (exocyst subunit). Upon insulin stimulation, GIV associates with GLUT4-storage vesicles. Loss of GIV or its GEF function impairs membrane association of Exo70 and exocytosis of GLUT4 vesicles in response to insulin.\",\n      \"method\": \"In vitro direct binding assay, Co-immunoprecipitation, vesicle fractionation, GLUT4 exocytosis assay with GIV knockdown/GEF mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct binding with functional loss-of-function assay, single lab\",\n      \"pmids\": [\"26514725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In zebrafish, exoc7 loss-of-function causes microcephaly, demonstrating an essential role for EXOC7 in cerebral cortical development. In humans, partial loss-of-function variants in EXOC7 cause brain atrophy, seizures, and developmental delay.\",\n      \"method\": \"Zebrafish exoc7 knockout, in vitro EXOC7 splice-variant modeling, human genetic mapping (homozygosity mapping + exome sequencing)\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish KO with defined morphological phenotype plus human genetic variants modeled in vitro, single study\",\n      \"pmids\": [\"32103185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EXO70 protein promotes dengue virus secretion/egression from infected cells. EXO70 knockdown significantly attenuates dengue virus production without affecting viral transcription or translation, indicating a specific role in virus exocytosis.\",\n      \"method\": \"siRNA knockdown, viral titer assay, viral RNA/protein quantification\",\n      \"journal\": \"Microbes and infection\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — siRNA knockdown with specific step-dissection showing no effect on replication but effect on egression, single lab\",\n      \"pmids\": [\"21034848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In C. elegans, exoc-7 (exo70) and exoc-8 (exo84) mutants show pleiotropic behavioral defects. exoc-8 and exoc-7;exoc-8 double mutations cause increased size of rab-10 RNAi-induced endocytic vacuoles in intestinal epithelia and affect RAB-10 expression and endocytic marker accumulation, linking Exo70 to RAB-10-dependent endosomal trafficking.\",\n      \"method\": \"C. elegans genetic mutant analysis, targeted RNAi screen for small GTPases, fluorescence microscopy of endocytic markers\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with targeted RNAi screen and multiple marker readouts, single lab\",\n      \"pmids\": [\"22389680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Drosophila, Exo70 is required for synaptic growth at the neuromuscular junction (NMJ). exo70 genetically interacts with the small GTPase ralA to regulate synaptic growth. Loss of Exo70 impairs integral membrane protein transport to the cell surface at synaptic terminals and blocks JNK signaling-, activity-, and temperature-induced synaptic outgrowths.\",\n      \"method\": \"Drosophila exo70 mutant alleles, genetic interaction (double mutant) with ralA, electrophysiology (mEPSP), immunofluorescence, membrane protein trafficking assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent mutant alleles with genetic epistasis, electrophysiology, and trafficking assays, single lab\",\n      \"pmids\": [\"30209205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Transglutaminases TGM1 and TGM3 transamidate Exo70 on Gln5 with Lys56 of cystatin A, promoting Exo70 association with other exocyst subunits and enhancing MMP secretion, invadopodia formation, and integrin delivery to the leading edge. Tumor suppressor LKB1 phosphorylates TGM1 (Thr386) and TGM3 (Thr282) to inhibit their interaction with Exo70 and block transamidation. The FDA-approved drug cantharidin inhibits Exo70 transamidation and suppresses tumor cell migration.\",\n      \"method\": \"Mass spectrometry identification of modification sites, site-directed mutagenesis, in vitro transamidation assay, kinase assay, Co-immunoprecipitation, invasion and invadopodia assays, in vivo tumor model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — PTM identified by MS, validated by mutagenesis and in vitro assay, upstream kinase (LKB1) mechanism defined, multiple cellular phenotype readouts\",\n      \"pmids\": [\"39146185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Exo70 promotes cisplatin efflux from epithelial ovarian cancer cells through exocytosis, contributing to cisplatin resistance. Cisplatin-induced autophagy-lysosomal degradation of Exo70 is modulated by AMPK/mTOR phosphorylation. Knockdown of Exo70 or inhibition with ES2 reverses cisplatin resistance both in vitro and in vivo.\",\n      \"method\": \"Exo70 knockdown, ES2 inhibitor treatment, cisplatin efflux/uptake assay, autophagy pathway analysis (AMPK/mTOR phosphorylation), in vivo xenograft model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional exocytosis assay of cisplatin efflux with knockdown and inhibitor, in vivo validation, single lab\",\n      \"pmids\": [\"34298686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Exoc7/Exo70 opposes Prpf19/prp19 in regulating expanded ATXN3-polyQ protein toxicity in SCA3 models. Exoc7/exo70 modulates expanded ATXN3-polyQ levels by regulating the E3 ligase function of Prpf19, counteracting polyubiquitination and degradation of mutant ATXN3.\",\n      \"method\": \"Mammalian cell transfection, Drosophila disease model, ubiquitination assay, protein level analysis, genetic interaction\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic interaction in two model systems with mechanistic assays for ubiquitination, single lab\",\n      \"pmids\": [\"33542212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Following mild traumatic brain injury in mice, Exo70 redistributes from the microsomal fraction into the synaptic compartment. Exocyst complex assembly and its interaction with GluN2B (NMDA receptor subunit) increase in the synaptic compartment after brain trauma.\",\n      \"method\": \"Subcellular fractionation, Co-immunoprecipitation, mouse repeated mTBI model\",\n      \"journal\": \"Biological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — subcellular fractionation with Co-IP showing interaction change, single lab, one model system\",\n      \"pmids\": [\"33593425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The brain-specific Cdc42b isoform (but not ubiquitous Cdc42u) interacts with Exo70 and regulates exocytosis of post-Golgi vesicles in the axonal growth cone to promote axon formation. Inactivation of Arhgef7 (activator of Cdc42b) or Cdc42b interferes with this exocytosis. Mammalian Cdc42u does not interact with Exo70.\",\n      \"method\": \"Co-immunoprecipitation of Cdc42 isoforms with Exo70, live-cell imaging of post-Golgi vesicle exocytosis, siRNA knockdown, dominant-negative expression\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP showing isoform specificity plus functional exocytosis assay with loss-of-function, single lab\",\n      \"pmids\": [\"36543541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GIV/Girdin fulfills the function of yeast Bem1p as a polarity scaffold for Exo70 in mammalian cells; both bind Exo70 via similar short-linear interaction motifs and each prefers its evolutionary counterpart. Selective disruption of the GIV-Exo70 interaction blocks delivery of MT1-MMP to invadosomes and impairs collagen degradation.\",\n      \"method\": \"Co-immunoprecipitation, motif-based interaction assay, MT1-MMP trafficking assay, collagen degradation assay, haptotaxis assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with functional disruption experiment and defined cargo-delivery phenotype, single lab\",\n      \"pmids\": [\"32590327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kinase suppressor of Ras 1 (KSR1) promotes fatty acid-stimulated neurotensin secretion via ERK1/2 signaling, which acts through Exo70. Inhibition of Exo70 potently inhibits basal and docosahexaenoic acid-stimulated neurotensin secretion from human endocrine cells, while Exo70 overexpression enhances it.\",\n      \"method\": \"Exo70 knockdown and overexpression, neurotensin secretion assay, ERK inhibitor treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown and overexpression with secretion assay, no mechanistic dissection of Exo70's direct role, single lab\",\n      \"pmids\": [\"30917119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Exo70 redistributes from microsomes to synaptic compartment and increases interaction with GluN2B after mTBI. Exo70 overexpression in CA1 pyramidal neurons via lentiviral transduction prevented mTBI-induced cognitive impairment, preserved synaptic GluN2B-containing NMDARs, and maintained downstream signaling, suggesting Exo70 regulates NMDAR trafficking at synapses.\",\n      \"method\": \"Lentiviral Exo70 overexpression in vivo, Morris water maze, electrophysiology (synaptic transmission and LTP), GluN2B co-immunoprecipitation, mouse mTBI model\",\n      \"journal\": \"Antioxidants\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with cognitive and electrophysiological phenotype readouts plus molecular interaction data, single lab\",\n      \"pmids\": [\"40563275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cytoplasmic METTL3 interacts with EXOC7, promoting EXOC7 stabilization. METTL3 knockdown impairs vesicle trafficking and breast cancer secretome, impairs invadopodia formation and collagen invasion independently of METTL3's catalytic activity, implicating METTL3-mediated stabilization of EXOC7 as a non-catalytic mechanism.\",\n      \"method\": \"Co-immunoprecipitation of METTL3 and EXOC7, METTL3 knockdown, catalytic-dead METTL3 mutant rescue, vesicle trafficking assay, invasion assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with functional knockdown data but preprint, single lab, catalytic mutant rescue not fully mechanistically resolved\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"EXOC7/Exo70 is a multifunctional subunit of the octameric exocyst tethering complex that anchors the complex to the plasma membrane through direct binding to PI4,5P2 (via its C-terminal domain D) and polarity scaffolds (Bem1p in yeast; GIV/Girdin in mammals), rides independently of actin to exocytic sites, and tethers post-Golgi secretory vesicles for SNARE-mediated fusion; beyond exocytosis, Exo70 directly activates the Arp2/3 complex (facilitated by WAVE2) to drive actin branching and membrane protrusion for cell migration, undergoes isoform switching during EMT to regulate tumor invasion, and is post-translationally regulated by ERK1/2 phosphorylation (promoting exocyst assembly), ULK1 phosphorylation (inhibiting oligomerization and assembly), and TGM1/3 transamidation (promoting exocyst assembly and MMP secretion), with upstream control by small GTPases TC10 and Cdc42b in neurons to coordinate membrane expansion during axon formation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EXOC7/Exo70 is a subunit of the octameric exocyst tethering complex that captures post-Golgi secretory vesicles at the plasma membrane for SNARE-mediated fusion, and which doubles as a direct effector of actin remodeling during cell migration [#1, #3, #12]. Exo70 anchors the exocyst to the plasma membrane through direct binding of its C-terminal Domain D to PI(4,5)P2, an interaction essential for exocyst membrane association and, together with Domain C, for actin-independent localization of Exo70 to exocytic sites [#0, #19]. Crystal structures reveal an extended ~160 Å rod of contiguous alpha-helical bundles whose C-terminal modules mediate binding to other exocyst subunits and to the GTP-loaded Rho3 GTPase [#4, #5, #2]; in yeast this membrane targeting also requires the polarity scaffold Bem1p, a role fulfilled in mammalian cells by GIV/Girdin [#20, #34]. Beyond tethering, Exo70 acts as a kinetic activator of the Arp2/3 complex by facilitating its engagement with WAVE2 to drive actin branching, and independently deforms membranes into negative curvature via oligomerization to build protrusions and direct cell migration [#8, #7, #3]. Exo70 function is gated by opposing post-translational modifications: ERK1/2 phosphorylation and TGM1/3 transamidation each promote exocyst assembly and MMP/invadopodia-driven invasion, whereas ULK1 phosphorylation inhibits Exo70 oligomerization and assembly [#6, #29, #10]. Exocyst-mediated trafficking through Exo70 is required for insulin-stimulated GLUT4 exocytosis in adipocytes, for axon and neurite outgrowth downstream of TC10 and the brain-specific Cdc42b GTPase, and for E-cadherin junction maturation [#17, #11, #33, #13]. An EMT-associated isoform switch controlled by ESRP1 partitions these activities between epithelial and invasive mesenchymal programs [#9]. Loss-of-function variants in EXOC7 cause brain atrophy, seizures, and developmental delay, with zebrafish exoc7 loss producing microcephaly [#25].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that a small GTPase directly engages Exo70 placed the protein within polarized GTPase signaling rather than being a passive structural subunit.\",\n      \"evidence\": \"Yeast two-hybrid and in vitro pulldown with purified Rho3, with GTP/GDP loading and localization in budding yeast\",\n      \"pmids\": [\"10207081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the membrane-targeting determinants of Exo70\", \"Functional consequence of Rho3 binding for vesicle tethering not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Live imaging answered how the exocyst assembles by showing Exo70 marks the plasma-membrane landmark to which vesicle-borne subunits dock, defining a spatial logic for tethering.\",\n      \"evidence\": \"FRAP, immunogold EM, and live video microscopy with actin disruption in budding yeast\",\n      \"pmids\": [\"15583031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of actin-independent membrane anchoring not yet identified\", \"Mechanism of vesicle subunit recruitment unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"High-resolution structures defined the Exo70 fold as an extended alpha-helical rod, providing the architecture for its subunit and GTPase contacts.\",\n      \"evidence\": \"X-ray crystallography of yeast Exo70p at 2.0 Å and 3.5 Å with Rho3 binding (Kd ~70 µM) and interaction mapping\",\n      \"pmids\": [\"16249794\", \"16359701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the assembled exocyst octamer\", \"Lipid-binding surface not localized structurally at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery of a direct Exo70–Arp2/3 interaction revealed a tethering subunit doubling as an actin-cytoskeleton regulator, linking secretion machinery to motility.\",\n      \"evidence\": \"Co-IP, RNAi knockdown, antibody microinjection, and cell migration assays under EGF signaling\",\n      \"pmids\": [\"17086175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether Arp2/3 regulation is separable from exocyst tethering\", \"Biochemical mechanism of Arp2/3 modulation not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying Domain D–PI(4,5)P2 binding answered how Exo70 anchors the exocyst to the plasma membrane independently of GTPases.\",\n      \"evidence\": \"In vitro lipid-binding assay, site-directed mutagenesis, and genetic/cell biology in yeast; vesicle-class selectivity defined by exo70 mutants\",\n      \"pmids\": [\"17717527\", \"17339375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How lipid binding cooperates with protein landmarks for site selection not fully resolved\", \"Vesicle-class selectivity mechanism (Bgl2p vs invertase) single-lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linking TC10 GTPase to Exo70 translocation defined an upstream signaling input driving polarized membrane addition during axon formation.\",\n      \"evidence\": \"siRNA and dominant-negative TC10/Exo70, subcellular fractionation, and imaging in primary hippocampal neurons and growth cones (IGF-1 stimulation)\",\n      \"pmids\": [\"19846717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface between TC10 and Exo70 not mapped\", \"Coupling to specific cargo at growth cone not yet defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two studies resolved opposing biochemical roles in actin and assembly: Exo70 kinetically activates Arp2/3 via WAVE2, and ERK1/2 phosphorylation promotes exocyst assembly for secretion and invasion.\",\n      \"evidence\": \"In vitro actin polymerization and TIRF single-filament imaging; in vitro kinase assay with phospho-defective mutant and invadopodia/exocytosis readouts\",\n      \"pmids\": [\"22748316\", \"22595671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How actin-nucleation and tethering activities are temporally coordinated unclear\", \"ERK1/2 phospho-site relationship to other PTMs not yet defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mechanistic and isoform studies established that Exo70 directly deforms membranes by oligomerization and that an ESRP1-controlled isoform switch routes its activities into invasion versus epithelial programs.\",\n      \"evidence\": \"Liposome tubulation, mutagenesis, MD simulation, migration assays; RNA isoform analysis, isoform-specific Co-IP with Arp2/3, and mouse metastasis model\",\n      \"pmids\": [\"23948253\", \"24331928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between curvature generation and Arp2/3 activation not integrated\", \"Epithelial isoform's effect on Snail/ZEB2 mechanism not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying ULK1 as an inhibitory kinase counteracting ERK1/2 defined a bidirectional phospho-switch governing Exo70 oligomerization and exocyst assembly.\",\n      \"evidence\": \"In vitro kinase assay, phospho-site mutagenesis, oligomerization and Co-IP assays, invasion assays\",\n      \"pmids\": [\"31913283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals selecting ULK1 versus ERK1/2 dominance not defined\", \"Quantitative stoichiometry of dual phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing GIV/Girdin as the mammalian Bem1p counterpart resolved how Exo70 is targeted by a polarity scaffold in metazoan cells, with direct relevance to MT1-MMP delivery.\",\n      \"evidence\": \"Motif-based interaction assay, Co-IP, and MT1-MMP trafficking/collagen degradation assays; complemented by yeast Bem1p direct-binding and separation-of-function mutants\",\n      \"pmids\": [\"32590327\", \"25313406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural detail of the GIV/Bem1p short-linear-motif interface limited\", \"In vivo requirement of GIV-Exo70 axis not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic evidence linked EXOC7 to human neurodevelopment, defining a Mendelian disease association.\",\n      \"evidence\": \"Zebrafish exoc7 loss-of-function (microcephaly), in vitro splice-variant modeling, and human homozygosity mapping with exome sequencing\",\n      \"pmids\": [\"32103185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular mechanism connecting exocyst defect to cortical phenotype not defined\", \"Single study; allelic series limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery of TGM1/3 transamidation as an assembly-promoting PTM, antagonized by LKB1 phosphorylation, added a covalent regulatory layer and a druggable node for invasion.\",\n      \"evidence\": \"MS site identification, mutagenesis, in vitro transamidation and kinase assays, invadopodia/invasion assays, in vivo tumor model, cantharidin inhibition\",\n      \"pmids\": [\"39146185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay of transamidation with phospho-switch not integrated\", \"Generality across non-tumor contexts untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct Exo70 activities — PI(4,5)P2 anchoring, vesicle tethering, Arp2/3 activation, and membrane curvature generation — are integrated and switched in space and time by its overlapping PTM and GTPase inputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model coupling tethering and actin functions\", \"Crosstalk among ERK1/2, ULK1, and TGM1/3 modifications in vivo undefined\", \"Cargo-selection logic across tissues incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [14, 33]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 12, 17]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [11, 17, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 10, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 25, 33]}\n    ],\n    \"complexes\": [\"exocyst\"],\n    \"partners\": [\"RHO3\", \"BEM1\", \"ARPC (Arp2/3 complex)\", \"GIV/CCDC88A\", \"ESRP1\", \"TC10/RHOQ\", \"CDC42\", \"NUP62\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}