{"gene":"PREX2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2004,"finding":"PREX2 (P-Rex2) is a guanine-nucleotide exchange factor (GEF) that activates the small GTPase Rac and is regulated by phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and Gβγ subunits of heterotrimeric G proteins in vitro and in vivo.","method":"In vitro GEF assay, in vivo functional assays; cloning from human skeletal muscle and brain libraries","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — two independent papers (PMID:15304343 and PMID:15304342) simultaneously reported GEF activity and PIP3/Gβγ regulation using in vitro assays, replicated across two labs","pmids":["15304343","15304342"],"is_preprint":false},{"year":2013,"finding":"P-REX2 inhibits PTEN through two interfaces: the PH domain of P-REX2 inhibits PTEN by interacting with its catalytic region, while the inositol polyphosphate 4-phosphatase (IP4P) domain of P-REX2 provides high-affinity binding to the PDZ-binding domain of PTEN. P-REX2 inhibition of PTEN requires C-terminal phosphorylation of PTEN to release the P-REX2 PH domain from its neighboring DH domain.","method":"Domain-mapping biochemical assays, deletion constructs, phosphorylation site analysis; Prex2 knockout mice showing increased Pten activity and decreased insulin signaling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (domain deletion, mutagenesis, knockout mouse model with defined metabolic phenotype) in a single rigorous study","pmids":["24367090"],"is_preprint":false},{"year":2015,"finding":"PTEN inhibits PREX2 GEF activity toward RAC1, thereby suppressing cell migration and invasion. This inhibition requires the tail domain of PTEN but not its lipid phosphatase activity. Cancer-derived somatic PREX2 mutants are resistant to PTEN-mediated inhibition of invasion and either escape PTEN binding or are not blocked in their GEF activity by PTEN.","method":"Fluorescent nucleotide exchange assays (in vitro GEF assay), mouse embryonic fibroblasts, breast cancer cell line invasion assays, domain deletion/mutant analysis","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro GEF activity assay with mutagenesis, multiple cell line models, and cancer mutant characterization in a single study","pmids":["25829446"],"is_preprint":false},{"year":2015,"finding":"PAK kinases phosphorylate PREX2 following Rac1 activation, creating a negative feedback loop. PAK-mediated phosphorylation of PREX2 reduces its GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ, and also prevents PREX2 from localizing to the cellular membrane.","method":"In vitro GEF assays, mass spectrometry phosphorylation mapping, cell fractionation, insulin stimulation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — phosphorylation mapped by MS, GEF activity assay, membrane localization by fractionation, multiple orthogonal methods in single study","pmids":["26438819"],"is_preprint":false},{"year":2008,"finding":"P-Rex2 is specifically expressed in Purkinje neurons of the cerebellum and is required for Purkinje cell dendrite morphology and motor coordination. P-Rex2 knockout mice show thinned main dendrites in Purkinje cells, progressive motor coordination defects, and double P-Rex1/P-Rex2 knockout mice are ataxic.","method":"P-Rex2 knockout mouse generation and analysis, Purkinje cell morphology imaging, behavioral motor coordination tests","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse model with defined cellular (dendrite morphology) and behavioral phenotypes, multiple genetic models (single and double KO)","pmids":["18334636"],"is_preprint":false},{"year":2021,"finding":"The PTEN:P-Rex2 complex is assembled via PDZ-interacting motif in the PTEN C-terminal tail binding to the second PDZ domain of P-Rex2, bridging PTEN across the P-Rex2 surface to block PI(3,4,5)P3 hydrolysis. Conversely, PTEN allosterically promotes an autoinhibited conformation of P-Rex2 and blocks its binding to Gβγ. Cancer-associated PTEN-deactivating mutations combined with P-Rex2 truncations drive Rac1 activation to a greater extent than either single variant alone.","method":"Cross-linking mass spectrometry, functional GEF assays, domain mutant analysis","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — cross-linking MS structural analysis combined with functional assays and cancer mutant characterization in a single rigorous study","pmids":["33947796"],"is_preprint":false},{"year":2017,"finding":"GNMT interacts with PREX2 and promotes its degradation through an E3 ligase HectH9-mediated proteasomal ubiquitination pathway. Depletion of GNMT or HectH9 results in AKT activation in a PREX2-dependent manner.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, siRNA knockdown, GNMT knockout mice","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and knockout mouse model, multiple orthogonal methods but single lab","pmids":["28205209"],"is_preprint":false},{"year":2018,"finding":"The crystal structure of the P-Rex2 PH domain at 1.9 Å resolution reveals conformational differences in loop regions compared to P-Rex1. Biochemical studies show the P-Rex2 PH domain binds PIP3 similarly to P-Rex1; binding is critical for P-Rex2 activity but not for membrane localization.","method":"X-ray crystallography (1.9 Å), biochemical PIP3 binding assays","journal":"Journal of structural biology: X","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with biochemical functional validation of PIP3 binding, single lab but rigorous structural/biochemical methods","pmids":["34958187"],"is_preprint":false},{"year":2026,"finding":"Cryo-EM structure of full-length P-Rex2 reveals that, while overall similar to P-Rex1, there is a substantial repositioning of the N-terminal module relative to the C-terminal core, potentially precluding intramolecular autoinhibitory interactions seen in P-Rex1. HDX-MS shows P-Rex2 dynamics are unaffected by IP4 (PIP3 headgroup), unlike P-Rex1, suggesting a different autoinhibition mechanism.","method":"Cryo-EM (moderate resolution), hydrogen-deuterium exchange mass spectrometry (HDX-MS), SEC-SAXS, biochemical GEF assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure combined with HDX-MS and biochemical assays, multiple orthogonal structural/biophysical methods in a single study","pmids":["42248461"],"is_preprint":false},{"year":2012,"finding":"Ectopic expression of mutant PREX2 accelerates tumor formation of immortalized human melanocytes in vivo, establishing PREX2 as a functionally relevant mutated gene in melanoma. PREX2 was identified as a PTEN-interacting protein and negative regulator of PTEN.","method":"Whole-genome sequencing of 25 melanomas; in vivo xenograft tumor formation assay with mutant PREX2-expressing melanocytes","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo tumor formation established oncogenic function, but the key experiment was not reproduced in a subsequent replication study (PMID:28100394)","pmids":["22622578"],"is_preprint":false},{"year":2016,"finding":"Truncating PREX2 mutations activate its RAC1 guanine nucleotide exchanger activity, leading to increased PI3K/AKT signaling and enhanced cell proliferation.","method":"GEF activity assays with truncation mutants, AKT phosphorylation readout, cell proliferation assays","journal":"Molecular & cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — GEF assay with mutants and downstream signaling readout, single lab, review/commentary format with limited methodological detail","pmids":["27314100"],"is_preprint":false},{"year":2019,"finding":"The PREX2 somatic mutation S1113R (identified in HCC) impairs HectH9-mediated ubiquitination of PREX2, resulting in extended protein half-life and enhanced protein stability, and promotes cell migration and AKT pathway activation.","method":"Protein stability/half-life assays (cycloheximide chase), ubiquitination assay, cell migration assay, AKT phosphorylation analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays (protein stability, ubiquitination, migration, signaling) in a single study, single lab","pmids":["30796242"],"is_preprint":false},{"year":2020,"finding":"CELF2 interacts with PREX2 and reduces the association of PREX2 with PTEN, thereby upregulating PTEN phosphatase activity and suppressing AKT phosphorylation and cell proliferation.","method":"Co-immunoprecipitation (CELF2-PREX2 interaction), PTEN phosphatase activity assay, AKT phosphorylation analysis, CELF2 overexpression/knockdown, PDX tumor model","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and functional assays (PTEN activity, AKT phosphorylation) combined with in vivo PDX model, single lab","pmids":["31241130"],"is_preprint":false},{"year":2022,"finding":"P-Rex2 regulates GluR1-containing AMPA receptor trafficking and dendritic spine morphology via Rac1/pGluR1 pathway in dorsal horn neurons, contributing to bone cancer pain. P-Rex2 knockdown reduced spinal p-Rac1, p-GluR1, spine number, and reversed AMPAR-induced current in dorsal horn neurons.","method":"Intrathecal RNAi lentivirus injection, Western blot for p-Rac1/p-GluR1, spine density imaging, whole-cell patch clamp recording of AMPAR currents","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with electrophysiology and morphological readouts, multiple orthogonal methods, single lab","pmids":["35083941"],"is_preprint":false},{"year":2025,"finding":"AHCYL1 is a novel PREX2-interacting protein that enhances PREX2 GEF activity by alleviating the mutual inhibition between PREX2 and PTEN, thereby intensifying PREX2-driven Rac1 activation and tumor-promoting effects in NSCLC.","method":"Pull-down assay with LC-MS/MS (identification of AHCYL1), in vitro GEF assay, active Rac1 pull-down assay, Western blotting, CDX mouse model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel interactor identified by MS/pull-down, mechanistically validated by in vitro GEF assay and active Rac1 pull-down, single lab","pmids":["40365293"],"is_preprint":false},{"year":2025,"finding":"P-Rex2 suppresses glucose uptake into liver and skeletal muscle independently of its catalytic (GEF) activity, as shown using catalytically-inactive Prex2GD knock-in mice. In hepatocytes, P-Rex2 suppresses Glut2 cell-surface levels, mitochondrial membrane potential, and ATP production. P-Rex2 also suppresses insulin secretion by pancreatic islets. The orphan GPCR Gpr21 was identified as a P-Rex2 target, with P-Rex2 proposed to limit hepatic glucose clearance by controlling Gpr21 trafficking.","method":"Prex2 knockout and catalytically-inactive Prex2GD knock-in mice, glucose uptake assays, Glut2 surface localization assay, mitochondrial function assay, insulin secretion assay, GPCR trafficking studies","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — catalytically-inactive knock-in mouse distinguishes GEF-dependent vs. adaptor functions, multiple orthogonal cellular assays, clean genetic dissection","pmids":["40764335"],"is_preprint":false},{"year":2024,"finding":"PREX2 promotes radiation resistance in colorectal cancer by facilitating DNA repair through upregulation of DNA-PKcs and suppressing radiation-induced immunogenic cell death and CD8+ T cell infiltration via inhibition of the cGAS/STING/IFN signaling pathway.","method":"RNA-seq, Western blotting, colony formation assay, apoptosis assay, comet assay, xenograft tumor models, small-molecule PREX2 inhibitor (PREX-in1)","journal":"BMC medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo methods linking PREX2 to DNA-PKcs and cGAS/STING pathway, single lab","pmids":["38609982"],"is_preprint":false},{"year":2025,"finding":"Genetic loss of PREX2 in BRAF-mutant melanoma confers sensitivity to MAPK pathway inhibitors, and pharmacologic targeting of PI3Kβ (downstream of PREX2/RAC1) phenocopies PREX2 deficiency, establishing a druggable PREX2/RAC1/PI3Kβ signaling axis.","method":"Genetically engineered mouse models (PREX2 deletion), patient-derived BRAFV600E melanoma cell lines, pharmacologic PI3Kβ inhibition, MAPK inhibitor sensitivity assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacologic epistasis in mouse models and patient-derived lines, single lab, genetic and pharmacologic evidence convergent","pmids":["39636745"],"is_preprint":false},{"year":2026,"finding":"Cryo-EM structure of full-length P-Rex2 (preprint version) shows substantial repositioning of the N-terminal module relative to C-terminal core compared to P-Rex1; HDX-MS shows P-Rex2 is unaffected by IP4 unlike P-Rex1; biochemical assays indicate P-Rex2 may be more tightly regulated by autoinhibition via a mechanism divergent from P-Rex1.","method":"Cryo-EM, HDX-MS, SEC-SAXS, in vitro GEF assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous structural/biophysical methods but preprint, single lab; peer-reviewed version (PMID:42248461) independently confirms","pmids":["41542420"],"is_preprint":true}],"current_model":"PREX2 is a PIP3- and Gβγ-regulated guanine nucleotide exchange factor (GEF) for the small GTPase RAC1; it forms a mutually inhibitory complex with the tumor suppressor PTEN (anchored via its PDZ domain interactions), whereby PTEN allosterically autoinhibits PREX2 GEF activity and blocks Gβγ binding, while the PREX2 PH domain inhibits PTEN's lipid phosphatase activity; this complex is negatively regulated by PAK-mediated phosphorylation of PREX2 (feedback inhibition), by HectH9-mediated ubiquitin-proteasomal degradation (promoted by GNMT), and by CELF2 (which disrupts the PREX2-PTEN interaction); in addition to its catalytic role, PREX2 exerts GEF-independent adaptor functions in controlling glucose homeostasis (suppressing hepatic Glut2 surface levels and Gpr21 GPCR trafficking, and limiting skeletal muscle glucose uptake), and its specific expression in cerebellar Purkinje cells is required for normal dendrite morphology and motor coordination."},"narrative":{"mechanistic_narrative":"PREX2 (P-Rex2) is a phosphatidylinositol-(3,4,5)-trisphosphate (PIP3)- and Gβγ-regulated guanine nucleotide exchange factor (GEF) that activates the small GTPase Rac, coupling PI3K and G-protein signaling to Rac-dependent control of cell migration, proliferation, and tissue morphogenesis [PMID:15304343, PMID:15304342, PMID:25829446]. PREX2 engages the tumor suppressor PTEN in a mutually inhibitory complex: PTEN's C-terminal PDZ-binding motif binds the second PDZ domain of PREX2, bridging across the protein to block PIP3 hydrolysis, while PTEN reciprocally drives an autoinhibited PREX2 conformation and blocks Gβγ binding; PREX2 inhibition of PTEN requires PTEN C-terminal phosphorylation to release the PREX2 PH domain from its neighboring DH domain [PMID:24367090, PMID:33947796]. PIP3 binding through the PREX2 PH domain is critical for GEF activity, and full-length structural analysis shows PREX2 adopts an autoinhibition mechanism divergent from the related P-Rex1, with PIP3-headgroup-independent dynamics [PMID:34958187, PMID:42248461]. This complex is held under multiple layers of negative control: PAK kinases phosphorylate PREX2 downstream of Rac1 activation to form a feedback loop that impairs PIP3/Gβγ binding and membrane localization [PMID:26438819]; GNMT and the E3 ligase HectH9 drive ubiquitin-proteasomal degradation of PREX2 [PMID:28205209]; and CELF2 disrupts the PREX2-PTEN interaction to restore PTEN phosphatase activity [PMID:31241130]. Cancer-associated PREX2 truncations and somatic mutations escape PTEN-mediated inhibition or HectH9-mediated degradation, hyperactivating Rac1 and PI3K/AKT signaling to promote invasion, proliferation, and tumorigenesis [PMID:25829446, PMID:33947796, PMID:30796242]. Beyond its catalytic role, PREX2 exerts GEF-independent adaptor functions in glucose homeostasis, suppressing hepatic Glut2 surface levels, mitochondrial function, islet insulin secretion, and Gpr21 GPCR trafficking [PMID:40764335]. PREX2 is also specifically expressed in cerebellar Purkinje cells, where it is required for normal dendrite morphology and motor coordination [PMID:18334636].","teleology":[{"year":2004,"claim":"Established the founding biochemical identity of PREX2 as a signal-integrating Rac GEF, answering what enzymatic activity it carries and what regulates it.","evidence":"In vitro GEF assays and in vivo functional assays following cloning from human skeletal muscle and brain libraries, replicated across two labs","pmids":["15304343","15304342"],"confidence":"High","gaps":["Did not define Rac isoform selectivity in vivo","No structural basis for PIP3/Gβγ regulation"]},{"year":2008,"claim":"Defined a physiological neuronal role, showing PREX2 is required in cerebellar Purkinje cells for dendrite morphology and motor coordination.","evidence":"Single and double Prex1/Prex2 knockout mice with Purkinje cell morphology imaging and motor behavioral testing","pmids":["18334636"],"confidence":"High","gaps":["Did not establish whether the dendrite phenotype is GEF-dependent","Downstream effectors in Purkinje cells not identified"]},{"year":2012,"claim":"Linked PREX2 to cancer by identifying it as a recurrently mutated, PTEN-interacting gene whose mutants accelerate melanoma formation.","evidence":"Whole-genome sequencing of melanomas and in vivo xenograft tumor formation with mutant PREX2-expressing melanocytes","pmids":["22622578"],"confidence":"Medium","gaps":["The tumor-acceleration experiment was not reproduced in a later replication study","Did not resolve which mutation classes are oncogenic"]},{"year":2013,"claim":"Resolved the molecular architecture of PREX2-mediated PTEN inhibition, defining two distinct domain interfaces and a phosphorylation-dependent switch.","evidence":"Domain-mapping and deletion constructs, phosphorylation site analysis, and Prex2 knockout mice with metabolic readouts","pmids":["24367090"],"confidence":"High","gaps":["Did not establish the reciprocal effect of PTEN on PREX2 GEF activity","No full-length structure of the complex"]},{"year":2015,"claim":"Demonstrated the reciprocal arm of the complex — PTEN inhibits PREX2 GEF activity via its tail independently of phosphatase activity — and showed cancer mutants escape this control.","evidence":"Fluorescent nucleotide exchange GEF assays, MEFs, breast cancer invasion assays, and mutant analysis","pmids":["25829446"],"confidence":"High","gaps":["Structural basis of mutual inhibition not resolved at this stage","Did not identify which somatic mutants act by escaping binding versus blocking inhibition"]},{"year":2015,"claim":"Identified PAK-mediated phosphorylation as a Rac1-triggered negative feedback loop constraining PREX2 activity and membrane targeting.","evidence":"In vitro GEF assays, mass spectrometry phosphosite mapping, cell fractionation, and insulin stimulation","pmids":["26438819"],"confidence":"High","gaps":["Did not establish phosphatase that reverses PAK sites","In vivo relevance of feedback loop not tested"]},{"year":2017,"claim":"Defined a degradation arm of PREX2 control, showing GNMT and HectH9 drive proteasomal turnover and that their loss activates AKT through PREX2.","evidence":"Co-IP, ubiquitination assays, proteasome inhibitor experiments, siRNA knockdown, and GNMT knockout mice","pmids":["28205209"],"confidence":"Medium","gaps":["Single lab without reciprocal validation of the GNMT-HectH9-PREX2 axis","Ubiquitination site on PREX2 not mapped"]},{"year":2016,"claim":"Mechanistically connected PREX2 truncations to gain-of-function, showing they activate Rac1 GEF activity and drive PI3K/AKT signaling and proliferation.","evidence":"GEF assays with truncation mutants, AKT phosphorylation readout, and proliferation assays","pmids":["27314100"],"confidence":"Medium","gaps":["Commentary format with limited methodological detail","Did not define which truncation boundaries are required"]},{"year":2018,"claim":"Provided the first PREX2 structural data, resolving the PH domain and establishing PIP3 binding as critical for activity but dispensable for membrane localization.","evidence":"X-ray crystallography at 1.9 Å and biochemical PIP3 binding assays","pmids":["34958187"],"confidence":"High","gaps":["Isolated domain only, not full-length context","Mechanism of PIP3-independent membrane targeting unresolved"]},{"year":2019,"claim":"Linked a specific cancer somatic mutation (S1113R) to escape from HectH9 ubiquitination, increasing PREX2 stability and driving migration and AKT activation.","evidence":"Cycloheximide-chase stability assays, ubiquitination assays, migration assays, and AKT phosphorylation analysis","pmids":["30796242"],"confidence":"Medium","gaps":["Single lab study","Structural basis for impaired ubiquitination not defined"]},{"year":2020,"claim":"Identified CELF2 as a disruptor of the PREX2-PTEN interaction that restores PTEN activity and suppresses proliferation.","evidence":"Co-IP, PTEN phosphatase activity assays, AKT phosphorylation analysis, CELF2 perturbation, and a PDX model","pmids":["31241130"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal structural mapping","Direct versus indirect disruption mechanism unclear"]},{"year":2021,"claim":"Resolved the structural logic of the mutual inhibition, defining the PTEN PDZ-motif–PREX2 PDZ2 bridge and showing combined PTEN-inactivating plus PREX2-truncating variants synergistically activate Rac1.","evidence":"Cross-linking mass spectrometry, functional GEF assays, and domain mutant analysis","pmids":["33947796"],"confidence":"High","gaps":["Moderate structural resolution, no atomic model of full complex","Did not test combinatorial variants in vivo"]},{"year":2022,"claim":"Extended neuronal function beyond cerebellum, showing PREX2 controls AMPA receptor trafficking and dendritic spine morphology via Rac1/pGluR1 in dorsal horn neurons during bone cancer pain.","evidence":"Intrathecal RNAi, Western blot of p-Rac1/p-GluR1, spine imaging, and patch-clamp AMPAR recordings","pmids":["35083941"],"confidence":"Medium","gaps":["Single lab without genetic knockout confirmation","Direct GEF-substrate link to GluR1 trafficking not established"]},{"year":2024,"claim":"Connected PREX2 to therapy resistance, showing it facilitates DNA repair via DNA-PKcs and suppresses radiation-induced immunogenic cell death through cGAS/STING/IFN inhibition.","evidence":"RNA-seq, Western blot, colony formation, comet assay, xenografts, and the small-molecule inhibitor PREX-in1","pmids":["38609982"],"confidence":"Medium","gaps":["Mechanism linking GEF activity to DNA-PKcs upregulation unresolved","Single lab"]},{"year":2025,"claim":"Dissected GEF-independent adaptor functions, showing PREX2 suppresses glucose uptake, Glut2 surface levels, mitochondrial function, insulin secretion, and Gpr21 trafficking independently of catalysis.","evidence":"Prex2 knockout and catalytically-inactive Prex2GD knock-in mice with glucose uptake, Glut2 surface, mitochondrial, insulin secretion, and GPCR trafficking assays","pmids":["40764335"],"confidence":"High","gaps":["Molecular adaptor mechanism for Gpr21/Glut2 trafficking not defined","Binding partners mediating adaptor function unidentified"]},{"year":2025,"claim":"Established a druggable PREX2/RAC1/PI3Kβ axis, showing PREX2 loss sensitizes BRAF-mutant melanoma to MAPK inhibitors and PI3Kβ inhibition phenocopies PREX2 deficiency.","evidence":"PREX2-deletion mouse models, patient-derived BRAFV600E melanoma lines, pharmacologic PI3Kβ inhibition, and MAPK inhibitor sensitivity assays","pmids":["39636745"],"confidence":"Medium","gaps":["Single lab","Clinical applicability of the axis untested"]},{"year":2025,"claim":"Identified AHCYL1 as an activating interactor that relieves PREX2-PTEN mutual inhibition to amplify Rac1 activation and tumor promotion in NSCLC.","evidence":"Pull-down with LC-MS/MS, in vitro GEF assays, active Rac1 pull-down, Western blot, and a CDX mouse model","pmids":["40365293"],"confidence":"Medium","gaps":["Single lab without reciprocal interaction mapping","Structural basis for relief of inhibition unknown"]},{"year":2026,"claim":"Resolved full-length PREX2 architecture, revealing a repositioned N-terminal module and IP4-independent dynamics indicating an autoinhibition mechanism divergent from P-Rex1.","evidence":"Cryo-EM, HDX-MS, SEC-SAXS, and in vitro GEF assays (peer-reviewed, with a parallel preprint version)","pmids":["42248461","41542420"],"confidence":"High","gaps":["Moderate cryo-EM resolution limits side-chain detail","Conformational transition to the active GEF state not captured"]},{"year":null,"claim":"The molecular identity of the adaptor-mode binding partners that mediate GEF-independent control of Glut2 and Gpr21 trafficking, and how membrane targeting occurs without PIP3 binding, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No partner identified for the adaptor function","Mechanism of PIP3-independent membrane localization unresolved","Active-state structural transition uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,17]}],"complexes":["PTEN:P-Rex2 complex"],"partners":["PTEN","RAC1","GNMT","HECTH9","CELF2","AHCYL1","PAK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q70Z35","full_name":"Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein","aliases":["DEP domain-containing protein 2"],"length_aa":1606,"mass_kda":182.6,"function":"Functions as a RAC1 guanine nucleotide exchange factor (GEF), activating Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein. Mediates the activation of RAC1 in a PI3K-dependent manner. May be an important mediator of Rac signaling, acting directly downstream of both G protein-coupled receptors and phosphoinositide 3-kinase","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q70Z35/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PREX2","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/PREX2","total_profiled":1310},"omim":[{"mim_id":"612139","title":"PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE-DEPENDENT RAC EXCHANGER 2; PREX2","url":"https://www.omim.org/entry/612139"},{"mim_id":"606905","title":"PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE-DEPENDENT RAC EXCHANGER 1; PREX1","url":"https://www.omim.org/entry/606905"},{"mim_id":"260350","title":"PANCREATIC CANCER","url":"https://www.omim.org/entry/260350"},{"mim_id":"155600","title":"MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 1; CMM1","url":"https://www.omim.org/entry/155600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PREX2"},"hgnc":{"alias_symbol":["DEP.2","FLJ12987","P-REX2","PPP1R129"],"prev_symbol":["DEPDC2"]},"alphafold":{"accession":"Q70Z35","domains":[{"cath_id":"1.20.900.10","chopping":"14-220","consensus_level":"high","plddt":89.3971,"start":14,"end":220},{"cath_id":"2.30.29.30","chopping":"234-279_293-367","consensus_level":"medium","plddt":87.0098,"start":234,"end":367},{"cath_id":"1.10.10.10","chopping":"394-470","consensus_level":"medium","plddt":84.069,"start":394,"end":470},{"cath_id":"1.10.10.10","chopping":"481-571","consensus_level":"high","plddt":86.4443,"start":481,"end":571},{"cath_id":"2.30.42.10","chopping":"585-675","consensus_level":"medium","plddt":88.5386,"start":585,"end":675},{"cath_id":"2.30.42.10","chopping":"677-768_804-814","consensus_level":"medium","plddt":82.223,"start":677,"end":814}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q70Z35","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q70Z35-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q70Z35-F1-predicted_aligned_error_v6.png","plddt_mean":79.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PREX2","jax_strain_url":"https://www.jax.org/strain/search?query=PREX2"},"sequence":{"accession":"Q70Z35","fasta_url":"https://rest.uniprot.org/uniprotkb/Q70Z35.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q70Z35/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q70Z35"}},"corpus_meta":[{"pmid":"22622578","id":"PMC_22622578","title":"Melanoma genome sequencing reveals frequent PREX2 mutations.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22622578","citation_count":590,"is_preprint":false},{"pmid":"15304343","id":"PMC_15304343","title":"P-Rex2, a new guanine-nucleotide exchange factor for Rac.","date":"2004","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15304343","citation_count":89,"is_preprint":false},{"pmid":"15304342","id":"PMC_15304342","title":"P-REX2, a novel PI-3-kinase sensitive Rac exchange factor.","date":"2004","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15304342","citation_count":83,"is_preprint":false},{"pmid":"25829446","id":"PMC_25829446","title":"PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion.","date":"2015","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25829446","citation_count":63,"is_preprint":false},{"pmid":"18334636","id":"PMC_18334636","title":"P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18334636","citation_count":59,"is_preprint":false},{"pmid":"24367090","id":"PMC_24367090","title":"Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24367090","citation_count":58,"is_preprint":false},{"pmid":"31241130","id":"PMC_31241130","title":"CELF2 suppresses non-small cell lung carcinoma growth by inhibiting the PREX2-PTEN interaction.","date":"2020","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31241130","citation_count":44,"is_preprint":false},{"pmid":"28710285","id":"PMC_28710285","title":"P-Rex1 and P-Rex2 RacGEFs and cancer.","date":"2017","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/28710285","citation_count":39,"is_preprint":false},{"pmid":"28205209","id":"PMC_28205209","title":"Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma.","date":"2017","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28205209","citation_count":28,"is_preprint":false},{"pmid":"25151370","id":"PMC_25151370","title":"The effect of CXCL9 on the invasion ability of hepatocellular carcinoma through up-regulation of PREX2.","date":"2014","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/25151370","citation_count":27,"is_preprint":false},{"pmid":"31582017","id":"PMC_31582017","title":"Involvement of TLR4/ CXCL9/ PREX-2 pathway in the development of hepatocellular carcinoma (HCC) and the promising role of early administration of lactobacillus plantarum in Wistar rats.","date":"2019","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/31582017","citation_count":22,"is_preprint":false},{"pmid":"30796242","id":"PMC_30796242","title":"Somatic mutations of PREX2 gene in patients with hepatocellular carcinoma.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30796242","citation_count":21,"is_preprint":false},{"pmid":"28100394","id":"PMC_28100394","title":"Replication Study: Melanoma genome sequencing reveals frequent PREX2 mutations.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28100394","citation_count":20,"is_preprint":false},{"pmid":"26438819","id":"PMC_26438819","title":"p21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26438819","citation_count":20,"is_preprint":false},{"pmid":"38609982","id":"PMC_38609982","title":"PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer.","date":"2024","source":"BMC medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38609982","citation_count":16,"is_preprint":false},{"pmid":"26998152","id":"PMC_26998152","title":"Upregulation of PREX2 promotes the proliferation and migration of hepatocellular carcinoma cells via PTEN-AKT signaling.","date":"2016","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/26998152","citation_count":16,"is_preprint":false},{"pmid":"33947796","id":"PMC_33947796","title":"Structural analysis of the PTEN:P-Rex2 signaling complex reveals how cancer-associated mutations coordinate to hyperactivate Rac1.","date":"2021","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/33947796","citation_count":13,"is_preprint":false},{"pmid":"27446408","id":"PMC_27446408","title":"PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway.","date":"2016","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/27446408","citation_count":10,"is_preprint":false},{"pmid":"39636745","id":"PMC_39636745","title":"Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma.","date":"2025","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39636745","citation_count":7,"is_preprint":false},{"pmid":"34958187","id":"PMC_34958187","title":"Structural and biochemical characterization of the pleckstrin homology domain of the RhoGEF P-Rex2 and its regulation by PIP3.","date":"2018","source":"Journal of structural biology: X","url":"https://pubmed.ncbi.nlm.nih.gov/34958187","citation_count":5,"is_preprint":false},{"pmid":"27314100","id":"PMC_27314100","title":"Mechanistic insights into the role of truncating PREX2 mutations in melanoma.","date":"2016","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27314100","citation_count":5,"is_preprint":false},{"pmid":"34705970","id":"PMC_34705970","title":"PREX2 gene's expression in gastric antral epithelial cells of patients with H. pylori infection.","date":"2021","source":"Arquivos de gastroenterologia","url":"https://pubmed.ncbi.nlm.nih.gov/34705970","citation_count":4,"is_preprint":false},{"pmid":"35083941","id":"PMC_35083941","title":"P-Rex2 mediation of synaptic plasticity contributes to bone cancer pain.","date":"2022","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/35083941","citation_count":3,"is_preprint":false},{"pmid":"40764335","id":"PMC_40764335","title":"P-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40764335","citation_count":3,"is_preprint":false},{"pmid":"23844743","id":"PMC_23844743","title":"P-Rex2, a Rac-guanine nucleotide exchange factor, is expressed selectively in ribbon synaptic terminals of the mouse retina.","date":"2013","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23844743","citation_count":3,"is_preprint":false},{"pmid":"25490935","id":"PMC_25490935","title":"Registered report: Melanoma genome sequencing reveals frequent PREX2 mutations.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25490935","citation_count":3,"is_preprint":false},{"pmid":"41542420","id":"PMC_41542420","title":"P-Rex2 exhibits unique structural features and regulatory mechanisms distinct from the closely related RhoGEF P-Rex1.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41542420","citation_count":2,"is_preprint":false},{"pmid":"40365293","id":"PMC_40365293","title":"AHCYL1 mediates the tumor-promoting effect of PREX2 in non-small cell lung carcinoma.","date":"2025","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/40365293","citation_count":1,"is_preprint":false},{"pmid":"34988572","id":"PMC_34988572","title":"Sustainable and cost-effective ternary electrolyte Et3NHCl-AlCl3-Mg(DEP)2 for high-performance rechargeable magnesium batteries.","date":"2022","source":"Physical chemistry chemical physics : PCCP","url":"https://pubmed.ncbi.nlm.nih.gov/34988572","citation_count":1,"is_preprint":false},{"pmid":"40971540","id":"PMC_40971540","title":"Unraveling the role of PREX2 mutations as a biomarker for immunotherapy response in colorectal cancer.","date":"2025","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/40971540","citation_count":1,"is_preprint":false},{"pmid":"42248461","id":"PMC_42248461","title":"The Rho guanine-nucleotide exchange factor P-Rex2 exhibits structural and regulatory features distinct from the related RhoGEF P-Rex1.","date":"2026","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42248461","citation_count":0,"is_preprint":false},{"pmid":"34386078","id":"PMC_34386078","title":"PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34386078","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17217,"output_tokens":4922,"usd":0.062741,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13193,"output_tokens":5363,"usd":0.10002,"stage2_stop_reason":"end_turn"},"total_usd":0.162761,"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\": 2004,\n      \"finding\": \"PREX2 (P-Rex2) is a guanine-nucleotide exchange factor (GEF) that activates the small GTPase Rac and is regulated by phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and Gβγ subunits of heterotrimeric G proteins in vitro and in vivo.\",\n      \"method\": \"In vitro GEF assay, in vivo functional assays; cloning from human skeletal muscle and brain libraries\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two independent papers (PMID:15304343 and PMID:15304342) simultaneously reported GEF activity and PIP3/Gβγ regulation using in vitro assays, replicated across two labs\",\n      \"pmids\": [\"15304343\", \"15304342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"P-REX2 inhibits PTEN through two interfaces: the PH domain of P-REX2 inhibits PTEN by interacting with its catalytic region, while the inositol polyphosphate 4-phosphatase (IP4P) domain of P-REX2 provides high-affinity binding to the PDZ-binding domain of PTEN. P-REX2 inhibition of PTEN requires C-terminal phosphorylation of PTEN to release the P-REX2 PH domain from its neighboring DH domain.\",\n      \"method\": \"Domain-mapping biochemical assays, deletion constructs, phosphorylation site analysis; Prex2 knockout mice showing increased Pten activity and decreased insulin signaling\",\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 — multiple orthogonal methods (domain deletion, mutagenesis, knockout mouse model with defined metabolic phenotype) in a single rigorous study\",\n      \"pmids\": [\"24367090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTEN inhibits PREX2 GEF activity toward RAC1, thereby suppressing cell migration and invasion. This inhibition requires the tail domain of PTEN but not its lipid phosphatase activity. Cancer-derived somatic PREX2 mutants are resistant to PTEN-mediated inhibition of invasion and either escape PTEN binding or are not blocked in their GEF activity by PTEN.\",\n      \"method\": \"Fluorescent nucleotide exchange assays (in vitro GEF assay), mouse embryonic fibroblasts, breast cancer cell line invasion assays, domain deletion/mutant analysis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro GEF activity assay with mutagenesis, multiple cell line models, and cancer mutant characterization in a single study\",\n      \"pmids\": [\"25829446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PAK kinases phosphorylate PREX2 following Rac1 activation, creating a negative feedback loop. PAK-mediated phosphorylation of PREX2 reduces its GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ, and also prevents PREX2 from localizing to the cellular membrane.\",\n      \"method\": \"In vitro GEF assays, mass spectrometry phosphorylation mapping, cell fractionation, insulin stimulation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — phosphorylation mapped by MS, GEF activity assay, membrane localization by fractionation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"26438819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"P-Rex2 is specifically expressed in Purkinje neurons of the cerebellum and is required for Purkinje cell dendrite morphology and motor coordination. P-Rex2 knockout mice show thinned main dendrites in Purkinje cells, progressive motor coordination defects, and double P-Rex1/P-Rex2 knockout mice are ataxic.\",\n      \"method\": \"P-Rex2 knockout mouse generation and analysis, Purkinje cell morphology imaging, behavioral motor coordination tests\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse model with defined cellular (dendrite morphology) and behavioral phenotypes, multiple genetic models (single and double KO)\",\n      \"pmids\": [\"18334636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The PTEN:P-Rex2 complex is assembled via PDZ-interacting motif in the PTEN C-terminal tail binding to the second PDZ domain of P-Rex2, bridging PTEN across the P-Rex2 surface to block PI(3,4,5)P3 hydrolysis. Conversely, PTEN allosterically promotes an autoinhibited conformation of P-Rex2 and blocks its binding to Gβγ. Cancer-associated PTEN-deactivating mutations combined with P-Rex2 truncations drive Rac1 activation to a greater extent than either single variant alone.\",\n      \"method\": \"Cross-linking mass spectrometry, functional GEF assays, domain mutant analysis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — cross-linking MS structural analysis combined with functional assays and cancer mutant characterization in a single rigorous study\",\n      \"pmids\": [\"33947796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GNMT interacts with PREX2 and promotes its degradation through an E3 ligase HectH9-mediated proteasomal ubiquitination pathway. Depletion of GNMT or HectH9 results in AKT activation in a PREX2-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, siRNA knockdown, GNMT knockout mice\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and knockout mouse model, multiple orthogonal methods but single lab\",\n      \"pmids\": [\"28205209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The crystal structure of the P-Rex2 PH domain at 1.9 Å resolution reveals conformational differences in loop regions compared to P-Rex1. Biochemical studies show the P-Rex2 PH domain binds PIP3 similarly to P-Rex1; binding is critical for P-Rex2 activity but not for membrane localization.\",\n      \"method\": \"X-ray crystallography (1.9 Å), biochemical PIP3 binding assays\",\n      \"journal\": \"Journal of structural biology: X\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biochemical functional validation of PIP3 binding, single lab but rigorous structural/biochemical methods\",\n      \"pmids\": [\"34958187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cryo-EM structure of full-length P-Rex2 reveals that, while overall similar to P-Rex1, there is a substantial repositioning of the N-terminal module relative to the C-terminal core, potentially precluding intramolecular autoinhibitory interactions seen in P-Rex1. HDX-MS shows P-Rex2 dynamics are unaffected by IP4 (PIP3 headgroup), unlike P-Rex1, suggesting a different autoinhibition mechanism.\",\n      \"method\": \"Cryo-EM (moderate resolution), hydrogen-deuterium exchange mass spectrometry (HDX-MS), SEC-SAXS, biochemical GEF assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure combined with HDX-MS and biochemical assays, multiple orthogonal structural/biophysical methods in a single study\",\n      \"pmids\": [\"42248461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ectopic expression of mutant PREX2 accelerates tumor formation of immortalized human melanocytes in vivo, establishing PREX2 as a functionally relevant mutated gene in melanoma. PREX2 was identified as a PTEN-interacting protein and negative regulator of PTEN.\",\n      \"method\": \"Whole-genome sequencing of 25 melanomas; in vivo xenograft tumor formation assay with mutant PREX2-expressing melanocytes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo tumor formation established oncogenic function, but the key experiment was not reproduced in a subsequent replication study (PMID:28100394)\",\n      \"pmids\": [\"22622578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Truncating PREX2 mutations activate its RAC1 guanine nucleotide exchanger activity, leading to increased PI3K/AKT signaling and enhanced cell proliferation.\",\n      \"method\": \"GEF activity assays with truncation mutants, AKT phosphorylation readout, cell proliferation assays\",\n      \"journal\": \"Molecular & cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — GEF assay with mutants and downstream signaling readout, single lab, review/commentary format with limited methodological detail\",\n      \"pmids\": [\"27314100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The PREX2 somatic mutation S1113R (identified in HCC) impairs HectH9-mediated ubiquitination of PREX2, resulting in extended protein half-life and enhanced protein stability, and promotes cell migration and AKT pathway activation.\",\n      \"method\": \"Protein stability/half-life assays (cycloheximide chase), ubiquitination assay, cell migration assay, AKT phosphorylation analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays (protein stability, ubiquitination, migration, signaling) in a single study, single lab\",\n      \"pmids\": [\"30796242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CELF2 interacts with PREX2 and reduces the association of PREX2 with PTEN, thereby upregulating PTEN phosphatase activity and suppressing AKT phosphorylation and cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation (CELF2-PREX2 interaction), PTEN phosphatase activity assay, AKT phosphorylation analysis, CELF2 overexpression/knockdown, PDX tumor model\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and functional assays (PTEN activity, AKT phosphorylation) combined with in vivo PDX model, single lab\",\n      \"pmids\": [\"31241130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"P-Rex2 regulates GluR1-containing AMPA receptor trafficking and dendritic spine morphology via Rac1/pGluR1 pathway in dorsal horn neurons, contributing to bone cancer pain. P-Rex2 knockdown reduced spinal p-Rac1, p-GluR1, spine number, and reversed AMPAR-induced current in dorsal horn neurons.\",\n      \"method\": \"Intrathecal RNAi lentivirus injection, Western blot for p-Rac1/p-GluR1, spine density imaging, whole-cell patch clamp recording of AMPAR currents\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with electrophysiology and morphological readouts, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35083941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AHCYL1 is a novel PREX2-interacting protein that enhances PREX2 GEF activity by alleviating the mutual inhibition between PREX2 and PTEN, thereby intensifying PREX2-driven Rac1 activation and tumor-promoting effects in NSCLC.\",\n      \"method\": \"Pull-down assay with LC-MS/MS (identification of AHCYL1), in vitro GEF assay, active Rac1 pull-down assay, Western blotting, CDX mouse model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel interactor identified by MS/pull-down, mechanistically validated by in vitro GEF assay and active Rac1 pull-down, single lab\",\n      \"pmids\": [\"40365293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"P-Rex2 suppresses glucose uptake into liver and skeletal muscle independently of its catalytic (GEF) activity, as shown using catalytically-inactive Prex2GD knock-in mice. In hepatocytes, P-Rex2 suppresses Glut2 cell-surface levels, mitochondrial membrane potential, and ATP production. P-Rex2 also suppresses insulin secretion by pancreatic islets. The orphan GPCR Gpr21 was identified as a P-Rex2 target, with P-Rex2 proposed to limit hepatic glucose clearance by controlling Gpr21 trafficking.\",\n      \"method\": \"Prex2 knockout and catalytically-inactive Prex2GD knock-in mice, glucose uptake assays, Glut2 surface localization assay, mitochondrial function assay, insulin secretion assay, GPCR trafficking studies\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytically-inactive knock-in mouse distinguishes GEF-dependent vs. adaptor functions, multiple orthogonal cellular assays, clean genetic dissection\",\n      \"pmids\": [\"40764335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PREX2 promotes radiation resistance in colorectal cancer by facilitating DNA repair through upregulation of DNA-PKcs and suppressing radiation-induced immunogenic cell death and CD8+ T cell infiltration via inhibition of the cGAS/STING/IFN signaling pathway.\",\n      \"method\": \"RNA-seq, Western blotting, colony formation assay, apoptosis assay, comet assay, xenograft tumor models, small-molecule PREX2 inhibitor (PREX-in1)\",\n      \"journal\": \"BMC medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo methods linking PREX2 to DNA-PKcs and cGAS/STING pathway, single lab\",\n      \"pmids\": [\"38609982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic loss of PREX2 in BRAF-mutant melanoma confers sensitivity to MAPK pathway inhibitors, and pharmacologic targeting of PI3Kβ (downstream of PREX2/RAC1) phenocopies PREX2 deficiency, establishing a druggable PREX2/RAC1/PI3Kβ signaling axis.\",\n      \"method\": \"Genetically engineered mouse models (PREX2 deletion), patient-derived BRAFV600E melanoma cell lines, pharmacologic PI3Kβ inhibition, MAPK inhibitor sensitivity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacologic epistasis in mouse models and patient-derived lines, single lab, genetic and pharmacologic evidence convergent\",\n      \"pmids\": [\"39636745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cryo-EM structure of full-length P-Rex2 (preprint version) shows substantial repositioning of the N-terminal module relative to C-terminal core compared to P-Rex1; HDX-MS shows P-Rex2 is unaffected by IP4 unlike P-Rex1; biochemical assays indicate P-Rex2 may be more tightly regulated by autoinhibition via a mechanism divergent from P-Rex1.\",\n      \"method\": \"Cryo-EM, HDX-MS, SEC-SAXS, in vitro GEF assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous structural/biophysical methods but preprint, single lab; peer-reviewed version (PMID:42248461) independently confirms\",\n      \"pmids\": [\"41542420\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PREX2 is a PIP3- and Gβγ-regulated guanine nucleotide exchange factor (GEF) for the small GTPase RAC1; it forms a mutually inhibitory complex with the tumor suppressor PTEN (anchored via its PDZ domain interactions), whereby PTEN allosterically autoinhibits PREX2 GEF activity and blocks Gβγ binding, while the PREX2 PH domain inhibits PTEN's lipid phosphatase activity; this complex is negatively regulated by PAK-mediated phosphorylation of PREX2 (feedback inhibition), by HectH9-mediated ubiquitin-proteasomal degradation (promoted by GNMT), and by CELF2 (which disrupts the PREX2-PTEN interaction); in addition to its catalytic role, PREX2 exerts GEF-independent adaptor functions in controlling glucose homeostasis (suppressing hepatic Glut2 surface levels and Gpr21 GPCR trafficking, and limiting skeletal muscle glucose uptake), and its specific expression in cerebellar Purkinje cells is required for normal dendrite morphology and motor coordination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PREX2 (P-Rex2) is a phosphatidylinositol-(3,4,5)-trisphosphate (PIP3)- and Gβγ-regulated guanine nucleotide exchange factor (GEF) that activates the small GTPase Rac, coupling PI3K and G-protein signaling to Rac-dependent control of cell migration, proliferation, and tissue morphogenesis [#0, #2]. PREX2 engages the tumor suppressor PTEN in a mutually inhibitory complex: PTEN's C-terminal PDZ-binding motif binds the second PDZ domain of PREX2, bridging across the protein to block PIP3 hydrolysis, while PTEN reciprocally drives an autoinhibited PREX2 conformation and blocks Gβγ binding; PREX2 inhibition of PTEN requires PTEN C-terminal phosphorylation to release the PREX2 PH domain from its neighboring DH domain [#1, #5]. PIP3 binding through the PREX2 PH domain is critical for GEF activity, and full-length structural analysis shows PREX2 adopts an autoinhibition mechanism divergent from the related P-Rex1, with PIP3-headgroup-independent dynamics [#7, #8]. This complex is held under multiple layers of negative control: PAK kinases phosphorylate PREX2 downstream of Rac1 activation to form a feedback loop that impairs PIP3/Gβγ binding and membrane localization [#3]; GNMT and the E3 ligase HectH9 drive ubiquitin-proteasomal degradation of PREX2 [#6]; and CELF2 disrupts the PREX2-PTEN interaction to restore PTEN phosphatase activity [#12]. Cancer-associated PREX2 truncations and somatic mutations escape PTEN-mediated inhibition or HectH9-mediated degradation, hyperactivating Rac1 and PI3K/AKT signaling to promote invasion, proliferation, and tumorigenesis [#2, #5, #11]. Beyond its catalytic role, PREX2 exerts GEF-independent adaptor functions in glucose homeostasis, suppressing hepatic Glut2 surface levels, mitochondrial function, islet insulin secretion, and Gpr21 GPCR trafficking [#15]. PREX2 is also specifically expressed in cerebellar Purkinje cells, where it is required for normal dendrite morphology and motor coordination [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the founding biochemical identity of PREX2 as a signal-integrating Rac GEF, answering what enzymatic activity it carries and what regulates it.\",\n      \"evidence\": \"In vitro GEF assays and in vivo functional assays following cloning from human skeletal muscle and brain libraries, replicated across two labs\",\n      \"pmids\": [\"15304343\", \"15304342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define Rac isoform selectivity in vivo\", \"No structural basis for PIP3/Gβγ regulation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a physiological neuronal role, showing PREX2 is required in cerebellar Purkinje cells for dendrite morphology and motor coordination.\",\n      \"evidence\": \"Single and double Prex1/Prex2 knockout mice with Purkinje cell morphology imaging and motor behavioral testing\",\n      \"pmids\": [\"18334636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether the dendrite phenotype is GEF-dependent\", \"Downstream effectors in Purkinje cells not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked PREX2 to cancer by identifying it as a recurrently mutated, PTEN-interacting gene whose mutants accelerate melanoma formation.\",\n      \"evidence\": \"Whole-genome sequencing of melanomas and in vivo xenograft tumor formation with mutant PREX2-expressing melanocytes\",\n      \"pmids\": [\"22622578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The tumor-acceleration experiment was not reproduced in a later replication study\", \"Did not resolve which mutation classes are oncogenic\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the molecular architecture of PREX2-mediated PTEN inhibition, defining two distinct domain interfaces and a phosphorylation-dependent switch.\",\n      \"evidence\": \"Domain-mapping and deletion constructs, phosphorylation site analysis, and Prex2 knockout mice with metabolic readouts\",\n      \"pmids\": [\"24367090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the reciprocal effect of PTEN on PREX2 GEF activity\", \"No full-length structure of the complex\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated the reciprocal arm of the complex — PTEN inhibits PREX2 GEF activity via its tail independently of phosphatase activity — and showed cancer mutants escape this control.\",\n      \"evidence\": \"Fluorescent nucleotide exchange GEF assays, MEFs, breast cancer invasion assays, and mutant analysis\",\n      \"pmids\": [\"25829446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of mutual inhibition not resolved at this stage\", \"Did not identify which somatic mutants act by escaping binding versus blocking inhibition\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified PAK-mediated phosphorylation as a Rac1-triggered negative feedback loop constraining PREX2 activity and membrane targeting.\",\n      \"evidence\": \"In vitro GEF assays, mass spectrometry phosphosite mapping, cell fractionation, and insulin stimulation\",\n      \"pmids\": [\"26438819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish phosphatase that reverses PAK sites\", \"In vivo relevance of feedback loop not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a degradation arm of PREX2 control, showing GNMT and HectH9 drive proteasomal turnover and that their loss activates AKT through PREX2.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, proteasome inhibitor experiments, siRNA knockdown, and GNMT knockout mice\",\n      \"pmids\": [\"28205209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without reciprocal validation of the GNMT-HectH9-PREX2 axis\", \"Ubiquitination site on PREX2 not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mechanistically connected PREX2 truncations to gain-of-function, showing they activate Rac1 GEF activity and drive PI3K/AKT signaling and proliferation.\",\n      \"evidence\": \"GEF assays with truncation mutants, AKT phosphorylation readout, and proliferation assays\",\n      \"pmids\": [\"27314100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Commentary format with limited methodological detail\", \"Did not define which truncation boundaries are required\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the first PREX2 structural data, resolving the PH domain and establishing PIP3 binding as critical for activity but dispensable for membrane localization.\",\n      \"evidence\": \"X-ray crystallography at 1.9 Å and biochemical PIP3 binding assays\",\n      \"pmids\": [\"34958187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isolated domain only, not full-length context\", \"Mechanism of PIP3-independent membrane targeting unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked a specific cancer somatic mutation (S1113R) to escape from HectH9 ubiquitination, increasing PREX2 stability and driving migration and AKT activation.\",\n      \"evidence\": \"Cycloheximide-chase stability assays, ubiquitination assays, migration assays, and AKT phosphorylation analysis\",\n      \"pmids\": [\"30796242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study\", \"Structural basis for impaired ubiquitination not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified CELF2 as a disruptor of the PREX2-PTEN interaction that restores PTEN activity and suppresses proliferation.\",\n      \"evidence\": \"Co-IP, PTEN phosphatase activity assays, AKT phosphorylation analysis, CELF2 perturbation, and a PDX model\",\n      \"pmids\": [\"31241130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal structural mapping\", \"Direct versus indirect disruption mechanism unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the structural logic of the mutual inhibition, defining the PTEN PDZ-motif–PREX2 PDZ2 bridge and showing combined PTEN-inactivating plus PREX2-truncating variants synergistically activate Rac1.\",\n      \"evidence\": \"Cross-linking mass spectrometry, functional GEF assays, and domain mutant analysis\",\n      \"pmids\": [\"33947796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Moderate structural resolution, no atomic model of full complex\", \"Did not test combinatorial variants in vivo\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended neuronal function beyond cerebellum, showing PREX2 controls AMPA receptor trafficking and dendritic spine morphology via Rac1/pGluR1 in dorsal horn neurons during bone cancer pain.\",\n      \"evidence\": \"Intrathecal RNAi, Western blot of p-Rac1/p-GluR1, spine imaging, and patch-clamp AMPAR recordings\",\n      \"pmids\": [\"35083941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without genetic knockout confirmation\", \"Direct GEF-substrate link to GluR1 trafficking not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected PREX2 to therapy resistance, showing it facilitates DNA repair via DNA-PKcs and suppresses radiation-induced immunogenic cell death through cGAS/STING/IFN inhibition.\",\n      \"evidence\": \"RNA-seq, Western blot, colony formation, comet assay, xenografts, and the small-molecule inhibitor PREX-in1\",\n      \"pmids\": [\"38609982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GEF activity to DNA-PKcs upregulation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dissected GEF-independent adaptor functions, showing PREX2 suppresses glucose uptake, Glut2 surface levels, mitochondrial function, insulin secretion, and Gpr21 trafficking independently of catalysis.\",\n      \"evidence\": \"Prex2 knockout and catalytically-inactive Prex2GD knock-in mice with glucose uptake, Glut2 surface, mitochondrial, insulin secretion, and GPCR trafficking assays\",\n      \"pmids\": [\"40764335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular adaptor mechanism for Gpr21/Glut2 trafficking not defined\", \"Binding partners mediating adaptor function unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a druggable PREX2/RAC1/PI3Kβ axis, showing PREX2 loss sensitizes BRAF-mutant melanoma to MAPK inhibitors and PI3Kβ inhibition phenocopies PREX2 deficiency.\",\n      \"evidence\": \"PREX2-deletion mouse models, patient-derived BRAFV600E melanoma lines, pharmacologic PI3Kβ inhibition, and MAPK inhibitor sensitivity assays\",\n      \"pmids\": [\"39636745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Clinical applicability of the axis untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified AHCYL1 as an activating interactor that relieves PREX2-PTEN mutual inhibition to amplify Rac1 activation and tumor promotion in NSCLC.\",\n      \"evidence\": \"Pull-down with LC-MS/MS, in vitro GEF assays, active Rac1 pull-down, Western blot, and a CDX mouse model\",\n      \"pmids\": [\"40365293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without reciprocal interaction mapping\", \"Structural basis for relief of inhibition unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved full-length PREX2 architecture, revealing a repositioned N-terminal module and IP4-independent dynamics indicating an autoinhibition mechanism divergent from P-Rex1.\",\n      \"evidence\": \"Cryo-EM, HDX-MS, SEC-SAXS, and in vitro GEF assays (peer-reviewed, with a parallel preprint version)\",\n      \"pmids\": [\"42248461\", \"41542420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Moderate cryo-EM resolution limits side-chain detail\", \"Conformational transition to the active GEF state not captured\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity of the adaptor-mode binding partners that mediate GEF-independent control of Glut2 and Gpr21 trafficking, and how membrane targeting occurs without PIP3 binding, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No partner identified for the adaptor function\", \"Mechanism of PIP3-independent membrane localization unresolved\", \"Active-state structural transition uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 17]}\n    ],\n    \"complexes\": [\"PTEN:P-Rex2 complex\"],\n    \"partners\": [\"PTEN\", \"RAC1\", \"GNMT\", \"HectH9\", \"CELF2\", \"AHCYL1\", \"PAK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}