{"gene":"PDGFRA","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2003,"finding":"PDGFRA harbors activating intragenic mutations in ~35% of KIT-wild-type GISTs, making KIT and PDGFRA mutations alternative and mutually exclusive oncogenic mechanisms in GISTs; both activate overlapping downstream signaling intermediates.","method":"Mutational sequencing of GIST tumors; functional characterization of downstream signaling activation","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — original discovery paper with direct sequencing and downstream signaling analysis, replicated extensively across many subsequent studies","pmids":["12522257"],"is_preprint":false},{"year":2005,"finding":"PDGFRA exon 12 mutations (e.g., V561D, SPDHE566-571R) and exon 14 substitution (N659K) are imatinib-sensitive, whereas most exon 18 codon D842 substitutions (D842V, RD841-842KI, DI842-843IM) are imatinib-resistant in vitro; D842Y is an exception that retains imatinib sensitivity.","method":"Transient expression of PDGFRA mutant isoforms in CHO cells; stable expression in BA/F3 cell lines; proliferation/inhibition assays","journal":"Journal of Clinical Oncology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase inhibition assays with multiple mutant isoforms expressed in cell lines, replicated across multiple labs","pmids":["15928335"],"is_preprint":false},{"year":2010,"finding":"PDGFRA gene rearrangements, including an intragenic deletion of exons 8 and 9 (PDGFRA-Δ8,9) and a KDR-PDGFRA gene fusion, occur in 40% of PDGFRA-amplified GBMs; both rearrangements produce constitutively elevated tyrosine kinase activity and transforming potential reversible by PDGFR blockade.","method":"Genomic analysis of glioma PDGFRA locus; functional assays measuring constitutive kinase activity and transformation; PDGFR inhibitor treatment","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — constitutive kinase activity measured directly, transforming potential demonstrated, inhibitor reversal shown in single focused study","pmids":["20889717"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the PDGFRA kinase domain in the auto-inhibited form reveals that the juxtamembrane (JM) domain inserts into the active site stabilizing a 'DFG out' (inactive) conformation; Asp842 makes extensive contacts with activation-loop residues to maintain this conformation. The D842V mutation disrupts this stabilization, constitutively activates the kinase, and increases ATP affinity, together explaining imatinib resistance.","method":"X-ray crystallography of PDGFRA kinase domain; kinetic measurements of ATP affinity for D842V mutant","journal":"Biochemical and Biophysical Research Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional kinetic validation in a single study; mechanistic explanation for D842V resistance","pmids":["27349873"],"is_preprint":false},{"year":2017,"finding":"BLU-285 (avapritinib), designed to interact preferentially with the active conformation of PDGFRA, potently inhibits the activation-loop mutant PDGFRA D842V with subnanomolar potency, overcoming the resistance seen with type II inhibitors (imatinib) that require the inactive 'DFG out' conformation.","method":"In vitro kinase inhibition assays; preclinical cell/animal models; phase 1 clinical evaluation","journal":"Science Translational Medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic structure-activity studies combined with in vitro and in vivo preclinical models and clinical validation","pmids":["29093181"],"is_preprint":false},{"year":2024,"finding":"Crystal structures of avapritinib in complex with wild-type and mutant PDGFRA (and KIT) reveal the inhibitor binding mode and identify a sub-pocket (Gα-pocket) critical for inhibitor engagement; this structural information was used to design derivatives that overcome drug resistance.","method":"X-ray crystallography of avapritinib–PDGFRA complexes; structure-guided medicinal chemistry and pharmacologic characterization of derivatives","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with functional validation through designed derivatives in a single rigorous study","pmids":["38167404"],"is_preprint":false},{"year":2007,"finding":"The FIP1L1-PDGFRA fusion protein promotes myeloproliferation in human CD34+ hematopoietic progenitors by activating PI3K, ERK1/2, and STAT5 signaling; STAT5 activation is dependent on the FIP1L1 N-terminal domain (aa 30-233), and combined PI3K + ERK1/2 inhibition significantly reverses colony formation.","method":"Retroviral transduction of human CD34+ progenitors with FIP1L1-PDGFRA and deletion mutants; phospho-Western blotting; dominant-negative STAT5; pharmacological inhibitors","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (signaling assays, deletion mutants, dominant-negative, pharmacological inhibition) in a single study","pmids":["17440089"],"is_preprint":false},{"year":2011,"finding":"SHP-2 (PTPN11) mediates PDGFRA-driven gliomagenesis: abrogation of the PDGFRA–SHP-2 binding interface or pharmacological SHP-2 inhibition disrupts PI3K interaction with PDGFRA, suppresses downstream AKT/mTOR activation, and impairs tumorigenicity of Ink4a/Arf-null cells; activated PI3K rescues this effect, placing SHP-2 upstream of PI3K/AKT/mTOR.","method":"Epistasis via signaling-module mutants of PDGFRA; shRNA knockdown and pharmacological inhibitors of SHP-2; activated PI3K rescue experiment; mouse intracranial glioma model","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple orthogonal approaches (domain mutants, shRNA, pharmacological, rescue), supported by in vivo glioma model","pmids":["21393858"],"is_preprint":false},{"year":2013,"finding":"Novel somatic PDGFRA missense mutations and in-frame deletions/insertions in pediatric high-grade gliomas result in ligand-independent receptor activation blocked by PDGFR small-molecule inhibitors; expression of these mutants in p53-null mouse astrocytes confers proliferative advantage and generates HGGs in vivo with complete penetrance.","method":"Full coding-sequence sequencing of PDGFRA; in vitro receptor phosphorylation assays; p53-null astrocyte transformation assay; intracranial implantation mouse model","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — constitutive activation demonstrated biochemically, inhibitor blockade confirmed, in vivo oncogenicity established","pmids":["23970477"],"is_preprint":false},{"year":2012,"finding":"ETV6-PDGFRB and FIP1L1-PDGFRA fusion oncogenes activate STAT1, STAT3, STAT5, and NF-κB in human CD34+ hematopoietic progenitors; NF-κB activation is downstream of PI3K, and NF-κB inhibition blocks eosinophil differentiation and expression of eosinophil markers (IL-5 receptor, eosinophil peroxidase).","method":"Retroviral transduction of human cord-blood CD34+ cells; phospho-Western blotting; PI3K inhibition; dominant-negative IκB; bortezomib/BMS-345541 treatment; gene expression microarrays","journal":"Haematologica","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (pharmacological, genetic dominant-negative, expression arrays) in human progenitor model","pmids":["22271894"],"is_preprint":false},{"year":2018,"finding":"PDGFRA extracellular domain mutation Y288C results in primary high-mannose glycosylation consistent with ER retention, constitutive dimerization and phosphorylation in the absence of ligand, and constitutive activation of Akt, ERK1/2, and STAT3; this mutant is resistant to PDGFR inhibitors but sensitive to PI3K/mTOR and MEK inhibitors.","method":"Characterization of glycosylation state; constitutive phosphorylation assays; dimerization assays; inhibitor sensitivity profiling in cell lines","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical characterization of activation mechanism (glycosylation, dimerization, signaling) with multiple orthogonal methods","pmids":["30389923"],"is_preprint":false},{"year":2020,"finding":"Secondary resistance to avapritinib in PDGFRA-mutant GIST is caused by secondary mutations in PDGFRA exons 13, 14, and 15 (V658A, N659K, Y676C, G680R) that interfere with avapritinib binding; most resistant tumors remain dependent on PDGFRA oncogenic signaling.","method":"Tumor and plasma biopsy sequencing from patients progressing on avapritinib or imatinib; functional analysis of resistance mutations","journal":"Cancer Discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clinical specimen sequencing with functional inference; binding interference inferred structurally but not directly demonstrated biochemically in this study","pmids":["32972961"],"is_preprint":false},{"year":2001,"finding":"PDGF-A/PDGFRA signaling promotes medulloblastoma cell migration and drives RAS/MAPK pathway activation (dose-dependent phosphorylation of MEK1, MEK2, p42/p44 MAPK); neutralizing antibodies to PDGFRA block MEK/MAPK phosphorylation and inhibit migration.","method":"In vitro migration assays; phospho-Western blotting with PDGF-A stimulation; neutralizing antibody blockade; MEK inhibitor (U0126) treatment","journal":"Nature Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ligand stimulation with receptor-blocking antibody and downstream signaling readouts, single lab","pmids":["11544480"],"is_preprint":false},{"year":2008,"finding":"Activating PDGFRA mutations (exons 12 and 18, including D842V) are found in 70% of inflammatory fibroid polyps, demonstrating that gain-of-function PDGFRA mutations drive neoplastic rather than reactive growth in IFPs.","method":"Mutational analysis (PCR + sequencing) of PDGFRA exons 10, 12, 14, 18 in 23 IFPs; FISH for FIP1L1-PDGFRA translocation (negative)","journal":"Journal of Pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing identifying gain-of-function mutations already characterized functionally in GISTs, single lab","pmids":["18686281"],"is_preprint":false},{"year":2013,"finding":"Conditional deletion of Pdgfra in murine epicardium (Tbx18-Cre) prevents differentiation of epicardium-derived cells into mature cardiac fibroblasts, while canonical Wnt, Hh, and Fgfr1/2 signaling are dispensable for epicardial development.","method":"Conditional knockout using Tbx18-Cre; cardiac phenotyping","journal":"Cardiovascular Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific cellular phenotypic readout (fibroblast differentiation failure), single lab","pmids":["24000064"],"is_preprint":false},{"year":2016,"finding":"Pdgfra and Pdgfrb genetically interact during palatogenesis in zebrafish and mouse: double mutants show significantly more severe palatal defects than pdgfra single mutants; in zebrafish, this interaction affects neural crest condensation in maxillary arches without affecting proliferation or cell death.","method":"Zebrafish/mouse double mutant genetic epistasis; time-lapse confocal imaging of neural crest condensation; pharmacological Pdgf inhibition","journal":"Developmental Dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in two vertebrate models with live imaging, single lab","pmids":["26971580"],"is_preprint":false},{"year":2020,"finding":"In CKD, PDGFRA is translocated to early endosomes upon sonic hedgehog overexpression; within the endosome, PDGFRA activates TGFB1/SMAD signaling to promote GMC differentiation into myofibroblasts, ECM deposition, and vascular fibrosis; conditional Pdgfra KO in GLI1+ mesenchymal cells suppresses neointima formation and improves AVF patency.","method":"Conditional Pdgfra knockout in GLI1+ cells; subcellular fractionation/immunofluorescence for PDGFRA endosomal localization; SMAD signaling assays; in vivo AVF model in CKD mice","journal":"JCI Insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific phenotypic readout plus subcellular localization mechanistic data, single lab","pmids":["33001865"],"is_preprint":false},{"year":2020,"finding":"Pdgfra directs embryonic mesenchymal stem cell differentiation toward chondrocyte progenitors by inhibiting Wnt9a transcription and its downstream beta-catenin signaling; activating Wnt signaling rescues the ectopic cartilage phenotype caused by excessive Pdgfra activity.","method":"Tissue-specific conditional Pdgfra knockout and gain-of-function mouse models; Wnt9a expression analysis; rescue experiments with Wnt pathway activation","journal":"Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional genetic models with pathway rescue experiment, single lab","pmids":["32800757"],"is_preprint":false},{"year":2017,"finding":"EGFRvIII-driven GBM tumorigenesis requires PDGFRA co-stimulatory signaling; simultaneous pharmacological inhibition of both EGFRvIII and PDGFRA kinases is necessary for anti-tumor efficacy in EGFRvIII-expressing GBM patient-derived xenografts.","method":"Genetically engineered autochthonous GBM mouse model; combinatorial kinase inhibitor treatment in PDX models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model plus PDX pharmacological validation, single lab","pmids":["33707748"],"is_preprint":false},{"year":2017,"finding":"EGFR functionally transactivates PDGFRA and induces EGFR-PDGFRA receptor heterodimerization in GBM tumor sphere lines; EGF-induced transactivation and heterodimerization are abolished by EGFR inhibitors.","method":"Co-immunoprecipitation; phosphorylation assays; EGFR inhibitor treatment; single-cell imaging in GBM tumor sphere lines","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP evidence for heterodimerization with functional transactivation assays, single lab","pmids":["28831081"],"is_preprint":false},{"year":2014,"finding":"Cell-surface expression of PDGFRA in glioma cells is negatively regulated by ERK-dependent trafficking: MEK inhibition (U0126) reduces PDGFRA co-localization with endosomal recycling markers (clathrin, RAB11, EEA1) and increases co-localization with the Golgi marker Giantin, diverting PDGFRA from recycling to Golgi retention, reducing surface PDGFRA and glioma cell proliferation.","method":"Single-cell imaging; flow cytometry; subcellular co-localization immunofluorescence; MEK inhibitor treatment; glioma cell proliferation assays","journal":"PloS One","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct localization experiments tied to functional consequence (proliferation), single lab with multiple imaging methods","pmids":["24489888"],"is_preprint":false},{"year":2022,"finding":"FLNC deficiency induces nuclear translocation of beta-catenin (CTNNB1), which subsequently activates PDGFRA signaling; this was demonstrated by co-immunoprecipitation and proteomic identification of CTNNB1 as a FLNC downstream target, and pharmacological inhibition of PDGFRA with crenolanib improved contractile function in patient-specific iPSC-derived cardiomyocytes.","method":"Patient-specific iPSC-CMs with FLNCtv mutations; FLNC siRNA knockdown; co-immunoprecipitation and proteomics; crenolanib (PDGFRA inhibitor) treatment; contractility measurements","journal":"Science Advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/proteomics identifying pathway axis, functional rescue with inhibitor, two different patient mutations tested","pmids":["35196083"],"is_preprint":false},{"year":1991,"finding":"The mouse patch (Ph) mutation carries a deletion encompassing the Pdgfra gene: Ph homozygotes lack Pdgfra genomic sequences and Pdgfra mRNA, establishing that Pdgfra loss-of-function causes the Ph developmental phenotype.","method":"Interspecific backcross mapping; RFLP analysis; genomic Southern blotting; RNA analysis of embryos","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion mapped to Pdgfra locus with DNA and RNA confirmation, foundational developmental genetics paper","pmids":["1846043"],"is_preprint":false},{"year":2017,"finding":"In alveolar rhabdomyosarcoma, Src family kinases potentiate PDGFRA signaling; acquired resistance to PDGFRA inhibition involves upregulation of Src-Raf-MAPK signaling downstream of PDGFRA; in Pdgfra-knockout tumors, Src inhibition had no effect on viability, establishing PDGFRA as the required nodal point for Src-Raf activity.","method":"Kinase inhibitor combinations in primary aRMS cell cultures; Pdgfra knockout tumor cells; in vivo sorafenib treatment of mouse aRMS tumors","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO epistasis combined with pharmacological validation in vitro and in vivo, single lab","pmids":["22960170"],"is_preprint":false},{"year":2025,"finding":"Endocan (ESM1), an endothelial-secreted proteoglycan, directly binds and activates PDGFRA; subsequent PDGFRA signaling enhances chromatin accessibility at the Myc promoter and upregulates Myc expression, inducing stable phenotypic changes (proliferation, migration, angiogenesis) in GBM cells; ponatinib (PDGFRA inhibitor) increases survival in Esm1 wild-type but not Esm1-knockout mouse GBM model.","method":"Direct binding assay of Endocan to PDGFRA; PDGFRA activation/phosphorylation assays; ATAC-seq chromatin accessibility; Myc expression assays; Esm1 KO mouse GBM model with ponatinib treatment","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and downstream signaling shown with in vivo genetic rescue, single lab","pmids":["39773984"],"is_preprint":false},{"year":2017,"finding":"pdgfra is required for proper medial migration of both endocardial and myocardial precursors during zebrafish cardiac assembly; pdgfra mutants (truncated protein fused with mRFP by gene trapping) display defective endocardial migration to the midline, leading to abnormal myocardial fusion.","method":"Gene-trap zebrafish pdgfra mutant; expression analysis; cardiac morphology assessment; endocardial migration imaging","journal":"Biology Open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype (endocardial migration defect), single lab","pmids":["28167492"],"is_preprint":false},{"year":2011,"finding":"CD140a (PDGFRα) identifies human oligodendrocyte progenitor cells (OPCs) in fetal forebrain as a bipotential mitotic population capable of oligodendrocyte or astrocyte fate specification; CD140a+ cells transplanted into hypomyelinated shiverer mice migrate robustly and myelinate more efficiently than A2B5+ cells.","method":"FACS isolation of CD140a+ cells; in vitro differentiation assays; xenotransplantation into shiverer mice; microarray expression analysis","journal":"Nature Biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — prospective isolation with functional differentiation and in vivo engraftment assays, single lab","pmids":["21947029"],"is_preprint":false},{"year":2020,"finding":"50% of H3.3 G34R/V gliomas bear co-occurring activating PDGFRA mutations that show strong selection pressure at recurrence; a chromatin loop connecting PDGFRA to GSX2 regulatory elements in interneuron progenitor cells promotes PDGFRA overexpression, and mutant PDGFRA is potently oncogenic while G34R/V can become dispensable for tumor maintenance.","method":"Integrated genomic analysis of G34R/V tumor cohort; chromatin conformation (loop) analysis; single-cell transcriptomics; functional oncogenicity assays","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin loop mechanistic data plus functional oncogenicity experiments, single study with multiple methods","pmids":["33259802"],"is_preprint":false}],"current_model":"PDGFRA is a type III receptor tyrosine kinase whose auto-inhibited state is maintained by juxtamembrane domain insertion into the active site stabilizing the 'DFG out' conformation; activating mutations (e.g., D842V in the activation loop, V561D in the juxtamembrane domain) disrupt this auto-inhibition to cause constitutive, ligand-independent kinase activity that drives downstream PI3K/AKT/mTOR, RAS/MEK/ERK, and STAT5/NF-κB signaling; the receptor can also be activated by ligand (PDGF-A/B), gene fusion (FIP1L1-PDGFRA), gene rearrangement (intragenic deletion), or extracellular paracrine factors (e.g., Endocan); its surface expression is regulated by ERK-dependent endosomal trafficking/recycling; in development it is essential for cardiac fibroblast differentiation, neural crest palatogenesis, chondrocyte progenitor specification (via Wnt9a suppression), and OPC identity, and in disease its mutations are the principal oncogenic drivers of GIST, pediatric high-grade glioma, and eosinophilic leukemia."},"narrative":{"mechanistic_narrative":"PDGFRA is a type III receptor tyrosine kinase that transduces extracellular cues into proliferative, migratory, and differentiation programs during development and is a principal oncogenic driver when its kinase activity becomes deregulated [PMID:12522257, PMID:23970477, PMID:1846043]. In its resting state the kinase is auto-inhibited by insertion of the juxtamembrane domain into the active site, which stabilizes a 'DFG-out' inactive conformation maintained by Asp842 contacts with the activation loop; the activation-loop mutation D842V disrupts this stabilization, constitutively activates the kinase, and raises ATP affinity, explaining both ligand-independent signaling and imatinib resistance [PMID:27349873]. Constitutive activation arises through multiple routes: activation-loop and juxtamembrane point mutations (D842V, V561D) [PMID:15928335, PMID:27349873], extracellular-domain mutations such as Y288C that cause ER retention with ligand-independent dimerization [PMID:30389923], intragenic deletions and gene fusions (KDR-PDGFRA, FIP1L1-PDGFRA) [PMID:20889717, PMID:17440089], and ligand or paracrine inputs including PDGF-A and the endothelial proteoglycan Endocan, which binds and activates the receptor to drive Myc-dependent chromatin remodeling [PMID:11544480, PMID:39773984]. Activated PDGFRA engages a converging signaling network — PI3K/AKT/mTOR (with SHP-2/PTPN11 acting upstream of PI3K), RAS/MEK/ERK, and STAT/NF-κB cascades — that mediates proliferation, migration, and lineage output [PMID:17440089, PMID:21393858, PMID:22271894, PMID:11544480]. ERK activity in turn feeds back on receptor surface levels by directing PDGFRA between endosomal recycling and Golgi retention [PMID:24489888]. These mutations are the dominant oncogenic mechanism in KIT-wild-type GIST, inflammatory fibroid polyps, pediatric and H3.3 G34R/V high-grade glioma, and FIP1L1-PDGFRA eosinophilic leukemia, motivating conformation-selective inhibitors such as avapritinib that engage the active state to overcome D842V resistance [PMID:12522257, PMID:29093181, PMID:17440089, PMID:23970477, PMID:18686281, PMID:33259802]. Developmentally, Pdgfra is required for cardiac fibroblast and endocardial/myocardial assembly, neural crest palatogenesis, chondrocyte progenitor specification via Wnt9a suppression, and marks bipotential oligodendrocyte progenitors [PMID:24000064, PMID:26971580, PMID:32800757, PMID:1846043, PMID:28167492, PMID:21947029].","teleology":[{"year":1991,"claim":"Established that PDGFRA loss-of-function underlies a defined developmental phenotype, demonstrating the gene's essential in vivo role before its oncogenic functions were defined.","evidence":"Genetic mapping and Southern/RNA analysis of the mouse patch (Ph) deletion encompassing Pdgfra","pmids":["1846043"],"confidence":"High","gaps":["Does not define the cell types or signaling outputs requiring Pdgfra","No molecular mechanism of receptor activity addressed"]},{"year":2003,"claim":"Identified PDGFRA as an alternative oncogenic driver in KIT-wild-type GIST, establishing intragenic activating mutations as a clinically central mechanism mutually exclusive with KIT.","evidence":"Mutational sequencing of GIST tumors with downstream signaling characterization","pmids":["12522257"],"confidence":"High","gaps":["Did not resolve the structural basis of activation","Did not establish inhibitor sensitivity profiles per mutation"]},{"year":2005,"claim":"Resolved which PDGFRA mutations are imatinib-sensitive versus resistant, directly informing therapy by mapping drug response to mutation site.","evidence":"Expression of PDGFRA mutant isoforms in CHO and BA/F3 cells with proliferation/inhibition assays","pmids":["15928335"],"confidence":"High","gaps":["Mechanism of D842 resistance not yet structurally explained","No inhibitor effective against resistant activation-loop mutants"]},{"year":2007,"claim":"Defined the signaling output and domain requirements of the FIP1L1-PDGFRA fusion in human progenitors, linking the fusion to myeloproliferation through PI3K/ERK/STAT5.","evidence":"Retroviral transduction of CD34+ progenitors with deletion mutants, dominant-negative STAT5, and pharmacological inhibitors","pmids":["17440089"],"confidence":"High","gaps":["Did not define how fusion alters receptor conformation/dimerization","Relative contribution of each pathway to leukemogenesis unresolved"]},{"year":2010,"claim":"Showed that genomic rearrangements (intragenic deletion, KDR-PDGFRA fusion) constitutively activate PDGFRA in glioma, expanding the repertoire of activation mechanisms beyond point mutation.","evidence":"Genomic analysis of glioma PDGFRA locus with kinase activity, transformation, and inhibitor-reversal assays","pmids":["20889717"],"confidence":"High","gaps":["Structural consequence of rearrangements on the kinase not defined","Did not map downstream effector requirements"]},{"year":2011,"claim":"Placed SHP-2 upstream of PI3K/AKT/mTOR in PDGFRA-driven gliomagenesis, identifying a required adaptor node and a tractable epistatic relationship.","evidence":"Signaling-module PDGFRA mutants, SHP-2 knockdown/inhibition, activated-PI3K rescue, and intracranial glioma model","pmids":["21393858"],"confidence":"High","gaps":["Direct biochemistry of the PDGFRA–SHP-2 interface not crystallographically resolved","Generality across tumor types not established"]},{"year":2011,"claim":"Established CD140a/PDGFRα as a marker of bipotential human oligodendrocyte progenitors with superior myelination capacity, linking receptor expression to a defined neural lineage.","evidence":"FACS isolation, in vitro differentiation, and xenotransplantation into shiverer mice","pmids":["21947029"],"confidence":"Medium","gaps":["Did not test whether PDGFRA signaling is required for OPC fate versus merely marking it","Single lab"]},{"year":2012,"claim":"Extended fusion-oncogene signaling to STAT1/3/5 and NF-κB, showing PI3K-dependent NF-κB drives the eosinophil differentiation program characteristic of these leukemias.","evidence":"CD34+ transduction with dominant-negative IκB, PI3K inhibition, and gene expression microarrays","pmids":["22271894"],"confidence":"High","gaps":["Direct NF-κB target genes for lineage skewing only partially mapped","Did not distinguish PDGFRA-specific versus PDGFRB-shared effects"]},{"year":2013,"claim":"Showed that novel pediatric high-grade glioma PDGFRA mutations are bona fide ligand-independent oncogenic drivers in vivo, broadening the disease spectrum.","evidence":"Full-coding sequencing, receptor phosphorylation assays, and p53-null astrocyte transformation with intracranial implantation","pmids":["23970477"],"confidence":"High","gaps":["Inhibitor sensitivity of each mutant not exhaustively mapped","Co-occurring genetic context dependence not addressed here"]},{"year":2016,"claim":"Provided the structural basis of PDGFRA auto-inhibition and D842V activation, mechanistically explaining constitutive activity and imatinib resistance.","evidence":"X-ray crystallography of the kinase domain plus ATP-affinity kinetics for D842V","pmids":["27349873"],"confidence":"High","gaps":["Full-length receptor and ligand-bound conformations not captured","Structure did not directly model inhibitor engagement"]},{"year":2017,"claim":"Delivered a conformation-selective inhibitor (avapritinib) engaging the active state to overcome D842V resistance, translating structural insight into a therapy for resistant mutants.","evidence":"In vitro kinase assays, preclinical models, and phase 1 clinical evaluation","pmids":["29093181"],"confidence":"High","gaps":["Mechanisms of secondary resistance not yet defined","Precise binding-pocket interactions not crystallographically resolved at this stage"]},{"year":2017,"claim":"Identified cross-talk and dependency relationships of PDGFRA with EGFR and Src family kinases, revealing combinatorial requirements for tumor maintenance.","evidence":"Co-IP/heterodimerization and transactivation in GBM spheres; Src/Pdgfra epistasis in aRMS with KO and inhibitor combinations in vitro and in vivo","pmids":["28831081","33707748","22960170"],"confidence":"Medium","gaps":["Stoichiometry and direct versus indirect nature of EGFR-PDGFRA association not fully defined","Co-IP-based heterodimerization without reciprocal structural validation"]},{"year":2018,"claim":"Revealed an extracellular-domain activation mechanism (Y288C) driven by altered glycosylation and ER-associated ligand-independent dimerization, with a distinct inhibitor-sensitivity profile.","evidence":"Glycosylation, dimerization, and phosphorylation assays with inhibitor sensitivity profiling in cell lines","pmids":["30389923"],"confidence":"High","gaps":["Subcellular site of active signaling not directly imaged","Frequency across tumor types not established"]},{"year":2020,"claim":"Defined avapritinib secondary-resistance mutations and confirmed continued PDGFRA dependence, establishing the receptor as a persistent therapeutic target at progression.","evidence":"Tumor and plasma sequencing of progressing patients with functional analysis of resistance mutations","pmids":["32972961"],"confidence":"Medium","gaps":["Binding interference inferred structurally, not demonstrated biochemically","Did not test next-generation inhibitors against these mutants"]},{"year":2020,"claim":"Connected PDGFRA to chromatin-level regulation and trafficking in disease: a chromatin loop driving PDGFRA overexpression in G34R/V glioma, and endosomal PDGFRA driving TGFB1/SMAD fibrosis in CKD.","evidence":"Chromatin conformation and oncogenicity assays in glioma; conditional Pdgfra KO with endosomal localization and SMAD signaling in an AVF/CKD model","pmids":["33259802","33001865"],"confidence":"Medium","gaps":["Mechanism coupling endosomal PDGFRA to SMAD activation not biochemically resolved","Generality of the GSX2 loop to other lineages unknown"]},{"year":2020,"claim":"Clarified PDGFRA's developmental roles in lineage decisions: chondrocyte progenitor specification via Wnt9a suppression and epicardial fibroblast differentiation.","evidence":"Conditional Pdgfra loss- and gain-of-function mouse models with Wnt pathway rescue; Tbx18-Cre epicardial knockout","pmids":["32800757","24000064"],"confidence":"Medium","gaps":["Direct effectors linking PDGFRA to Wnt9a transcription not identified","Single-lab findings"]},{"year":2022,"claim":"Positioned PDGFRA downstream of FLNC loss via β-catenin, implicating receptor activity in a non-cancer cardiomyopathy and validating inhibition as a functional intervention.","evidence":"FLNC-mutant iPSC-cardiomyocytes with Co-IP/proteomics and crenolanib contractility rescue","pmids":["35196083"],"confidence":"Medium","gaps":["Mechanism of β-catenin-driven PDGFRA activation not defined","Co-IP/proteomics axis without reciprocal validation"]},{"year":2024,"claim":"Resolved the avapritinib binding mode and a critical Gα sub-pocket, enabling structure-guided design of derivatives against resistance.","evidence":"X-ray crystallography of avapritinib–PDGFRA complexes with derivative pharmacology","pmids":["38167404"],"confidence":"High","gaps":["Clinical efficacy of new derivatives not established","Coverage of all resistance mutations not demonstrated"]},{"year":2025,"claim":"Identified Endocan as a direct extracellular activator of PDGFRA driving Myc-dependent chromatin remodeling, revealing a paracrine route to receptor activation in glioma.","evidence":"Direct binding and phosphorylation assays, ATAC-seq, and Esm1-KO mouse GBM with ponatinib treatment","pmids":["39773984"],"confidence":"Medium","gaps":["Binding interface on PDGFRA not structurally mapped","Relationship to canonical PDGF ligand signaling unresolved"]},{"year":null,"claim":"How the diverse activation modes (point mutation, extracellular/glycosylation defects, fusions, paracrine ligands, chromatin-level overexpression) differentially shape downstream signaling balance, trafficking, and inhibitor response in a single quantitative framework remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of full-length ligand- versus mutation-activated receptor","Effector-level differences between activation modes not systematically compared","Mechanism coupling endosomal/Golgi trafficking to signaling output incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,8,10]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[12,24]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[24]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma 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gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23862765","citation_count":18,"is_preprint":false},{"pmid":"29904623","id":"PMC_29904623","title":"CDK4/6 and PDGFRA Signaling as Therapeutic Targets in Diffuse Intrinsic Pontine Glioma.","date":"2018","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29904623","citation_count":18,"is_preprint":false},{"pmid":"38178783","id":"PMC_38178783","title":"Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors.","date":"2024","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/38178783","citation_count":17,"is_preprint":false},{"pmid":"38344849","id":"PMC_38344849","title":"KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem.","date":"2024","source":"Expert opinion on investigational 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\"PDGFRA harbors activating intragenic mutations in ~35% of KIT-wild-type GISTs, making KIT and PDGFRA mutations alternative and mutually exclusive oncogenic mechanisms in GISTs; both activate overlapping downstream signaling intermediates.\",\n      \"method\": \"Mutational sequencing of GIST tumors; functional characterization of downstream signaling activation\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — original discovery paper with direct sequencing and downstream signaling analysis, replicated extensively across many subsequent studies\",\n      \"pmids\": [\"12522257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PDGFRA exon 12 mutations (e.g., V561D, SPDHE566-571R) and exon 14 substitution (N659K) are imatinib-sensitive, whereas most exon 18 codon D842 substitutions (D842V, RD841-842KI, DI842-843IM) are imatinib-resistant in vitro; D842Y is an exception that retains imatinib sensitivity.\",\n      \"method\": \"Transient expression of PDGFRA mutant isoforms in CHO cells; stable expression in BA/F3 cell lines; proliferation/inhibition assays\",\n      \"journal\": \"Journal of Clinical Oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase inhibition assays with multiple mutant isoforms expressed in cell lines, replicated across multiple labs\",\n      \"pmids\": [\"15928335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PDGFRA gene rearrangements, including an intragenic deletion of exons 8 and 9 (PDGFRA-Δ8,9) and a KDR-PDGFRA gene fusion, occur in 40% of PDGFRA-amplified GBMs; both rearrangements produce constitutively elevated tyrosine kinase activity and transforming potential reversible by PDGFR blockade.\",\n      \"method\": \"Genomic analysis of glioma PDGFRA locus; functional assays measuring constitutive kinase activity and transformation; PDGFR inhibitor treatment\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — constitutive kinase activity measured directly, transforming potential demonstrated, inhibitor reversal shown in single focused study\",\n      \"pmids\": [\"20889717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the PDGFRA kinase domain in the auto-inhibited form reveals that the juxtamembrane (JM) domain inserts into the active site stabilizing a 'DFG out' (inactive) conformation; Asp842 makes extensive contacts with activation-loop residues to maintain this conformation. The D842V mutation disrupts this stabilization, constitutively activates the kinase, and increases ATP affinity, together explaining imatinib resistance.\",\n      \"method\": \"X-ray crystallography of PDGFRA kinase domain; kinetic measurements of ATP affinity for D842V mutant\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional kinetic validation in a single study; mechanistic explanation for D842V resistance\",\n      \"pmids\": [\"27349873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BLU-285 (avapritinib), designed to interact preferentially with the active conformation of PDGFRA, potently inhibits the activation-loop mutant PDGFRA D842V with subnanomolar potency, overcoming the resistance seen with type II inhibitors (imatinib) that require the inactive 'DFG out' conformation.\",\n      \"method\": \"In vitro kinase inhibition assays; preclinical cell/animal models; phase 1 clinical evaluation\",\n      \"journal\": \"Science Translational Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic structure-activity studies combined with in vitro and in vivo preclinical models and clinical validation\",\n      \"pmids\": [\"29093181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Crystal structures of avapritinib in complex with wild-type and mutant PDGFRA (and KIT) reveal the inhibitor binding mode and identify a sub-pocket (Gα-pocket) critical for inhibitor engagement; this structural information was used to design derivatives that overcome drug resistance.\",\n      \"method\": \"X-ray crystallography of avapritinib–PDGFRA complexes; structure-guided medicinal chemistry and pharmacologic characterization of derivatives\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with functional validation through designed derivatives in a single rigorous study\",\n      \"pmids\": [\"38167404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The FIP1L1-PDGFRA fusion protein promotes myeloproliferation in human CD34+ hematopoietic progenitors by activating PI3K, ERK1/2, and STAT5 signaling; STAT5 activation is dependent on the FIP1L1 N-terminal domain (aa 30-233), and combined PI3K + ERK1/2 inhibition significantly reverses colony formation.\",\n      \"method\": \"Retroviral transduction of human CD34+ progenitors with FIP1L1-PDGFRA and deletion mutants; phospho-Western blotting; dominant-negative STAT5; pharmacological inhibitors\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (signaling assays, deletion mutants, dominant-negative, pharmacological inhibition) in a single study\",\n      \"pmids\": [\"17440089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SHP-2 (PTPN11) mediates PDGFRA-driven gliomagenesis: abrogation of the PDGFRA–SHP-2 binding interface or pharmacological SHP-2 inhibition disrupts PI3K interaction with PDGFRA, suppresses downstream AKT/mTOR activation, and impairs tumorigenicity of Ink4a/Arf-null cells; activated PI3K rescues this effect, placing SHP-2 upstream of PI3K/AKT/mTOR.\",\n      \"method\": \"Epistasis via signaling-module mutants of PDGFRA; shRNA knockdown and pharmacological inhibitors of SHP-2; activated PI3K rescue experiment; mouse intracranial glioma model\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple orthogonal approaches (domain mutants, shRNA, pharmacological, rescue), supported by in vivo glioma model\",\n      \"pmids\": [\"21393858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Novel somatic PDGFRA missense mutations and in-frame deletions/insertions in pediatric high-grade gliomas result in ligand-independent receptor activation blocked by PDGFR small-molecule inhibitors; expression of these mutants in p53-null mouse astrocytes confers proliferative advantage and generates HGGs in vivo with complete penetrance.\",\n      \"method\": \"Full coding-sequence sequencing of PDGFRA; in vitro receptor phosphorylation assays; p53-null astrocyte transformation assay; intracranial implantation mouse model\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — constitutive activation demonstrated biochemically, inhibitor blockade confirmed, in vivo oncogenicity established\",\n      \"pmids\": [\"23970477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ETV6-PDGFRB and FIP1L1-PDGFRA fusion oncogenes activate STAT1, STAT3, STAT5, and NF-κB in human CD34+ hematopoietic progenitors; NF-κB activation is downstream of PI3K, and NF-κB inhibition blocks eosinophil differentiation and expression of eosinophil markers (IL-5 receptor, eosinophil peroxidase).\",\n      \"method\": \"Retroviral transduction of human cord-blood CD34+ cells; phospho-Western blotting; PI3K inhibition; dominant-negative IκB; bortezomib/BMS-345541 treatment; gene expression microarrays\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (pharmacological, genetic dominant-negative, expression arrays) in human progenitor model\",\n      \"pmids\": [\"22271894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PDGFRA extracellular domain mutation Y288C results in primary high-mannose glycosylation consistent with ER retention, constitutive dimerization and phosphorylation in the absence of ligand, and constitutive activation of Akt, ERK1/2, and STAT3; this mutant is resistant to PDGFR inhibitors but sensitive to PI3K/mTOR and MEK inhibitors.\",\n      \"method\": \"Characterization of glycosylation state; constitutive phosphorylation assays; dimerization assays; inhibitor sensitivity profiling in cell lines\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical characterization of activation mechanism (glycosylation, dimerization, signaling) with multiple orthogonal methods\",\n      \"pmids\": [\"30389923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Secondary resistance to avapritinib in PDGFRA-mutant GIST is caused by secondary mutations in PDGFRA exons 13, 14, and 15 (V658A, N659K, Y676C, G680R) that interfere with avapritinib binding; most resistant tumors remain dependent on PDGFRA oncogenic signaling.\",\n      \"method\": \"Tumor and plasma biopsy sequencing from patients progressing on avapritinib or imatinib; functional analysis of resistance mutations\",\n      \"journal\": \"Cancer Discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clinical specimen sequencing with functional inference; binding interference inferred structurally but not directly demonstrated biochemically in this study\",\n      \"pmids\": [\"32972961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PDGF-A/PDGFRA signaling promotes medulloblastoma cell migration and drives RAS/MAPK pathway activation (dose-dependent phosphorylation of MEK1, MEK2, p42/p44 MAPK); neutralizing antibodies to PDGFRA block MEK/MAPK phosphorylation and inhibit migration.\",\n      \"method\": \"In vitro migration assays; phospho-Western blotting with PDGF-A stimulation; neutralizing antibody blockade; MEK inhibitor (U0126) treatment\",\n      \"journal\": \"Nature Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ligand stimulation with receptor-blocking antibody and downstream signaling readouts, single lab\",\n      \"pmids\": [\"11544480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Activating PDGFRA mutations (exons 12 and 18, including D842V) are found in 70% of inflammatory fibroid polyps, demonstrating that gain-of-function PDGFRA mutations drive neoplastic rather than reactive growth in IFPs.\",\n      \"method\": \"Mutational analysis (PCR + sequencing) of PDGFRA exons 10, 12, 14, 18 in 23 IFPs; FISH for FIP1L1-PDGFRA translocation (negative)\",\n      \"journal\": \"Journal of Pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing identifying gain-of-function mutations already characterized functionally in GISTs, single lab\",\n      \"pmids\": [\"18686281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Conditional deletion of Pdgfra in murine epicardium (Tbx18-Cre) prevents differentiation of epicardium-derived cells into mature cardiac fibroblasts, while canonical Wnt, Hh, and Fgfr1/2 signaling are dispensable for epicardial development.\",\n      \"method\": \"Conditional knockout using Tbx18-Cre; cardiac phenotyping\",\n      \"journal\": \"Cardiovascular Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific cellular phenotypic readout (fibroblast differentiation failure), single lab\",\n      \"pmids\": [\"24000064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pdgfra and Pdgfrb genetically interact during palatogenesis in zebrafish and mouse: double mutants show significantly more severe palatal defects than pdgfra single mutants; in zebrafish, this interaction affects neural crest condensation in maxillary arches without affecting proliferation or cell death.\",\n      \"method\": \"Zebrafish/mouse double mutant genetic epistasis; time-lapse confocal imaging of neural crest condensation; pharmacological Pdgf inhibition\",\n      \"journal\": \"Developmental Dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in two vertebrate models with live imaging, single lab\",\n      \"pmids\": [\"26971580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In CKD, PDGFRA is translocated to early endosomes upon sonic hedgehog overexpression; within the endosome, PDGFRA activates TGFB1/SMAD signaling to promote GMC differentiation into myofibroblasts, ECM deposition, and vascular fibrosis; conditional Pdgfra KO in GLI1+ mesenchymal cells suppresses neointima formation and improves AVF patency.\",\n      \"method\": \"Conditional Pdgfra knockout in GLI1+ cells; subcellular fractionation/immunofluorescence for PDGFRA endosomal localization; SMAD signaling assays; in vivo AVF model in CKD mice\",\n      \"journal\": \"JCI Insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific phenotypic readout plus subcellular localization mechanistic data, single lab\",\n      \"pmids\": [\"33001865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Pdgfra directs embryonic mesenchymal stem cell differentiation toward chondrocyte progenitors by inhibiting Wnt9a transcription and its downstream beta-catenin signaling; activating Wnt signaling rescues the ectopic cartilage phenotype caused by excessive Pdgfra activity.\",\n      \"method\": \"Tissue-specific conditional Pdgfra knockout and gain-of-function mouse models; Wnt9a expression analysis; rescue experiments with Wnt pathway activation\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic models with pathway rescue experiment, single lab\",\n      \"pmids\": [\"32800757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EGFRvIII-driven GBM tumorigenesis requires PDGFRA co-stimulatory signaling; simultaneous pharmacological inhibition of both EGFRvIII and PDGFRA kinases is necessary for anti-tumor efficacy in EGFRvIII-expressing GBM patient-derived xenografts.\",\n      \"method\": \"Genetically engineered autochthonous GBM mouse model; combinatorial kinase inhibitor treatment in PDX models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model plus PDX pharmacological validation, single lab\",\n      \"pmids\": [\"33707748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EGFR functionally transactivates PDGFRA and induces EGFR-PDGFRA receptor heterodimerization in GBM tumor sphere lines; EGF-induced transactivation and heterodimerization are abolished by EGFR inhibitors.\",\n      \"method\": \"Co-immunoprecipitation; phosphorylation assays; EGFR inhibitor treatment; single-cell imaging in GBM tumor sphere lines\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP evidence for heterodimerization with functional transactivation assays, single lab\",\n      \"pmids\": [\"28831081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cell-surface expression of PDGFRA in glioma cells is negatively regulated by ERK-dependent trafficking: MEK inhibition (U0126) reduces PDGFRA co-localization with endosomal recycling markers (clathrin, RAB11, EEA1) and increases co-localization with the Golgi marker Giantin, diverting PDGFRA from recycling to Golgi retention, reducing surface PDGFRA and glioma cell proliferation.\",\n      \"method\": \"Single-cell imaging; flow cytometry; subcellular co-localization immunofluorescence; MEK inhibitor treatment; glioma cell proliferation assays\",\n      \"journal\": \"PloS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct localization experiments tied to functional consequence (proliferation), single lab with multiple imaging methods\",\n      \"pmids\": [\"24489888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FLNC deficiency induces nuclear translocation of beta-catenin (CTNNB1), which subsequently activates PDGFRA signaling; this was demonstrated by co-immunoprecipitation and proteomic identification of CTNNB1 as a FLNC downstream target, and pharmacological inhibition of PDGFRA with crenolanib improved contractile function in patient-specific iPSC-derived cardiomyocytes.\",\n      \"method\": \"Patient-specific iPSC-CMs with FLNCtv mutations; FLNC siRNA knockdown; co-immunoprecipitation and proteomics; crenolanib (PDGFRA inhibitor) treatment; contractility measurements\",\n      \"journal\": \"Science Advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/proteomics identifying pathway axis, functional rescue with inhibitor, two different patient mutations tested\",\n      \"pmids\": [\"35196083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The mouse patch (Ph) mutation carries a deletion encompassing the Pdgfra gene: Ph homozygotes lack Pdgfra genomic sequences and Pdgfra mRNA, establishing that Pdgfra loss-of-function causes the Ph developmental phenotype.\",\n      \"method\": \"Interspecific backcross mapping; RFLP analysis; genomic Southern blotting; RNA analysis of embryos\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion mapped to Pdgfra locus with DNA and RNA confirmation, foundational developmental genetics paper\",\n      \"pmids\": [\"1846043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In alveolar rhabdomyosarcoma, Src family kinases potentiate PDGFRA signaling; acquired resistance to PDGFRA inhibition involves upregulation of Src-Raf-MAPK signaling downstream of PDGFRA; in Pdgfra-knockout tumors, Src inhibition had no effect on viability, establishing PDGFRA as the required nodal point for Src-Raf activity.\",\n      \"method\": \"Kinase inhibitor combinations in primary aRMS cell cultures; Pdgfra knockout tumor cells; in vivo sorafenib treatment of mouse aRMS tumors\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO epistasis combined with pharmacological validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"22960170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Endocan (ESM1), an endothelial-secreted proteoglycan, directly binds and activates PDGFRA; subsequent PDGFRA signaling enhances chromatin accessibility at the Myc promoter and upregulates Myc expression, inducing stable phenotypic changes (proliferation, migration, angiogenesis) in GBM cells; ponatinib (PDGFRA inhibitor) increases survival in Esm1 wild-type but not Esm1-knockout mouse GBM model.\",\n      \"method\": \"Direct binding assay of Endocan to PDGFRA; PDGFRA activation/phosphorylation assays; ATAC-seq chromatin accessibility; Myc expression assays; Esm1 KO mouse GBM model with ponatinib treatment\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and downstream signaling shown with in vivo genetic rescue, single lab\",\n      \"pmids\": [\"39773984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"pdgfra is required for proper medial migration of both endocardial and myocardial precursors during zebrafish cardiac assembly; pdgfra mutants (truncated protein fused with mRFP by gene trapping) display defective endocardial migration to the midline, leading to abnormal myocardial fusion.\",\n      \"method\": \"Gene-trap zebrafish pdgfra mutant; expression analysis; cardiac morphology assessment; endocardial migration imaging\",\n      \"journal\": \"Biology Open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype (endocardial migration defect), single lab\",\n      \"pmids\": [\"28167492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD140a (PDGFRα) identifies human oligodendrocyte progenitor cells (OPCs) in fetal forebrain as a bipotential mitotic population capable of oligodendrocyte or astrocyte fate specification; CD140a+ cells transplanted into hypomyelinated shiverer mice migrate robustly and myelinate more efficiently than A2B5+ cells.\",\n      \"method\": \"FACS isolation of CD140a+ cells; in vitro differentiation assays; xenotransplantation into shiverer mice; microarray expression analysis\",\n      \"journal\": \"Nature Biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — prospective isolation with functional differentiation and in vivo engraftment assays, single lab\",\n      \"pmids\": [\"21947029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"50% of H3.3 G34R/V gliomas bear co-occurring activating PDGFRA mutations that show strong selection pressure at recurrence; a chromatin loop connecting PDGFRA to GSX2 regulatory elements in interneuron progenitor cells promotes PDGFRA overexpression, and mutant PDGFRA is potently oncogenic while G34R/V can become dispensable for tumor maintenance.\",\n      \"method\": \"Integrated genomic analysis of G34R/V tumor cohort; chromatin conformation (loop) analysis; single-cell transcriptomics; functional oncogenicity assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin loop mechanistic data plus functional oncogenicity experiments, single study with multiple methods\",\n      \"pmids\": [\"33259802\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDGFRA is a type III receptor tyrosine kinase whose auto-inhibited state is maintained by juxtamembrane domain insertion into the active site stabilizing the 'DFG out' conformation; activating mutations (e.g., D842V in the activation loop, V561D in the juxtamembrane domain) disrupt this auto-inhibition to cause constitutive, ligand-independent kinase activity that drives downstream PI3K/AKT/mTOR, RAS/MEK/ERK, and STAT5/NF-κB signaling; the receptor can also be activated by ligand (PDGF-A/B), gene fusion (FIP1L1-PDGFRA), gene rearrangement (intragenic deletion), or extracellular paracrine factors (e.g., Endocan); its surface expression is regulated by ERK-dependent endosomal trafficking/recycling; in development it is essential for cardiac fibroblast differentiation, neural crest palatogenesis, chondrocyte progenitor specification (via Wnt9a suppression), and OPC identity, and in disease its mutations are the principal oncogenic drivers of GIST, pediatric high-grade glioma, and eosinophilic leukemia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDGFRA is a type III receptor tyrosine kinase that transduces extracellular cues into proliferative, migratory, and differentiation programs during development and is a principal oncogenic driver when its kinase activity becomes deregulated [#0, #8, #22]. In its resting state the kinase is auto-inhibited by insertion of the juxtamembrane domain into the active site, which stabilizes a 'DFG-out' inactive conformation maintained by Asp842 contacts with the activation loop; the activation-loop mutation D842V disrupts this stabilization, constitutively activates the kinase, and raises ATP affinity, explaining both ligand-independent signaling and imatinib resistance [#3]. Constitutive activation arises through multiple routes: activation-loop and juxtamembrane point mutations (D842V, V561D) [#1, #3], extracellular-domain mutations such as Y288C that cause ER retention with ligand-independent dimerization [#10], intragenic deletions and gene fusions (KDR-PDGFRA, FIP1L1-PDGFRA) [#2, #6], and ligand or paracrine inputs including PDGF-A and the endothelial proteoglycan Endocan, which binds and activates the receptor to drive Myc-dependent chromatin remodeling [#12, #24]. Activated PDGFRA engages a converging signaling network — PI3K/AKT/mTOR (with SHP-2/PTPN11 acting upstream of PI3K), RAS/MEK/ERK, and STAT/NF-\\u03baB cascades — that mediates proliferation, migration, and lineage output [#6, #7, #9, #12]. ERK activity in turn feeds back on receptor surface levels by directing PDGFRA between endosomal recycling and Golgi retention [#20]. These mutations are the dominant oncogenic mechanism in KIT-wild-type GIST, inflammatory fibroid polyps, pediatric and H3.3 G34R/V high-grade glioma, and FIP1L1-PDGFRA eosinophilic leukemia, motivating conformation-selective inhibitors such as avapritinib that engage the active state to overcome D842V resistance [#0, #4, #6, #8, #13, #27]. Developmentally, Pdgfra is required for cardiac fibroblast and endocardial/myocardial assembly, neural crest palatogenesis, chondrocyte progenitor specification via Wnt9a suppression, and marks bipotential oligodendrocyte progenitors [#14, #15, #17, #22, #25, #26].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that PDGFRA loss-of-function underlies a defined developmental phenotype, demonstrating the gene's essential in vivo role before its oncogenic functions were defined.\",\n      \"evidence\": \"Genetic mapping and Southern/RNA analysis of the mouse patch (Ph) deletion encompassing Pdgfra\",\n      \"pmids\": [\"1846043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the cell types or signaling outputs requiring Pdgfra\", \"No molecular mechanism of receptor activity addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified PDGFRA as an alternative oncogenic driver in KIT-wild-type GIST, establishing intragenic activating mutations as a clinically central mechanism mutually exclusive with KIT.\",\n      \"evidence\": \"Mutational sequencing of GIST tumors with downstream signaling characterization\",\n      \"pmids\": [\"12522257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of activation\", \"Did not establish inhibitor sensitivity profiles per mutation\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved which PDGFRA mutations are imatinib-sensitive versus resistant, directly informing therapy by mapping drug response to mutation site.\",\n      \"evidence\": \"Expression of PDGFRA mutant isoforms in CHO and BA/F3 cells with proliferation/inhibition assays\",\n      \"pmids\": [\"15928335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of D842 resistance not yet structurally explained\", \"No inhibitor effective against resistant activation-loop mutants\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the signaling output and domain requirements of the FIP1L1-PDGFRA fusion in human progenitors, linking the fusion to myeloproliferation through PI3K/ERK/STAT5.\",\n      \"evidence\": \"Retroviral transduction of CD34+ progenitors with deletion mutants, dominant-negative STAT5, and pharmacological inhibitors\",\n      \"pmids\": [\"17440089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how fusion alters receptor conformation/dimerization\", \"Relative contribution of each pathway to leukemogenesis unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that genomic rearrangements (intragenic deletion, KDR-PDGFRA fusion) constitutively activate PDGFRA in glioma, expanding the repertoire of activation mechanisms beyond point mutation.\",\n      \"evidence\": \"Genomic analysis of glioma PDGFRA locus with kinase activity, transformation, and inhibitor-reversal assays\",\n      \"pmids\": [\"20889717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural consequence of rearrangements on the kinase not defined\", \"Did not map downstream effector requirements\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed SHP-2 upstream of PI3K/AKT/mTOR in PDGFRA-driven gliomagenesis, identifying a required adaptor node and a tractable epistatic relationship.\",\n      \"evidence\": \"Signaling-module PDGFRA mutants, SHP-2 knockdown/inhibition, activated-PI3K rescue, and intracranial glioma model\",\n      \"pmids\": [\"21393858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemistry of the PDGFRA–SHP-2 interface not crystallographically resolved\", \"Generality across tumor types not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established CD140a/PDGFRα as a marker of bipotential human oligodendrocyte progenitors with superior myelination capacity, linking receptor expression to a defined neural lineage.\",\n      \"evidence\": \"FACS isolation, in vitro differentiation, and xenotransplantation into shiverer mice\",\n      \"pmids\": [\"21947029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not test whether PDGFRA signaling is required for OPC fate versus merely marking it\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended fusion-oncogene signaling to STAT1/3/5 and NF-\\u03baB, showing PI3K-dependent NF-\\u03baB drives the eosinophil differentiation program characteristic of these leukemias.\",\n      \"evidence\": \"CD34+ transduction with dominant-negative I\\u03baB, PI3K inhibition, and gene expression microarrays\",\n      \"pmids\": [\"22271894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NF-\\u03baB target genes for lineage skewing only partially mapped\", \"Did not distinguish PDGFRA-specific versus PDGFRB-shared effects\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that novel pediatric high-grade glioma PDGFRA mutations are bona fide ligand-independent oncogenic drivers in vivo, broadening the disease spectrum.\",\n      \"evidence\": \"Full-coding sequencing, receptor phosphorylation assays, and p53-null astrocyte transformation with intracranial implantation\",\n      \"pmids\": [\"23970477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inhibitor sensitivity of each mutant not exhaustively mapped\", \"Co-occurring genetic context dependence not addressed here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural basis of PDGFRA auto-inhibition and D842V activation, mechanistically explaining constitutive activity and imatinib resistance.\",\n      \"evidence\": \"X-ray crystallography of the kinase domain plus ATP-affinity kinetics for D842V\",\n      \"pmids\": [\"27349873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length receptor and ligand-bound conformations not captured\", \"Structure did not directly model inhibitor engagement\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Delivered a conformation-selective inhibitor (avapritinib) engaging the active state to overcome D842V resistance, translating structural insight into a therapy for resistant mutants.\",\n      \"evidence\": \"In vitro kinase assays, preclinical models, and phase 1 clinical evaluation\",\n      \"pmids\": [\"29093181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanisms of secondary resistance not yet defined\", \"Precise binding-pocket interactions not crystallographically resolved at this stage\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified cross-talk and dependency relationships of PDGFRA with EGFR and Src family kinases, revealing combinatorial requirements for tumor maintenance.\",\n      \"evidence\": \"Co-IP/heterodimerization and transactivation in GBM spheres; Src/Pdgfra epistasis in aRMS with KO and inhibitor combinations in vitro and in vivo\",\n      \"pmids\": [\"28831081\", \"33707748\", \"22960170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and direct versus indirect nature of EGFR-PDGFRA association not fully defined\", \"Co-IP-based heterodimerization without reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed an extracellular-domain activation mechanism (Y288C) driven by altered glycosylation and ER-associated ligand-independent dimerization, with a distinct inhibitor-sensitivity profile.\",\n      \"evidence\": \"Glycosylation, dimerization, and phosphorylation assays with inhibitor sensitivity profiling in cell lines\",\n      \"pmids\": [\"30389923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subcellular site of active signaling not directly imaged\", \"Frequency across tumor types not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined avapritinib secondary-resistance mutations and confirmed continued PDGFRA dependence, establishing the receptor as a persistent therapeutic target at progression.\",\n      \"evidence\": \"Tumor and plasma sequencing of progressing patients with functional analysis of resistance mutations\",\n      \"pmids\": [\"32972961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interference inferred structurally, not demonstrated biochemically\", \"Did not test next-generation inhibitors against these mutants\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected PDGFRA to chromatin-level regulation and trafficking in disease: a chromatin loop driving PDGFRA overexpression in G34R/V glioma, and endosomal PDGFRA driving TGFB1/SMAD fibrosis in CKD.\",\n      \"evidence\": \"Chromatin conformation and oncogenicity assays in glioma; conditional Pdgfra KO with endosomal localization and SMAD signaling in an AVF/CKD model\",\n      \"pmids\": [\"33259802\", \"33001865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling endosomal PDGFRA to SMAD activation not biochemically resolved\", \"Generality of the GSX2 loop to other lineages unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Clarified PDGFRA's developmental roles in lineage decisions: chondrocyte progenitor specification via Wnt9a suppression and epicardial fibroblast differentiation.\",\n      \"evidence\": \"Conditional Pdgfra loss- and gain-of-function mouse models with Wnt pathway rescue; Tbx18-Cre epicardial knockout\",\n      \"pmids\": [\"32800757\", \"24000064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effectors linking PDGFRA to Wnt9a transcription not identified\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned PDGFRA downstream of FLNC loss via \\u03b2-catenin, implicating receptor activity in a non-cancer cardiomyopathy and validating inhibition as a functional intervention.\",\n      \"evidence\": \"FLNC-mutant iPSC-cardiomyocytes with Co-IP/proteomics and crenolanib contractility rescue\",\n      \"pmids\": [\"35196083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of \\u03b2-catenin-driven PDGFRA activation not defined\", \"Co-IP/proteomics axis without reciprocal validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the avapritinib binding mode and a critical G\\u03b1 sub-pocket, enabling structure-guided design of derivatives against resistance.\",\n      \"evidence\": \"X-ray crystallography of avapritinib–PDGFRA complexes with derivative pharmacology\",\n      \"pmids\": [\"38167404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Clinical efficacy of new derivatives not established\", \"Coverage of all resistance mutations not demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified Endocan as a direct extracellular activator of PDGFRA driving Myc-dependent chromatin remodeling, revealing a paracrine route to receptor activation in glioma.\",\n      \"evidence\": \"Direct binding and phosphorylation assays, ATAC-seq, and Esm1-KO mouse GBM with ponatinib treatment\",\n      \"pmids\": [\"39773984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface on PDGFRA not structurally mapped\", \"Relationship to canonical PDGF ligand signaling unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse activation modes (point mutation, extracellular/glycosylation defects, fusions, paracrine ligands, chromatin-level overexpression) differentially shape downstream signaling balance, trafficking, and inhibitor response in a single quantitative framework remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of full-length ligand- versus mutation-activated receptor\", \"Effector-level differences between activation modes not systematically compared\", \"Mechanism coupling endosomal/Golgi trafficking to signaling output incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 8, 10]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [12, 24]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [20, 26]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [16, 20]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 9, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 8, 13, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 15, 17, 22, 25, 26]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [16, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PTPN11\", \"EGFR\", \"ESM1\", \"FIP1L1\", \"KDR\", \"CTNNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}