{"gene":"PDGFRB","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2022,"finding":"PDGFRβ homodimers dimerize more quickly and show increased autophosphorylation compared to PDGFRα homodimers in response to PDGF ligand. PDGFRα homodimers are trafficked and degraded more quickly after activation, whereas PDGFRβ homodimers are more likely to be recycled back to the cell membrane. PDGFRβ homodimer activation results in greater amplitude of phospho-ERK1/2 and phospho-AKT signaling, as well as increased proliferation and migration. Inhibition of clathrin-mediated endocytosis alters cellular trafficking and downstream signaling, particularly for PDGFRα homodimers.","method":"Bimolecular fluorescence complementation (BiFC) cell lines stably expressing C-terminal PDGFR fusions; live imaging; western blot for phospho-ERK1/2 and phospho-AKT; proliferation and migration assays; clathrin inhibitor experiments","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (BiFC, biochemical signaling assays, functional assays) in a single rigorous study dissecting dimer-specific dynamics","pmids":["35946433"],"is_preprint":false},{"year":2007,"finding":"RhoB GTPase is required for PDGFR-β trafficking to a perinuclear late endosomal compartment and for downstream nuclear localization of Src, Akt, and ERK in vascular smooth muscle cells. In RhoB knockout cells, PDGF-stimulated PDGFR-β trafficking to late endosomes is abrogated, phosphorylation of Akt and ERK1/2 is reduced, and cell proliferation in response to PDGF is lost. Restoring RhoB expression rescues these defects.","method":"RhoB knockout mouse-derived vascular smooth muscle cells; subcellular fractionation/immunofluorescence for PDGFR-β trafficking; nuclear fractionation for Src/Akt/ERK; phosphorylation western blots; proliferation assays; RhoB re-expression rescue experiments","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal genetic rescue (KO + re-expression), multiple downstream readouts, clean localization experiments with functional consequences","pmids":["17951322"],"is_preprint":false},{"year":2014,"finding":"PDGFR-β activation promotes glioma tumorigenesis via a PDGFR-β/ACK1/AKT signaling axis. PDGF treatment promotes formation of complexes containing PDGFR-β and ACK1; PDGFR-β phosphorylates ACK1 at Y635, which is required for sequential AKT activation. PDK1 interacts with ACK1 during PDGF stimulation (requiring T325 of ACK1), and this interaction is required for ACK1 binding to PDGFR-β. ACK1 Y635F or T325A mutants abolish PDGFR-β-induced AKT activation, β-catenin nuclear translocation, and cyclin D1 expression, blocking cell cycle progression and tumorigenesis.","method":"Co-immunoprecipitation; site-directed mutagenesis of ACK1 (Y635F, T325A); dominant-negative and overexpression constructs; western blot for phosphorylation; cell cycle and proliferation assays; in vivo glioblastoma patient sample analysis","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis of specific phosphorylation sites, multiple orthogonal functional readouts in single study","pmids":["25257795"],"is_preprint":false},{"year":2019,"finding":"Integrin α11 interacts physically with PDGFRβ in a ligand-dependent manner in cancer-associated fibroblasts and promotes JNK activation downstream of PDGFRβ, leading to tenascin C production and CAF-induced tumor cell invasion. Pharmacological inhibition of PDGFRβ or JNK impaired tumor cell invasion induced by integrin α11-positive CAFs.","method":"Co-immunoprecipitation of integrin α11 with PDGFRβ; pharmacological inhibition of PDGFRβ and JNK; invasion assays with multiple human and murine CAF subpopulations; MMTV-PyMT mouse model with integrin α11 deficiency","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo genetic model, pharmacological validation, multiple CAF subpopulations tested","pmids":["31287804"],"is_preprint":false},{"year":2019,"finding":"Somatic activating PDGFRB variants (predominantly in the juxtamembrane domain or kinase activation loop) found in fusiform cerebral aneurysms confer non-ligand-dependent auto-phosphorylation with downstream activation of ERK, SRC, and AKT. These variant receptors are responsive to the kinase inhibitor sunitinib.","method":"Paired-sample exome sequencing; in vitro expression of discovered variants with phosphorylation assays; western blot for downstream signaling (ERK, SRC, AKT); sunitinib inhibition","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of variants with phosphorylation and downstream signaling assays, single lab","pmids":["31031011"],"is_preprint":false},{"year":2023,"finding":"Somatic PDGFRB mutations identified in intracranial aneurysms constitutively activate ERK and NF-κB signaling, enhance cell motility, and induce inflammation-related gene expression. Virus-mediated overexpression of mutant PDGFRB induced fusiform-like dilatation of the basilar artery in mice, blocked by systemic sunitinib administration.","method":"Whole-exome and targeted deep sequencing; in vitro signaling assays; spatial transcriptomics; in vivo mouse arterial dilatation model with viral overexpression; tyrosine kinase inhibitor treatment","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro signaling characterization plus in vivo mouse model with pharmacological rescue, replicated across human patient cohort","pmids":["37315111"],"is_preprint":false},{"year":2014,"finding":"PDGFRB mutations associated with idiopathic basal ganglia calcification (IBGC) impair receptor signaling. The L658P mutant has no kinase activity and fails to activate any downstream pathways. The R987W mutant activates Akt and MAP kinases but does not induce STAT3 phosphorylation and fails to phosphorylate phospholipase Cγ, and is more rapidly degraded upon PDGF binding.","method":"Transfection of mutant receptors in cell lines; kinase activity assays; phosphorylation western blots for multiple downstream effectors (Akt, MAPK, STAT3, PLCγ); receptor degradation assays","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct kinase activity assays and multiple downstream pathway analyses on specific mutants, single lab","pmids":["25292412"],"is_preprint":false},{"year":2022,"finding":"PDGFRB variants associated with primary familial brain calcification (PFBC) cause receptor loss of function through distinct mechanisms: some cause complete loss of tyrosine kinase activity; the p.Pro154Ser variant decreases receptor expression and abolishes PDGF-BB ligand binding; others show partial loss of function through reduced expression or reduced signaling. These findings establish that PFBC-associated PDGFRB variants result in loss-of-function rather than gain-of-function.","method":"Transfection of mutant receptors in cell lines; receptor expression assays; PDGF-BB binding assays; kinase activity assays; signaling/mitogenic activity assays","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct kinase assays, ligand-binding experiments, and expression analysis across 13 variants in multiple cell lines, single lab","pmids":["34494111"],"is_preprint":false},{"year":2017,"finding":"The EBF1-PDGFRB fusion protein causes multimerization and autophosphorylation, activates STAT5 signaling, and confers IL-7-independent cell proliferation. The transmembrane (TM) domain of PDGFRB is critically required for nuclear export of EBF1 and loss of EBF1 transcription factor function; deletion of the TM domain partially rescues EBF1 function and restores IL-7 dependence without requiring kinase inhibition. EBF1-PDGFRB synergizes with loss of IKAROS function to drive fully penetrant B-ALL in vivo.","method":"Mutagenesis of TM domain; STAT5 phosphorylation assays; cytokine-independence proliferation assays; in vivo B-ALL mouse model; co-expression with IKAROS loss-of-function","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of specific domain plus in vivo model and multiple orthogonal assays establishing mechanism of transformation","pmids":["28555080"],"is_preprint":false},{"year":2017,"finding":"JUN and JUNB transcription factors directly regulate PDGFRB expression in NPM-ALK-driven lymphoma cells. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice.","method":"Transcriptional regulation analysis; mouse model of NPM-ALK lymphomagenesis; PDGFRB inhibitor treatment; survival analysis in transgenic mice","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with pharmacological inhibition and transcriptional regulation, single lab","pmids":["23064464"],"is_preprint":false},{"year":2012,"finding":"PDGFR-β/PI3K/Akt signaling pathway mediates PDGF-BB-induced proliferation, migration, and angiogenesis in endothelial progenitor cells. Pharmacological inhibition of PDGFR kinase (AG1295), PI3K (LY294002), or Akt (sc-221226) each blocked these PDGF-BB-induced phenotypes.","method":"PDGFR-β overexpression in EPCs; inhibitor treatments (AG1295, LY294002, Akt inhibitor); proliferation, migration (scratch assay), and tube formation/angiogenesis assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with multiple inhibitors and multiple functional readouts, single lab","pmids":["22355314"],"is_preprint":false},{"year":2019,"finding":"PDGFR-β signaling promotes cardiomyocyte proliferation and heart regeneration through the PI3K/p-Akt pathway, which upregulates EZH2. Conditional knockout of Ezh2 blocks cardiomyocyte proliferation and H3K27me3 modification during neonatal heart regeneration with Ink4a/Arf upregulation, even in mice with myocyte-specific PDGFR-β activation. AAV9-mediated delivery of activated PDGFR-β enhances adult heart regeneration and systolic function.","method":"Conditional PDGFR-β activation in cardiomyocytes (transgenic mouse); conditional Ezh2 knockout; RNA sequencing; H3K27me3 ChIP; AAV9 gene therapy; cardiac functional analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (PDGFR-β activation plus Ezh2 KO double mutant), RNA-seq, chromatin modification assays, and in vivo therapeutic model","pmids":["31340157"],"is_preprint":false},{"year":2020,"finding":"PDGFR-β activation alone in renal mesenchymal cells is sufficient to drive progressive kidney fibrosis, causing mesangial cell pathological proliferation and phenotypic switch toward myofibroblasts, resulting in mesangioproliferative glomerulonephritis and interstitial fibrosis. PDGFR inhibition reversed fibrosis, more effectively in the tubulointerstitium than glomeruli.","method":"Transgenic mice with PDGFR-β activation specifically in renal mesenchymal cells; histopathology; gene expression profiling; PDGFR inhibitor treatment","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with specific cell-type activation, pharmacological rescue, and transcriptomic validation against human disease signatures","pmids":["31943786"],"is_preprint":false},{"year":2004,"finding":"c-Myc binds to the proximal promoter of the PDGFRB gene in proliferating rat fibroblasts (demonstrated by chromatin immunoprecipitation). Promoter-binding and transcriptional repression of PDGFRB by c-Myc are separable activities: c-Myc mutants unable to repress PDGFRB still bind its promoter. Trichostatin A (TSA, HDAC inhibitor) blocks Myc repression of PDGFRB without disrupting promoter binding, indicating that repression requires a post-binding, HDAC-dependent step.","method":"Chromatin immunoprecipitation (ChIP) in rat fibroblasts; c-Myc mutant constructs (dBR, d106-143); PDGFRB mRNA expression assays; TSA treatment","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating in vivo promoter occupancy plus mutational dissection of binding vs. repression activities, multiple orthogonal approaches","pmids":["15226411"],"is_preprint":false},{"year":2017,"finding":"Synectin regulates PDGFR-β and PDGFR-α through distinct mechanisms. For PDGFR-β, synectin knockdown reduces PDGFR-β transcription through histone modifications at the PDGFR-β promoter (dependent on p300 histone acetyltransferase, shown by chromatin IP). For PDGFR-α, synectin protects it from autophagic degradation; site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues is responsible for its autophagic degradation. Synectin knockdown decreases PDGF-dependent migration and proliferation of hepatic stellate cells.","method":"Synectin knockdown; chromatin IP of PDGFR-β promoter; mRNA sequencing; site-directed mutagenesis of PDGFR-α lysine ubiquitination sites; autophagy assays; migration and proliferation assays; mouse liver fibrosis model with HSC-specific synectin deletion","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — chromatin IP, mutagenesis, in vivo genetic model, and multiple mechanistic approaches distinguishing transcriptional vs. post-translational regulation of two receptors","pmids":["29263300"],"is_preprint":false},{"year":2008,"finding":"PDGFRβ functions as a binding receptor for Chlamydia trachomatis at the cell surface. Inhibition of PDGFRβ by RNA interference or PDGFRβ-neutralizing antibodies significantly reduces bacterial binding. PDGFRβ is phosphorylated upon infection and recruited to the site of bacterial attachment. Bacterial internalization can occur independently through activation of Abl kinase, converging on phosphorylation of the Rac GEF Vav2 and actin nucleators WAVE2 and Cortactin.","method":"RNAi screen in Drosophila S2 cells; siRNA knockdown of PDGFRβ in mammalian cells; neutralizing antibody against PDGFRβ; bacterial binding and internalization assays; phosphorylation assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal inhibition methods (siRNA + neutralizing antibody) for receptor function as bacterial binding site, single lab","pmids":["18369471"],"is_preprint":false},{"year":2004,"finding":"PDGF-BB and its receptor PDGFR-β are expressed in the developing mouse testis, with PDGFR-β specifically present on mesonephric p75NTR+ mesenchymal cells. PDGF-BB promotes migration and proliferation of these cells in vitro, and these responses involve MAPK and PI3K pathways (blocked by U0126 and LY294002, respectively). Addition of PDGF-BB to serum-free medium is sufficient to allow male urogenital ridge organ cultures to form testis cords.","method":"Immunomagnetic cell isolation; in vitro migration and proliferation assays; pharmacological inhibition of MAPK (U0126) and PI3K (LY294002); organ culture experiments; expression analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro assays with pharmacological pathway dissection plus organ culture, single lab","pmids":["14996938"],"is_preprint":false},{"year":2001,"finding":"Both PDGFRα and PDGFRβ promote fibroblast (NIH 3T3) cell migration, and their effects are additive. PDGFRβ activation alone (via dominant-negative α-PDGFR or antisense α-PDGFR constructs) is sufficient to induce NIH 3T3 cell migration, but with lower efficiency than co-activation of both receptors. This differs from smooth muscle cells where PDGFRα antagonizes PDGFRβ-induced migration.","method":"Dominant-negative PDGFRα and antisense PDGFRα constructs in NIH 3T3 cells; cell migration assays with PDGF-AA and PDGF-BB","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal genetic tools (dominant-negative and antisense) to isolate PDGFRβ-specific migration signaling, single lab","pmids":["11401517"],"is_preprint":false},{"year":2008,"finding":"PDGFR-β receptor (but not PDGFRα) is essential for vascular stability/pericyte recruitment in vivo. Anti-PDGFRβ neutralizing antibody significantly blocks PDGF-AB/FGF-2-induced vessel stability in a mouse cornea angiogenesis model, while PDGF-AA/FGF-2 (which does not bind PDGFRβ) cannot stabilize vessels.","method":"Mouse cornea angiogenesis model; anti-PDGFRβ neutralizing antibody; comparison of PDGF-AA/FGF-2 vs PDGF-AB/FGF-2 combinations; rat ischemic hind-limb model; immunohistochemistry for pericytes","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo neutralizing antibody with ligand-specificity comparison, single lab","pmids":["18827023"],"is_preprint":false},{"year":2021,"finding":"Pdgfrb signaling is conserved in zebrafish for vascular mural cell development. pdgfrb mutant zebrafish lack brain pericytes and show anatomically selective loss of vascular smooth muscle coverage (similar to mouse), but without early circulatory defects. At juvenile stages, pdgfrb mutants develop cranial hemorrhage and vessel dilation. pdgfrb mutants also display glomerular structural defects but normal hepatic stellate cell development, and defective mural cell investment on coronary vessels.","method":"pdgfb and pdgfrb mutant zebrafish genetic analysis; histology; vascular imaging; phenotypic characterization across developmental stages","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout model with detailed phenotypic characterization, ortholog study confirming conserved role","pmids":["34310924"],"is_preprint":false},{"year":2017,"finding":"PDGFR-β/STAT3 signaling is a key pathway inhibited by the combination of melatonin and sorafenib in pancreatic cancer cells. Proximity ligation assay and immunoprecipitation confirmed PDGFR-β interaction with STAT3 in this context.","method":"Phospho-RTK array; phospho-tyrosine kinase array; western blotting; proximity ligation assay; immunoprecipitation; PDAC xenograft model","journal":"Cellular physiology and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, proximity ligation and Co-IP demonstrate PDGFR-β/STAT3 interaction but limited mechanistic depth","pmids":["29953970"],"is_preprint":false},{"year":2016,"finding":"Pdgfra and pdgfrb genetically interact during palatogenesis in zebrafish and mouse. pdgfrb single mutants have no craniofacial defect, but pdgfra;pdgfrb double mutants show significantly more severe palatal defects than pdgfra single mutants, demonstrating genetic interaction. Time-lapse confocal imaging shows failure of proper neural crest condensation in double mutants. Both receptors are expressed by neural crest in pharyngeal arches.","method":"Zebrafish and mouse genetic mutant analysis; pharmacological Pdgf pathway inhibition; time-lapse confocal imaging; proliferation and cell death assays","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in two species (zebrafish and mouse) with live imaging functional readout","pmids":["26971580"],"is_preprint":false},{"year":2014,"finding":"miR-34a directly targets the 3'-UTR of PDGFR-β mRNA (confirmed by dual-luciferase assay), inhibiting PDGFR-β protein expression at a post-transcriptional level, suppressing Ras/MAPK signaling, and downregulating cyclin D1, CDK4/CDK6, cyclin E, and CDK2, resulting in G0/G1 cell cycle arrest in renal mesangial cells.","method":"Dual-luciferase 3'-UTR reporter assay; miR-34a overexpression/inhibition; cell cycle analysis; western blot for PDGFR-β, phospho-MEK1, cyclins; anti-Thy1 nephritis rat model","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct luciferase assay confirming miR-34a binding to PDGFR-β 3'-UTR plus downstream pathway analysis, single lab","pmids":["24638095"],"is_preprint":false},{"year":1999,"finding":"The TEL/PDGFR-β (T/P) fusion protein activates JNK/SAPK signaling through the PDGFR-β tyrosine kinase activity. A specific PDGFR-β kinase inhibitor abrogates JNK/SAPK activation. A dominant-negative MKK4 mutant prevents T/P-induced JNK/SAPK activation and decreases T/P-mediated apoptosis. PI3K inhibition potentiates T/P-mediated JNK/SAPK activation and cell death, indicating that PI3K promotes survival downstream of T/P.","method":"Stable Ba/F3 cell expression of T/P fusion; PDGFR-β kinase inhibitor treatment; dominant-negative MKK4 expression; PI3K inhibitor (LY294002) treatment; JNK/SAPK activity assays; apoptosis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and dominant-negative genetic approaches in isogenic cell lines, single lab","pmids":["10445851"],"is_preprint":false},{"year":2020,"finding":"Cadherin-11 (CDH11) binds directly to PDGFRβ and enhances cellular sensitivity to PDGF-BB by 10- to 100-fold, resulting in rapid and sustained AKT phosphorylation and promoting cell proliferation and tissue regeneration. Wound healing in Cdh11-/- mice is severely compromised, with decreased proliferation, AKT phosphorylation, and extracellular matrix synthesis.","method":"Co-immunoprecipitation of CDH11 with PDGFRβ; dose-response proliferation assays; AKT phosphorylation western blots; Cdh11-/- mouse wound healing model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating physical interaction, in vivo genetic model with functional readout, single lab","pmids":["31930567"],"is_preprint":false},{"year":2017,"finding":"GLI2 directly induces PDGFRB expression in gastric cancer cells by binding to the PDGFRB promoter region, confirmed by dual-luciferase assay. GLI2 or PDGFRB knockdown produces similar effects on reducing spheroid colony formation and CSC-related gene expression (CD44, Nanog, Oct4), placing PDGFRB downstream of GLI2 in a Hedgehog-driven CSC pathway.","method":"Dual-luciferase reporter assay for GLI2 binding to PDGFRB promoter; GLI2 overexpression; GLI2 and PDGFRB shRNA knockdown; spheroid colony formation assays; Western blot for CSC markers","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase assay plus functional knockdown, single lab, limited mechanistic follow-up","pmids":["28975979"],"is_preprint":false},{"year":2003,"finding":"PDGFR-alpha and PDGFR-beta function as receptors for adeno-associated virus type 5 (AAV-5) transduction. Expression of PDGFR-alpha and PDGFR-beta correlated significantly with AAV-5 transduction permissiveness across 43 cell lines. The tropism of AAV-5 in vivo correlated with PDGFR-alpha expression pattern.","method":"cDNA microarray expression profiling across 43 cell lines categorized as permissive/nonpermissive; correlation analysis; follow-up experiments confirming PDGFR role in AAV-5 transduction","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell-panel correlation plus functional confirmation experiments; replicated in vivo; primary focus is on PDGFRα but PDGFRβ also confirmed","pmids":["14502277"],"is_preprint":false},{"year":2017,"finding":"PDGFRB gain-of-function mutations (in transmembrane, juxtamembrane, and kinase domains) activate receptor signaling in the absence of ligand and transform fibroblasts in sporadic infantile myofibromatosis. All but one mutant (D850V) were sensitive to imatinib; D850V was inhibited by dasatinib and ponatinib.","method":"Sequencing of PDGFRB in myofibromatosis samples; functional assays of receptor activation (ligand-independent signaling); fibroblast transformation assays; tyrosine kinase inhibitor sensitivity testing","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of mutants with transformation assays and inhibitor sensitivity, single lab","pmids":["28334876"],"is_preprint":false},{"year":2019,"finding":"All PDGFRB gain-of-function mutations found in pediatric myofibroma are associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations.","method":"Targeted deep sequencing of PDGFRB; functional characterization of mutations for gain-of-function; imatinib sensitivity assays","journal":"JAMA dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of ligand-independent activation across multiple mutations, single large cohort study","pmids":["31017643"],"is_preprint":false},{"year":2016,"finding":"PDGFR-β-positive cells are the primary site of erythropoietin (EPO) production in the kidney. HIF-2α (not HIF-1α) is the essential transcription factor triggering EPO expression in PDGFR-β+ cells. Deletion of HIF-2α alone or combined with Vhl deletion in PDGFR-β+ cells abolishes EPO expression and reverses elevated hematocrit.","method":"Conditional Vhl deletion in PDGFR-β+ cells (transgenic mouse); HIF-1α and HIF-2α conditional deletion in PDGFR-β+ cells; plasma EPO and mRNA measurements; prolyl-hydroxylase inhibitor treatment","journal":"Pflugers Archiv","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with cell-type-specific Cre deletions, multiple conditional alleles tested, pharmacological validation","pmids":["27220347"],"is_preprint":false},{"year":2003,"finding":"NF2/Merlin overexpression in schwannoma cells accelerates internalization and degradation of PDGFR from the cell surface, inhibiting MAPK (Erk1/2) and PI3K (Akt) signaling downstream of PDGF. An interaction between PDGFR and EBP50/NHE-RF was found in primary human schwannoma tissue.","method":"Adenoviral NF2 gene transfer; receptor internalization assays; phosphorylation western blots (Erk1/2, Akt); co-expression analysis in schwannoma tissue","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, receptor trafficking assay without full mechanistic validation of the Merlin-EBP50-PDGFR complex","pmids":["14612918"],"is_preprint":false}],"current_model":"PDGFRB encodes a receptor tyrosine kinase that upon ligand (PDGF-BB/DD) binding forms homodimers (which dimerize faster and are more likely recycled) or heterodimers with PDGFRα, undergoes autophosphorylation, and activates multiple downstream pathways including PI3K/AKT, RAS/MAPK/ERK, STAT3, and JNK/SAPK; its trafficking to late endosomes is regulated by RhoB, its transcription is repressed by c-Myc through an HDAC-dependent mechanism and induced by JUN/JUNB and GLI2, its protein stability is regulated by synectin (transcriptionally for PDGFRβ, via autophagy for PDGFRα), it physically interacts with integrin α11 and cadherin-11 to modulate downstream JNK and AKT signaling respectively, it drives pericyte/vascular mural cell recruitment and vessel stability in vivo, promotes renal fibrosis via mesenchymal cell proliferation, and cardiomyocyte regeneration via PI3K/AKT/EZH2; loss-of-function PDGFRB variants cause primary familial brain calcification (PFBC) by impairing kinase activity or ligand binding, while gain-of-function variants drive ligand-independent activation in infantile myofibromatosis and fusiform cerebral aneurysms via constitutive ERK and NF-κB signaling."},"narrative":{"mechanistic_narrative":"PDGFRB encodes a receptor tyrosine kinase that, upon PDGF ligand binding, dimerizes and undergoes autophosphorylation to drive the proliferation, migration, and survival of mesenchymal and vascular mural cells [PMID:35946433]. PDGFRβ homodimers dimerize rapidly, generate high-amplitude phospho-ERK1/2 and phospho-AKT signaling, and are preferentially recycled to the membrane, in contrast to the faster-degraded PDGFRα homodimers [PMID:35946433]. Downstream of the activated receptor, PI3K/AKT signaling drives endothelial progenitor proliferation, migration, and angiogenesis [PMID:22355314], and AKT activation in tumor cells proceeds through a PDGFRβ/ACK1 axis in which the receptor phosphorylates ACK1 at Y635 to enable β-catenin nuclear translocation and cyclin D1 expression [PMID:25257795]. Receptor trafficking and signal compartmentalization depend on RhoB, which routes activated PDGFRβ to perinuclear late endosomes and supports nuclear localization of Src, Akt, and ERK [PMID:17951322]. The receptor's signaling output is tuned by direct physical partners: integrin α11 binds PDGFRβ ligand-dependently to promote JNK activation and CAF-driven tumor invasion [PMID:31287804], and cadherin-11 binds PDGFRβ to sensitize cells to PDGF-BB and sustain AKT-dependent proliferation and wound healing [PMID:31930567]. PDGFRB transcription is repressed by c-Myc through a post-binding, HDAC-dependent step [PMID:15226411], and is positively controlled by synectin via p300-dependent histone modification at its promoter [PMID:29263300]; the transcript is also targeted post-transcriptionally by miR-34a [PMID:24638095]. Physiologically, PDGFRβ is essential and ligand-specific for pericyte recruitment and vessel stability in vivo [PMID:18827023], and its conserved role in vascular mural cell development is demonstrated in zebrafish, where mutants lack brain pericytes and develop cranial hemorrhage [PMID:34310924]; PDGFRβ-positive cells also serve as the renal site of HIF-2α-dependent erythropoietin production [PMID:27220347]. Sustained PDGFRβ activity drives pathological fibrosis, as receptor activation alone in renal mesenchymal cells is sufficient to produce mesangioproliferative glomerulonephritis and interstitial fibrosis [PMID:31943786], and conversely promotes cardiomyocyte proliferation and heart regeneration through a PI3K/AKT/EZH2 axis [PMID:31340157]. Loss-of-function PDGFRB variants cause primary familial brain calcification (PFBC/IBGC) by abolishing kinase activity, reducing expression, or abrogating PDGF-BB binding [PMID:34494111, PMID:25292412], whereas ligand-independent gain-of-function variants drive infantile myofibromatosis [PMID:28334876, PMID:31017643] and fusiform cerebral aneurysms through constitutive ERK, SRC, AKT, and NF-κB signaling [PMID:31031011, PMID:37315111]. Oncogenic PDGFRB fusions (TEL/PDGFRβ, EBF1-PDGFRβ) constitutively activate the kinase to transform hematopoietic cells via JNK/SAPK and STAT5 signaling [PMID:10445851, PMID:28555080].","teleology":[{"year":1999,"claim":"Established that constitutive PDGFRβ kinase activity in an oncogenic fusion couples to a specific stress-kinase cascade, defining how the receptor drives transformation and apoptosis balance.","evidence":"TEL/PDGFRβ fusion expressed in Ba/F3 cells with PDGFRβ kinase inhibitor, dominant-negative MKK4, and PI3K inhibition","pmids":["10445851"],"confidence":"Medium","gaps":["Mechanism in primary leukemic cells not addressed","Relative contribution of JNK vs other pathways to transformation unresolved"]},{"year":2001,"claim":"Showed PDGFRβ activation is sufficient to drive fibroblast migration, distinguishing its cell-type-specific signaling from antagonistic behavior in smooth muscle.","evidence":"Dominant-negative and antisense PDGFRα constructs in NIH 3T3 cells with PDGF-AA/BB migration assays","pmids":["11401517"],"confidence":"Medium","gaps":["Molecular basis of additivity with PDGFRα not defined","Downstream effectors of migration not mapped"]},{"year":2004,"claim":"Defined how PDGFRB transcription is repressed, showing c-Myc occupies the promoter but requires a separable HDAC-dependent step to silence the gene.","evidence":"ChIP in rat fibroblasts with c-Myc mutants and TSA HDAC inhibitor treatment","pmids":["15226411"],"confidence":"High","gaps":["Identity of the HDAC complex recruited not established","Generality beyond fibroblasts not tested"]},{"year":2004,"claim":"Linked PDGFRβ to a developmental role, showing it drives migration/proliferation of mesonephric mesenchymal cells and supports testis cord formation.","evidence":"Immunomagnetic isolation, in vitro assays with MAPK/PI3K inhibitors, urogenital organ culture","pmids":["14996938"],"confidence":"Medium","gaps":["In vivo genetic requirement not demonstrated","Ligand source in vivo not defined"]},{"year":2007,"claim":"Identified RhoB as a required trafficking regulator routing activated PDGFRβ to late endosomes and enabling nuclear signaling and proliferation.","evidence":"RhoB knockout vascular smooth muscle cells with re-expression rescue, fractionation, and phosphorylation assays","pmids":["17951322"],"confidence":"High","gaps":["Direct RhoB-PDGFRβ interaction not shown","Mechanism of nuclear effector translocation unresolved"]},{"year":2008,"claim":"Established the ligand-specific in vivo requirement for PDGFRβ in pericyte recruitment and vessel stabilization.","evidence":"Mouse cornea angiogenesis and rat hind-limb ischemia models with anti-PDGFRβ neutralizing antibody and ligand comparisons","pmids":["18827023"],"confidence":"Medium","gaps":["Single-lab antibody-based loss of function","Downstream pericyte recruitment signaling not detailed"]},{"year":2008,"claim":"Revealed a non-canonical role for PDGFRβ as a cell-surface binding receptor exploited by Chlamydia trachomatis.","evidence":"Drosophila RNAi screen, siRNA and neutralizing antibody in mammalian cells, binding/internalization assays","pmids":["18369471"],"confidence":"Medium","gaps":["Direct bacterial ligand for PDGFRβ not identified","Single-lab characterization"]},{"year":2012,"claim":"Confirmed that PDGFRβ drives endothelial progenitor angiogenic behavior through a linear PI3K/AKT pathway.","evidence":"PDGFRβ overexpression in EPCs with PDGFR, PI3K, and Akt inhibitors and functional assays","pmids":["22355314"],"confidence":"Medium","gaps":["Pharmacological rather than genetic dissection","In vivo relevance not tested"]},{"year":2014,"claim":"Defined a PDGFRβ/ACK1/AKT axis, mapping the specific phosphorylation events that couple the receptor to β-catenin/cyclin D1-driven proliferation in glioma.","evidence":"Co-IP, site-directed mutagenesis (ACK1 Y635F, T325A), signaling and cell cycle assays, patient samples","pmids":["25257795"],"confidence":"High","gaps":["Contribution relative to direct PI3K coupling unresolved","In vivo therapeutic implication not tested"]},{"year":2014,"claim":"Defined the molecular consequences of IBGC-associated PDGFRB mutations, showing distinct loss-of-function modes from complete kinase dead to selective effector failure.","evidence":"Transfection of L658P and R987W mutants with kinase, multi-effector phosphorylation, and degradation assays","pmids":["25292412"],"confidence":"High","gaps":["Mechanism linking receptor hypofunction to calcification not established","In vivo modeling absent"]},{"year":2014,"claim":"Established post-transcriptional control of PDGFRβ by miR-34a, linking its downregulation to G0/G1 arrest in mesangial cells.","evidence":"Dual-luciferase 3'-UTR reporter, miR-34a gain/loss, cell cycle and pathway analysis, nephritis model","pmids":["24638095"],"confidence":"Medium","gaps":["In vivo therapeutic relevance limited","Single-lab study"]},{"year":2016,"claim":"Demonstrated genetic interaction between Pdgfra and Pdgfrb in cranial neural crest condensation during palatogenesis.","evidence":"Zebrafish and mouse single/double mutants, pathway inhibition, time-lapse imaging","pmids":["26971580"],"confidence":"Medium","gaps":["PDGFRβ-specific signaling in neural crest not isolated","Molecular basis of condensation failure unresolved"]},{"year":2016,"claim":"Identified PDGFRβ-positive cells as the renal HIF-2α-dependent erythropoietin-producing population, situating the receptor as a cell-identity marker for oxygen sensing.","evidence":"Conditional Vhl, Hif1a, Hif2a deletions in PDGFRβ+ cells with EPO measurements and PHD inhibition","pmids":["27220347"],"confidence":"High","gaps":["Whether PDGFRβ signaling itself regulates EPO not addressed","Receptor used as marker rather than effector"]},{"year":2017,"claim":"Showed PDGFRβ is a transcriptional target of JUN/JUNB and a therapeutic vulnerability in NPM-ALK lymphoma.","evidence":"Transcriptional regulation analysis, NPM-ALK transgenic mouse with PDGFRB inhibitor and survival","pmids":["23064464"],"confidence":"Medium","gaps":["Direct promoter binding by JUN/JUNB not shown","Single-lab study"]},{"year":2017,"claim":"Distinguished how an oncogenic fusion subverts PDGFRβ, showing its transmembrane domain mediates EBF1 nuclear export and that STAT5 activation drives cytokine-independent B-ALL.","evidence":"TM domain mutagenesis, STAT5 assays, cytokine-independence, in vivo B-ALL model with IKAROS loss","pmids":["28555080"],"confidence":"High","gaps":["Mechanism of TM-domain-driven nuclear export not molecularly resolved"]},{"year":2017,"claim":"Revealed dual regulation of receptor abundance by synectin, controlling PDGFRβ transcriptionally via p300-dependent histone modification.","evidence":"Synectin knockdown, ChIP of PDGFRβ promoter, mRNA-seq, fibrosis model","pmids":["29263300"],"confidence":"High","gaps":["Direct synectin recruitment to the promoter not shown","Mechanism distinguishing the two receptors incompletely defined"]},{"year":2017,"claim":"Defined the first ligand-independent gain-of-function PDGFRB mutations transforming fibroblasts in infantile myofibromatosis and their imatinib sensitivity.","evidence":"Sequencing, ligand-independent signaling assays, fibroblast transformation, TKI sensitivity testing","pmids":["28334876"],"confidence":"Medium","gaps":["In vivo modeling absent","D850V resistance mechanism not structurally defined"]},{"year":2019,"claim":"Established integrin α11 as a ligand-dependent PDGFRβ partner channeling signaling to JNK and CAF-mediated tumor invasion.","evidence":"Reciprocal Co-IP, pharmacological PDGFRβ/JNK inhibition, invasion assays, MMTV-PyMT mouse model","pmids":["31287804"],"confidence":"High","gaps":["Structural basis of the interaction not defined","How α11 biases signaling toward JNK unresolved"]},{"year":2019,"claim":"Connected PDGFRβ activation to cardiomyocyte proliferation via a PI3K/AKT/EZH2 epigenetic axis with therapeutic potential.","evidence":"Cardiomyocyte PDGFRβ activation and Ezh2 conditional KO, RNA-seq, H3K27me3 ChIP, AAV9 gene therapy","pmids":["31340157"],"confidence":"High","gaps":["Upstream ligand source in regenerating heart not defined","Direct EZH2 target genes incompletely mapped"]},{"year":2019,"claim":"Defined ligand-independent gain-of-function PDGFRB variants in fusiform cerebral aneurysms with druggable downstream signaling.","evidence":"Paired exome sequencing, variant expression with phosphorylation and ERK/SRC/AKT assays, sunitinib","pmids":["31031011"],"confidence":"Medium","gaps":["In vivo aneurysm modeling not in this study","Single-lab variant characterization"]},{"year":2019,"claim":"Extended the gain-of-function paradigm to pediatric myofibroma, confirming ligand-independent activation and broad imatinib sensitivity.","evidence":"Targeted deep sequencing and functional gain-of-function/imatinib assays in a cohort","pmids":["31017643"],"confidence":"Medium","gaps":["Mechanistic depth per variant limited","Resistance mechanisms not defined"]},{"year":2020,"claim":"Demonstrated PDGFRβ activation alone is sufficient to drive progressive kidney fibrosis through mesangial proliferation and myofibroblast conversion, reversible by inhibition.","evidence":"Transgenic PDGFRβ activation in renal mesenchymal cells, histopathology, expression profiling, PDGFR inhibition","pmids":["31943786"],"confidence":"High","gaps":["Differential glomerular vs interstitial reversibility mechanism unclear"]},{"year":2020,"claim":"Identified cadherin-11 as a direct PDGFRβ partner that markedly sensitizes cells to PDGF-BB and is required for AKT-dependent wound healing.","evidence":"Co-IP, dose-response proliferation, AKT phosphorylation, Cdh11-/- wound healing model","pmids":["31930567"],"confidence":"Medium","gaps":["Mechanism of sensitization (affinity vs trafficking) not defined","Single-lab study"]},{"year":2022,"claim":"Quantitatively dissected dimer-specific receptor dynamics, showing PDGFRβ homodimers signal more strongly and recycle preferentially versus PDGFRα.","evidence":"BiFC cell lines, live imaging, phospho-ERK/AKT blots, proliferation/migration and clathrin inhibition","pmids":["35946433"],"confidence":"High","gaps":["Structural basis of faster dimerization not defined","Heterodimer dynamics less fully characterized"]},{"year":2022,"claim":"Comprehensively established PFBC-associated PDGFRB variants as loss-of-function across multiple distinct mechanisms including abolished ligand binding.","evidence":"Transfection of 13 variants with expression, PDGF-BB binding, kinase, and signaling assays","pmids":["34494111"],"confidence":"High","gaps":["Link from receptor hypofunction to brain calcification mechanism unresolved","No in vivo validation"]},{"year":2023,"claim":"Validated in vivo that aneurysm-associated PDGFRB mutations drive arterial dilatation through constitutive ERK/NF-κB and inflammatory signaling, reversible by kinase inhibition.","evidence":"Exome/deep sequencing, signaling assays, spatial transcriptomics, viral mutant overexpression mouse model, sunitinib rescue","pmids":["37315111"],"confidence":"High","gaps":["Cell-type origin of inflammatory program not fully resolved","Translational dosing not established"]},{"year":null,"claim":"How distinct loss-of-function PDGFRB hypofunction states mechanistically cause brain calcification, and how dimer/partner-specific signaling outputs are selected to drive divergent fibrotic, regenerative, and transforming programs, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mechanistic link from receptor hypofunction to calcium deposition","Structural basis of partner-biased signaling (integrin α11, cadherin-11) undefined","Endosomal compartment determinants of signal duration vs degradation incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,6,7]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[6,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,18]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[15,26]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,15,18]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,30]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental 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in response to PDGF ligand. PDGFRα homodimers are trafficked and degraded more quickly after activation, whereas PDGFRβ homodimers are more likely to be recycled back to the cell membrane. PDGFRβ homodimer activation results in greater amplitude of phospho-ERK1/2 and phospho-AKT signaling, as well as increased proliferation and migration. Inhibition of clathrin-mediated endocytosis alters cellular trafficking and downstream signaling, particularly for PDGFRα homodimers.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC) cell lines stably expressing C-terminal PDGFR fusions; live imaging; western blot for phospho-ERK1/2 and phospho-AKT; proliferation and migration assays; clathrin inhibitor experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (BiFC, biochemical signaling assays, functional assays) in a single rigorous study dissecting dimer-specific dynamics\",\n      \"pmids\": [\"35946433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RhoB GTPase is required for PDGFR-β trafficking to a perinuclear late endosomal compartment and for downstream nuclear localization of Src, Akt, and ERK in vascular smooth muscle cells. In RhoB knockout cells, PDGF-stimulated PDGFR-β trafficking to late endosomes is abrogated, phosphorylation of Akt and ERK1/2 is reduced, and cell proliferation in response to PDGF is lost. Restoring RhoB expression rescues these defects.\",\n      \"method\": \"RhoB knockout mouse-derived vascular smooth muscle cells; subcellular fractionation/immunofluorescence for PDGFR-β trafficking; nuclear fractionation for Src/Akt/ERK; phosphorylation western blots; proliferation assays; RhoB re-expression rescue experiments\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal genetic rescue (KO + re-expression), multiple downstream readouts, clean localization experiments with functional consequences\",\n      \"pmids\": [\"17951322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDGFR-β activation promotes glioma tumorigenesis via a PDGFR-β/ACK1/AKT signaling axis. PDGF treatment promotes formation of complexes containing PDGFR-β and ACK1; PDGFR-β phosphorylates ACK1 at Y635, which is required for sequential AKT activation. PDK1 interacts with ACK1 during PDGF stimulation (requiring T325 of ACK1), and this interaction is required for ACK1 binding to PDGFR-β. ACK1 Y635F or T325A mutants abolish PDGFR-β-induced AKT activation, β-catenin nuclear translocation, and cyclin D1 expression, blocking cell cycle progression and tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation; site-directed mutagenesis of ACK1 (Y635F, T325A); dominant-negative and overexpression constructs; western blot for phosphorylation; cell cycle and proliferation assays; in vivo glioblastoma patient sample analysis\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis of specific phosphorylation sites, multiple orthogonal functional readouts in single study\",\n      \"pmids\": [\"25257795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Integrin α11 interacts physically with PDGFRβ in a ligand-dependent manner in cancer-associated fibroblasts and promotes JNK activation downstream of PDGFRβ, leading to tenascin C production and CAF-induced tumor cell invasion. Pharmacological inhibition of PDGFRβ or JNK impaired tumor cell invasion induced by integrin α11-positive CAFs.\",\n      \"method\": \"Co-immunoprecipitation of integrin α11 with PDGFRβ; pharmacological inhibition of PDGFRβ and JNK; invasion assays with multiple human and murine CAF subpopulations; MMTV-PyMT mouse model with integrin α11 deficiency\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo genetic model, pharmacological validation, multiple CAF subpopulations tested\",\n      \"pmids\": [\"31287804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Somatic activating PDGFRB variants (predominantly in the juxtamembrane domain or kinase activation loop) found in fusiform cerebral aneurysms confer non-ligand-dependent auto-phosphorylation with downstream activation of ERK, SRC, and AKT. These variant receptors are responsive to the kinase inhibitor sunitinib.\",\n      \"method\": \"Paired-sample exome sequencing; in vitro expression of discovered variants with phosphorylation assays; western blot for downstream signaling (ERK, SRC, AKT); sunitinib inhibition\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of variants with phosphorylation and downstream signaling assays, single lab\",\n      \"pmids\": [\"31031011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Somatic PDGFRB mutations identified in intracranial aneurysms constitutively activate ERK and NF-κB signaling, enhance cell motility, and induce inflammation-related gene expression. Virus-mediated overexpression of mutant PDGFRB induced fusiform-like dilatation of the basilar artery in mice, blocked by systemic sunitinib administration.\",\n      \"method\": \"Whole-exome and targeted deep sequencing; in vitro signaling assays; spatial transcriptomics; in vivo mouse arterial dilatation model with viral overexpression; tyrosine kinase inhibitor treatment\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro signaling characterization plus in vivo mouse model with pharmacological rescue, replicated across human patient cohort\",\n      \"pmids\": [\"37315111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDGFRB mutations associated with idiopathic basal ganglia calcification (IBGC) impair receptor signaling. The L658P mutant has no kinase activity and fails to activate any downstream pathways. The R987W mutant activates Akt and MAP kinases but does not induce STAT3 phosphorylation and fails to phosphorylate phospholipase Cγ, and is more rapidly degraded upon PDGF binding.\",\n      \"method\": \"Transfection of mutant receptors in cell lines; kinase activity assays; phosphorylation western blots for multiple downstream effectors (Akt, MAPK, STAT3, PLCγ); receptor degradation assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct kinase activity assays and multiple downstream pathway analyses on specific mutants, single lab\",\n      \"pmids\": [\"25292412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PDGFRB variants associated with primary familial brain calcification (PFBC) cause receptor loss of function through distinct mechanisms: some cause complete loss of tyrosine kinase activity; the p.Pro154Ser variant decreases receptor expression and abolishes PDGF-BB ligand binding; others show partial loss of function through reduced expression or reduced signaling. These findings establish that PFBC-associated PDGFRB variants result in loss-of-function rather than gain-of-function.\",\n      \"method\": \"Transfection of mutant receptors in cell lines; receptor expression assays; PDGF-BB binding assays; kinase activity assays; signaling/mitogenic activity assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct kinase assays, ligand-binding experiments, and expression analysis across 13 variants in multiple cell lines, single lab\",\n      \"pmids\": [\"34494111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The EBF1-PDGFRB fusion protein causes multimerization and autophosphorylation, activates STAT5 signaling, and confers IL-7-independent cell proliferation. The transmembrane (TM) domain of PDGFRB is critically required for nuclear export of EBF1 and loss of EBF1 transcription factor function; deletion of the TM domain partially rescues EBF1 function and restores IL-7 dependence without requiring kinase inhibition. EBF1-PDGFRB synergizes with loss of IKAROS function to drive fully penetrant B-ALL in vivo.\",\n      \"method\": \"Mutagenesis of TM domain; STAT5 phosphorylation assays; cytokine-independence proliferation assays; in vivo B-ALL mouse model; co-expression with IKAROS loss-of-function\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of specific domain plus in vivo model and multiple orthogonal assays establishing mechanism of transformation\",\n      \"pmids\": [\"28555080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JUN and JUNB transcription factors directly regulate PDGFRB expression in NPM-ALK-driven lymphoma cells. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice.\",\n      \"method\": \"Transcriptional regulation analysis; mouse model of NPM-ALK lymphomagenesis; PDGFRB inhibitor treatment; survival analysis in transgenic mice\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with pharmacological inhibition and transcriptional regulation, single lab\",\n      \"pmids\": [\"23064464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PDGFR-β/PI3K/Akt signaling pathway mediates PDGF-BB-induced proliferation, migration, and angiogenesis in endothelial progenitor cells. Pharmacological inhibition of PDGFR kinase (AG1295), PI3K (LY294002), or Akt (sc-221226) each blocked these PDGF-BB-induced phenotypes.\",\n      \"method\": \"PDGFR-β overexpression in EPCs; inhibitor treatments (AG1295, LY294002, Akt inhibitor); proliferation, migration (scratch assay), and tube formation/angiogenesis assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with multiple inhibitors and multiple functional readouts, single lab\",\n      \"pmids\": [\"22355314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDGFR-β signaling promotes cardiomyocyte proliferation and heart regeneration through the PI3K/p-Akt pathway, which upregulates EZH2. Conditional knockout of Ezh2 blocks cardiomyocyte proliferation and H3K27me3 modification during neonatal heart regeneration with Ink4a/Arf upregulation, even in mice with myocyte-specific PDGFR-β activation. AAV9-mediated delivery of activated PDGFR-β enhances adult heart regeneration and systolic function.\",\n      \"method\": \"Conditional PDGFR-β activation in cardiomyocytes (transgenic mouse); conditional Ezh2 knockout; RNA sequencing; H3K27me3 ChIP; AAV9 gene therapy; cardiac functional analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (PDGFR-β activation plus Ezh2 KO double mutant), RNA-seq, chromatin modification assays, and in vivo therapeutic model\",\n      \"pmids\": [\"31340157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PDGFR-β activation alone in renal mesenchymal cells is sufficient to drive progressive kidney fibrosis, causing mesangial cell pathological proliferation and phenotypic switch toward myofibroblasts, resulting in mesangioproliferative glomerulonephritis and interstitial fibrosis. PDGFR inhibition reversed fibrosis, more effectively in the tubulointerstitium than glomeruli.\",\n      \"method\": \"Transgenic mice with PDGFR-β activation specifically in renal mesenchymal cells; histopathology; gene expression profiling; PDGFR inhibitor treatment\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with specific cell-type activation, pharmacological rescue, and transcriptomic validation against human disease signatures\",\n      \"pmids\": [\"31943786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"c-Myc binds to the proximal promoter of the PDGFRB gene in proliferating rat fibroblasts (demonstrated by chromatin immunoprecipitation). Promoter-binding and transcriptional repression of PDGFRB by c-Myc are separable activities: c-Myc mutants unable to repress PDGFRB still bind its promoter. Trichostatin A (TSA, HDAC inhibitor) blocks Myc repression of PDGFRB without disrupting promoter binding, indicating that repression requires a post-binding, HDAC-dependent step.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) in rat fibroblasts; c-Myc mutant constructs (dBR, d106-143); PDGFRB mRNA expression assays; TSA treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating in vivo promoter occupancy plus mutational dissection of binding vs. repression activities, multiple orthogonal approaches\",\n      \"pmids\": [\"15226411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Synectin regulates PDGFR-β and PDGFR-α through distinct mechanisms. For PDGFR-β, synectin knockdown reduces PDGFR-β transcription through histone modifications at the PDGFR-β promoter (dependent on p300 histone acetyltransferase, shown by chromatin IP). For PDGFR-α, synectin protects it from autophagic degradation; site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues is responsible for its autophagic degradation. Synectin knockdown decreases PDGF-dependent migration and proliferation of hepatic stellate cells.\",\n      \"method\": \"Synectin knockdown; chromatin IP of PDGFR-β promoter; mRNA sequencing; site-directed mutagenesis of PDGFR-α lysine ubiquitination sites; autophagy assays; migration and proliferation assays; mouse liver fibrosis model with HSC-specific synectin deletion\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chromatin IP, mutagenesis, in vivo genetic model, and multiple mechanistic approaches distinguishing transcriptional vs. post-translational regulation of two receptors\",\n      \"pmids\": [\"29263300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PDGFRβ functions as a binding receptor for Chlamydia trachomatis at the cell surface. Inhibition of PDGFRβ by RNA interference or PDGFRβ-neutralizing antibodies significantly reduces bacterial binding. PDGFRβ is phosphorylated upon infection and recruited to the site of bacterial attachment. Bacterial internalization can occur independently through activation of Abl kinase, converging on phosphorylation of the Rac GEF Vav2 and actin nucleators WAVE2 and Cortactin.\",\n      \"method\": \"RNAi screen in Drosophila S2 cells; siRNA knockdown of PDGFRβ in mammalian cells; neutralizing antibody against PDGFRβ; bacterial binding and internalization assays; phosphorylation assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal inhibition methods (siRNA + neutralizing antibody) for receptor function as bacterial binding site, single lab\",\n      \"pmids\": [\"18369471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PDGF-BB and its receptor PDGFR-β are expressed in the developing mouse testis, with PDGFR-β specifically present on mesonephric p75NTR+ mesenchymal cells. PDGF-BB promotes migration and proliferation of these cells in vitro, and these responses involve MAPK and PI3K pathways (blocked by U0126 and LY294002, respectively). Addition of PDGF-BB to serum-free medium is sufficient to allow male urogenital ridge organ cultures to form testis cords.\",\n      \"method\": \"Immunomagnetic cell isolation; in vitro migration and proliferation assays; pharmacological inhibition of MAPK (U0126) and PI3K (LY294002); organ culture experiments; expression analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro assays with pharmacological pathway dissection plus organ culture, single lab\",\n      \"pmids\": [\"14996938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Both PDGFRα and PDGFRβ promote fibroblast (NIH 3T3) cell migration, and their effects are additive. PDGFRβ activation alone (via dominant-negative α-PDGFR or antisense α-PDGFR constructs) is sufficient to induce NIH 3T3 cell migration, but with lower efficiency than co-activation of both receptors. This differs from smooth muscle cells where PDGFRα antagonizes PDGFRβ-induced migration.\",\n      \"method\": \"Dominant-negative PDGFRα and antisense PDGFRα constructs in NIH 3T3 cells; cell migration assays with PDGF-AA and PDGF-BB\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal genetic tools (dominant-negative and antisense) to isolate PDGFRβ-specific migration signaling, single lab\",\n      \"pmids\": [\"11401517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PDGFR-β receptor (but not PDGFRα) is essential for vascular stability/pericyte recruitment in vivo. Anti-PDGFRβ neutralizing antibody significantly blocks PDGF-AB/FGF-2-induced vessel stability in a mouse cornea angiogenesis model, while PDGF-AA/FGF-2 (which does not bind PDGFRβ) cannot stabilize vessels.\",\n      \"method\": \"Mouse cornea angiogenesis model; anti-PDGFRβ neutralizing antibody; comparison of PDGF-AA/FGF-2 vs PDGF-AB/FGF-2 combinations; rat ischemic hind-limb model; immunohistochemistry for pericytes\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo neutralizing antibody with ligand-specificity comparison, single lab\",\n      \"pmids\": [\"18827023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pdgfrb signaling is conserved in zebrafish for vascular mural cell development. pdgfrb mutant zebrafish lack brain pericytes and show anatomically selective loss of vascular smooth muscle coverage (similar to mouse), but without early circulatory defects. At juvenile stages, pdgfrb mutants develop cranial hemorrhage and vessel dilation. pdgfrb mutants also display glomerular structural defects but normal hepatic stellate cell development, and defective mural cell investment on coronary vessels.\",\n      \"method\": \"pdgfb and pdgfrb mutant zebrafish genetic analysis; histology; vascular imaging; phenotypic characterization across developmental stages\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout model with detailed phenotypic characterization, ortholog study confirming conserved role\",\n      \"pmids\": [\"34310924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PDGFR-β/STAT3 signaling is a key pathway inhibited by the combination of melatonin and sorafenib in pancreatic cancer cells. Proximity ligation assay and immunoprecipitation confirmed PDGFR-β interaction with STAT3 in this context.\",\n      \"method\": \"Phospho-RTK array; phospho-tyrosine kinase array; western blotting; proximity ligation assay; immunoprecipitation; PDAC xenograft model\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, proximity ligation and Co-IP demonstrate PDGFR-β/STAT3 interaction but limited mechanistic depth\",\n      \"pmids\": [\"29953970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pdgfra and pdgfrb genetically interact during palatogenesis in zebrafish and mouse. pdgfrb single mutants have no craniofacial defect, but pdgfra;pdgfrb double mutants show significantly more severe palatal defects than pdgfra single mutants, demonstrating genetic interaction. Time-lapse confocal imaging shows failure of proper neural crest condensation in double mutants. Both receptors are expressed by neural crest in pharyngeal arches.\",\n      \"method\": \"Zebrafish and mouse genetic mutant analysis; pharmacological Pdgf pathway inhibition; time-lapse confocal imaging; proliferation and cell death assays\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in two species (zebrafish and mouse) with live imaging functional readout\",\n      \"pmids\": [\"26971580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-34a directly targets the 3'-UTR of PDGFR-β mRNA (confirmed by dual-luciferase assay), inhibiting PDGFR-β protein expression at a post-transcriptional level, suppressing Ras/MAPK signaling, and downregulating cyclin D1, CDK4/CDK6, cyclin E, and CDK2, resulting in G0/G1 cell cycle arrest in renal mesangial cells.\",\n      \"method\": \"Dual-luciferase 3'-UTR reporter assay; miR-34a overexpression/inhibition; cell cycle analysis; western blot for PDGFR-β, phospho-MEK1, cyclins; anti-Thy1 nephritis rat model\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct luciferase assay confirming miR-34a binding to PDGFR-β 3'-UTR plus downstream pathway analysis, single lab\",\n      \"pmids\": [\"24638095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The TEL/PDGFR-β (T/P) fusion protein activates JNK/SAPK signaling through the PDGFR-β tyrosine kinase activity. A specific PDGFR-β kinase inhibitor abrogates JNK/SAPK activation. A dominant-negative MKK4 mutant prevents T/P-induced JNK/SAPK activation and decreases T/P-mediated apoptosis. PI3K inhibition potentiates T/P-mediated JNK/SAPK activation and cell death, indicating that PI3K promotes survival downstream of T/P.\",\n      \"method\": \"Stable Ba/F3 cell expression of T/P fusion; PDGFR-β kinase inhibitor treatment; dominant-negative MKK4 expression; PI3K inhibitor (LY294002) treatment; JNK/SAPK activity assays; apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and dominant-negative genetic approaches in isogenic cell lines, single lab\",\n      \"pmids\": [\"10445851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cadherin-11 (CDH11) binds directly to PDGFRβ and enhances cellular sensitivity to PDGF-BB by 10- to 100-fold, resulting in rapid and sustained AKT phosphorylation and promoting cell proliferation and tissue regeneration. Wound healing in Cdh11-/- mice is severely compromised, with decreased proliferation, AKT phosphorylation, and extracellular matrix synthesis.\",\n      \"method\": \"Co-immunoprecipitation of CDH11 with PDGFRβ; dose-response proliferation assays; AKT phosphorylation western blots; Cdh11-/- mouse wound healing model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating physical interaction, in vivo genetic model with functional readout, single lab\",\n      \"pmids\": [\"31930567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GLI2 directly induces PDGFRB expression in gastric cancer cells by binding to the PDGFRB promoter region, confirmed by dual-luciferase assay. GLI2 or PDGFRB knockdown produces similar effects on reducing spheroid colony formation and CSC-related gene expression (CD44, Nanog, Oct4), placing PDGFRB downstream of GLI2 in a Hedgehog-driven CSC pathway.\",\n      \"method\": \"Dual-luciferase reporter assay for GLI2 binding to PDGFRB promoter; GLI2 overexpression; GLI2 and PDGFRB shRNA knockdown; spheroid colony formation assays; Western blot for CSC markers\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase assay plus functional knockdown, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"28975979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PDGFR-alpha and PDGFR-beta function as receptors for adeno-associated virus type 5 (AAV-5) transduction. Expression of PDGFR-alpha and PDGFR-beta correlated significantly with AAV-5 transduction permissiveness across 43 cell lines. The tropism of AAV-5 in vivo correlated with PDGFR-alpha expression pattern.\",\n      \"method\": \"cDNA microarray expression profiling across 43 cell lines categorized as permissive/nonpermissive; correlation analysis; follow-up experiments confirming PDGFR role in AAV-5 transduction\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-panel correlation plus functional confirmation experiments; replicated in vivo; primary focus is on PDGFRα but PDGFRβ also confirmed\",\n      \"pmids\": [\"14502277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PDGFRB gain-of-function mutations (in transmembrane, juxtamembrane, and kinase domains) activate receptor signaling in the absence of ligand and transform fibroblasts in sporadic infantile myofibromatosis. All but one mutant (D850V) were sensitive to imatinib; D850V was inhibited by dasatinib and ponatinib.\",\n      \"method\": \"Sequencing of PDGFRB in myofibromatosis samples; functional assays of receptor activation (ligand-independent signaling); fibroblast transformation assays; tyrosine kinase inhibitor sensitivity testing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of mutants with transformation assays and inhibitor sensitivity, single lab\",\n      \"pmids\": [\"28334876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"All PDGFRB gain-of-function mutations found in pediatric myofibroma are associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations.\",\n      \"method\": \"Targeted deep sequencing of PDGFRB; functional characterization of mutations for gain-of-function; imatinib sensitivity assays\",\n      \"journal\": \"JAMA dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of ligand-independent activation across multiple mutations, single large cohort study\",\n      \"pmids\": [\"31017643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDGFR-β-positive cells are the primary site of erythropoietin (EPO) production in the kidney. HIF-2α (not HIF-1α) is the essential transcription factor triggering EPO expression in PDGFR-β+ cells. Deletion of HIF-2α alone or combined with Vhl deletion in PDGFR-β+ cells abolishes EPO expression and reverses elevated hematocrit.\",\n      \"method\": \"Conditional Vhl deletion in PDGFR-β+ cells (transgenic mouse); HIF-1α and HIF-2α conditional deletion in PDGFR-β+ cells; plasma EPO and mRNA measurements; prolyl-hydroxylase inhibitor treatment\",\n      \"journal\": \"Pflugers Archiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with cell-type-specific Cre deletions, multiple conditional alleles tested, pharmacological validation\",\n      \"pmids\": [\"27220347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NF2/Merlin overexpression in schwannoma cells accelerates internalization and degradation of PDGFR from the cell surface, inhibiting MAPK (Erk1/2) and PI3K (Akt) signaling downstream of PDGF. An interaction between PDGFR and EBP50/NHE-RF was found in primary human schwannoma tissue.\",\n      \"method\": \"Adenoviral NF2 gene transfer; receptor internalization assays; phosphorylation western blots (Erk1/2, Akt); co-expression analysis in schwannoma tissue\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, receptor trafficking assay without full mechanistic validation of the Merlin-EBP50-PDGFR complex\",\n      \"pmids\": [\"14612918\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDGFRB encodes a receptor tyrosine kinase that upon ligand (PDGF-BB/DD) binding forms homodimers (which dimerize faster and are more likely recycled) or heterodimers with PDGFRα, undergoes autophosphorylation, and activates multiple downstream pathways including PI3K/AKT, RAS/MAPK/ERK, STAT3, and JNK/SAPK; its trafficking to late endosomes is regulated by RhoB, its transcription is repressed by c-Myc through an HDAC-dependent mechanism and induced by JUN/JUNB and GLI2, its protein stability is regulated by synectin (transcriptionally for PDGFRβ, via autophagy for PDGFRα), it physically interacts with integrin α11 and cadherin-11 to modulate downstream JNK and AKT signaling respectively, it drives pericyte/vascular mural cell recruitment and vessel stability in vivo, promotes renal fibrosis via mesenchymal cell proliferation, and cardiomyocyte regeneration via PI3K/AKT/EZH2; loss-of-function PDGFRB variants cause primary familial brain calcification (PFBC) by impairing kinase activity or ligand binding, while gain-of-function variants drive ligand-independent activation in infantile myofibromatosis and fusiform cerebral aneurysms via constitutive ERK and NF-κB signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDGFRB encodes a receptor tyrosine kinase that, upon PDGF ligand binding, dimerizes and undergoes autophosphorylation to drive the proliferation, migration, and survival of mesenchymal and vascular mural cells [#0]. PDGFRβ homodimers dimerize rapidly, generate high-amplitude phospho-ERK1/2 and phospho-AKT signaling, and are preferentially recycled to the membrane, in contrast to the faster-degraded PDGFRα homodimers [#0]. Downstream of the activated receptor, PI3K/AKT signaling drives endothelial progenitor proliferation, migration, and angiogenesis [#10], and AKT activation in tumor cells proceeds through a PDGFRβ/ACK1 axis in which the receptor phosphorylates ACK1 at Y635 to enable β-catenin nuclear translocation and cyclin D1 expression [#2]. Receptor trafficking and signal compartmentalization depend on RhoB, which routes activated PDGFRβ to perinuclear late endosomes and supports nuclear localization of Src, Akt, and ERK [#1]. The receptor's signaling output is tuned by direct physical partners: integrin α11 binds PDGFRβ ligand-dependently to promote JNK activation and CAF-driven tumor invasion [#3], and cadherin-11 binds PDGFRβ to sensitize cells to PDGF-BB and sustain AKT-dependent proliferation and wound healing [#24]. PDGFRB transcription is repressed by c-Myc through a post-binding, HDAC-dependent step [#13], and is positively controlled by synectin via p300-dependent histone modification at its promoter [#14]; the transcript is also targeted post-transcriptionally by miR-34a [#22]. Physiologically, PDGFRβ is essential and ligand-specific for pericyte recruitment and vessel stability in vivo [#18], and its conserved role in vascular mural cell development is demonstrated in zebrafish, where mutants lack brain pericytes and develop cranial hemorrhage [#19]; PDGFRβ-positive cells also serve as the renal site of HIF-2α-dependent erythropoietin production [#29]. Sustained PDGFRβ activity drives pathological fibrosis, as receptor activation alone in renal mesenchymal cells is sufficient to produce mesangioproliferative glomerulonephritis and interstitial fibrosis [#12], and conversely promotes cardiomyocyte proliferation and heart regeneration through a PI3K/AKT/EZH2 axis [#11]. Loss-of-function PDGFRB variants cause primary familial brain calcification (PFBC/IBGC) by abolishing kinase activity, reducing expression, or abrogating PDGF-BB binding [#7, #6], whereas ligand-independent gain-of-function variants drive infantile myofibromatosis [#27, #28] and fusiform cerebral aneurysms through constitutive ERK, SRC, AKT, and NF-κB signaling [#4, #5]. Oncogenic PDGFRB fusions (TEL/PDGFRβ, EBF1-PDGFRβ) constitutively activate the kinase to transform hematopoietic cells via JNK/SAPK and STAT5 signaling [#23, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that constitutive PDGFRβ kinase activity in an oncogenic fusion couples to a specific stress-kinase cascade, defining how the receptor drives transformation and apoptosis balance.\",\n      \"evidence\": \"TEL/PDGFRβ fusion expressed in Ba/F3 cells with PDGFRβ kinase inhibitor, dominant-negative MKK4, and PI3K inhibition\",\n      \"pmids\": [\"10445851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism in primary leukemic cells not addressed\", \"Relative contribution of JNK vs other pathways to transformation unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed PDGFRβ activation is sufficient to drive fibroblast migration, distinguishing its cell-type-specific signaling from antagonistic behavior in smooth muscle.\",\n      \"evidence\": \"Dominant-negative and antisense PDGFRα constructs in NIH 3T3 cells with PDGF-AA/BB migration assays\",\n      \"pmids\": [\"11401517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of additivity with PDGFRα not defined\", \"Downstream effectors of migration not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined how PDGFRB transcription is repressed, showing c-Myc occupies the promoter but requires a separable HDAC-dependent step to silence the gene.\",\n      \"evidence\": \"ChIP in rat fibroblasts with c-Myc mutants and TSA HDAC inhibitor treatment\",\n      \"pmids\": [\"15226411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the HDAC complex recruited not established\", \"Generality beyond fibroblasts not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked PDGFRβ to a developmental role, showing it drives migration/proliferation of mesonephric mesenchymal cells and supports testis cord formation.\",\n      \"evidence\": \"Immunomagnetic isolation, in vitro assays with MAPK/PI3K inhibitors, urogenital organ culture\",\n      \"pmids\": [\"14996938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo genetic requirement not demonstrated\", \"Ligand source in vivo not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified RhoB as a required trafficking regulator routing activated PDGFRβ to late endosomes and enabling nuclear signaling and proliferation.\",\n      \"evidence\": \"RhoB knockout vascular smooth muscle cells with re-expression rescue, fractionation, and phosphorylation assays\",\n      \"pmids\": [\"17951322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RhoB-PDGFRβ interaction not shown\", \"Mechanism of nuclear effector translocation unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the ligand-specific in vivo requirement for PDGFRβ in pericyte recruitment and vessel stabilization.\",\n      \"evidence\": \"Mouse cornea angiogenesis and rat hind-limb ischemia models with anti-PDGFRβ neutralizing antibody and ligand comparisons\",\n      \"pmids\": [\"18827023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab antibody-based loss of function\", \"Downstream pericyte recruitment signaling not detailed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a non-canonical role for PDGFRβ as a cell-surface binding receptor exploited by Chlamydia trachomatis.\",\n      \"evidence\": \"Drosophila RNAi screen, siRNA and neutralizing antibody in mammalian cells, binding/internalization assays\",\n      \"pmids\": [\"18369471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct bacterial ligand for PDGFRβ not identified\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Confirmed that PDGFRβ drives endothelial progenitor angiogenic behavior through a linear PI3K/AKT pathway.\",\n      \"evidence\": \"PDGFRβ overexpression in EPCs with PDGFR, PI3K, and Akt inhibitors and functional assays\",\n      \"pmids\": [\"22355314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological rather than genetic dissection\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a PDGFRβ/ACK1/AKT axis, mapping the specific phosphorylation events that couple the receptor to β-catenin/cyclin D1-driven proliferation in glioma.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis (ACK1 Y635F, T325A), signaling and cell cycle assays, patient samples\",\n      \"pmids\": [\"25257795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution relative to direct PI3K coupling unresolved\", \"In vivo therapeutic implication not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the molecular consequences of IBGC-associated PDGFRB mutations, showing distinct loss-of-function modes from complete kinase dead to selective effector failure.\",\n      \"evidence\": \"Transfection of L658P and R987W mutants with kinase, multi-effector phosphorylation, and degradation assays\",\n      \"pmids\": [\"25292412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking receptor hypofunction to calcification not established\", \"In vivo modeling absent\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established post-transcriptional control of PDGFRβ by miR-34a, linking its downregulation to G0/G1 arrest in mesangial cells.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR reporter, miR-34a gain/loss, cell cycle and pathway analysis, nephritis model\",\n      \"pmids\": [\"24638095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo therapeutic relevance limited\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated genetic interaction between Pdgfra and Pdgfrb in cranial neural crest condensation during palatogenesis.\",\n      \"evidence\": \"Zebrafish and mouse single/double mutants, pathway inhibition, time-lapse imaging\",\n      \"pmids\": [\"26971580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PDGFRβ-specific signaling in neural crest not isolated\", \"Molecular basis of condensation failure unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified PDGFRβ-positive cells as the renal HIF-2α-dependent erythropoietin-producing population, situating the receptor as a cell-identity marker for oxygen sensing.\",\n      \"evidence\": \"Conditional Vhl, Hif1a, Hif2a deletions in PDGFRβ+ cells with EPO measurements and PHD inhibition\",\n      \"pmids\": [\"27220347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDGFRβ signaling itself regulates EPO not addressed\", \"Receptor used as marker rather than effector\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed PDGFRβ is a transcriptional target of JUN/JUNB and a therapeutic vulnerability in NPM-ALK lymphoma.\",\n      \"evidence\": \"Transcriptional regulation analysis, NPM-ALK transgenic mouse with PDGFRB inhibitor and survival\",\n      \"pmids\": [\"23064464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding by JUN/JUNB not shown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished how an oncogenic fusion subverts PDGFRβ, showing its transmembrane domain mediates EBF1 nuclear export and that STAT5 activation drives cytokine-independent B-ALL.\",\n      \"evidence\": \"TM domain mutagenesis, STAT5 assays, cytokine-independence, in vivo B-ALL model with IKAROS loss\",\n      \"pmids\": [\"28555080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of TM-domain-driven nuclear export not molecularly resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed dual regulation of receptor abundance by synectin, controlling PDGFRβ transcriptionally via p300-dependent histone modification.\",\n      \"evidence\": \"Synectin knockdown, ChIP of PDGFRβ promoter, mRNA-seq, fibrosis model\",\n      \"pmids\": [\"29263300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct synectin recruitment to the promoter not shown\", \"Mechanism distinguishing the two receptors incompletely defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the first ligand-independent gain-of-function PDGFRB mutations transforming fibroblasts in infantile myofibromatosis and their imatinib sensitivity.\",\n      \"evidence\": \"Sequencing, ligand-independent signaling assays, fibroblast transformation, TKI sensitivity testing\",\n      \"pmids\": [\"28334876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo modeling absent\", \"D850V resistance mechanism not structurally defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established integrin α11 as a ligand-dependent PDGFRβ partner channeling signaling to JNK and CAF-mediated tumor invasion.\",\n      \"evidence\": \"Reciprocal Co-IP, pharmacological PDGFRβ/JNK inhibition, invasion assays, MMTV-PyMT mouse model\",\n      \"pmids\": [\"31287804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the interaction not defined\", \"How α11 biases signaling toward JNK unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected PDGFRβ activation to cardiomyocyte proliferation via a PI3K/AKT/EZH2 epigenetic axis with therapeutic potential.\",\n      \"evidence\": \"Cardiomyocyte PDGFRβ activation and Ezh2 conditional KO, RNA-seq, H3K27me3 ChIP, AAV9 gene therapy\",\n      \"pmids\": [\"31340157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream ligand source in regenerating heart not defined\", \"Direct EZH2 target genes incompletely mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined ligand-independent gain-of-function PDGFRB variants in fusiform cerebral aneurysms with druggable downstream signaling.\",\n      \"evidence\": \"Paired exome sequencing, variant expression with phosphorylation and ERK/SRC/AKT assays, sunitinib\",\n      \"pmids\": [\"31031011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo aneurysm modeling not in this study\", \"Single-lab variant characterization\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the gain-of-function paradigm to pediatric myofibroma, confirming ligand-independent activation and broad imatinib sensitivity.\",\n      \"evidence\": \"Targeted deep sequencing and functional gain-of-function/imatinib assays in a cohort\",\n      \"pmids\": [\"31017643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic depth per variant limited\", \"Resistance mechanisms not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated PDGFRβ activation alone is sufficient to drive progressive kidney fibrosis through mesangial proliferation and myofibroblast conversion, reversible by inhibition.\",\n      \"evidence\": \"Transgenic PDGFRβ activation in renal mesenchymal cells, histopathology, expression profiling, PDGFR inhibition\",\n      \"pmids\": [\"31943786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Differential glomerular vs interstitial reversibility mechanism unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified cadherin-11 as a direct PDGFRβ partner that markedly sensitizes cells to PDGF-BB and is required for AKT-dependent wound healing.\",\n      \"evidence\": \"Co-IP, dose-response proliferation, AKT phosphorylation, Cdh11-/- wound healing model\",\n      \"pmids\": [\"31930567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of sensitization (affinity vs trafficking) not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Quantitatively dissected dimer-specific receptor dynamics, showing PDGFRβ homodimers signal more strongly and recycle preferentially versus PDGFRα.\",\n      \"evidence\": \"BiFC cell lines, live imaging, phospho-ERK/AKT blots, proliferation/migration and clathrin inhibition\",\n      \"pmids\": [\"35946433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of faster dimerization not defined\", \"Heterodimer dynamics less fully characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Comprehensively established PFBC-associated PDGFRB variants as loss-of-function across multiple distinct mechanisms including abolished ligand binding.\",\n      \"evidence\": \"Transfection of 13 variants with expression, PDGF-BB binding, kinase, and signaling assays\",\n      \"pmids\": [\"34494111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link from receptor hypofunction to brain calcification mechanism unresolved\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Validated in vivo that aneurysm-associated PDGFRB mutations drive arterial dilatation through constitutive ERK/NF-κB and inflammatory signaling, reversible by kinase inhibition.\",\n      \"evidence\": \"Exome/deep sequencing, signaling assays, spatial transcriptomics, viral mutant overexpression mouse model, sunitinib rescue\",\n      \"pmids\": [\"37315111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type origin of inflammatory program not fully resolved\", \"Translational dosing not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct loss-of-function PDGFRB hypofunction states mechanistically cause brain calcification, and how dimer/partner-specific signaling outputs are selected to drive divergent fibrotic, regenerative, and transforming programs, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic link from receptor hypofunction to calcium deposition\", \"Structural basis of partner-biased signaling (integrin α11, cadherin-11) undefined\", \"Endosomal compartment determinants of signal duration vs degradation incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 6, 7]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 18]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [15, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 15, 18]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [16, 18, 19, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 6, 7, 12, 27, 28]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13, 14, 25]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PDGFRA\", \"ACK1\", \"ITGA11\", \"CDH11\", \"STAT3\", \"RhoB\", \"EBP50\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}