Affinage

RET

Proto-oncogene tyrosine-protein kinase receptor Ret · UniProt P07949

Length
1114 aa
Mass
124.3 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RET is a single-pass transmembrane receptor tyrosine kinase that transduces signals from GDNF-family ligands to control kidney organogenesis and peripheral nervous system development (PMID:3037315, PMID:8657282). Ligand recognition is indirect: RET partners with GPI-anchored GFRα co-receptors, and the specific GFRα paralog assembled into the complex dictates ligand selectivity (GFRα1-RET responds to GDNF and neurturin equivalently, while GFRα2-RET is biased toward neurturin) (PMID:9182803). Upon ligand engagement RET trans-autophosphorylates intracellular tyrosines that serve as docking sites for adaptor and effector proteins, most prominently Y1062, which couples RET to PI3K/AKT and to the ERK5/BMK1-MEF2C axis (PMID:10652352, PMID:11237712); additional sites recruit STAT3 (Y752/Y928), the bifunctional Dok1 scaffold that oppositely tunes Ras/ERK versus JNK output, and FKBP52 (Y905), while RET activation also engages c-Src kinase as a required mediator of mitogenesis (PMID:10070972, PMID:11536047, PMID:12087092, PMID:20442138). In renal development this signaling drives a branching-morphogenesis gene network through the ETS transcription factors Etv4/Etv5 and is held in check by the atypical cadherin FAT4, a juxtacrine negative regulator that perturbs RET-GFRα1-GDNF complex assembly (PMID:19898483, PMID:30853441); RET transcription itself is directly activated by TTF-1 (PMID:15548547). RET is alternatively spliced into RET9 and RET51 isoforms with distinct trafficking — RET9 accumulates in the Golgi whereas RET51 matures efficiently to the plasma membrane, is more rapidly recruited to clathrin/AP2-coated pits and recycled, producing faster and longer ERK/MAPK signaling, and is the functionally dominant isoform in thyroid carcinoma (PMID:22875993, PMID:26304132, PMID:27872141). Oncogenic activation occurs through extracellular cysteine mutations (MEN2A) that force constitutive disulfide-bonded dimerization, kinase-domain mutations (MEN2B M918T) that constitutively activate and alter catalytic specificity without covalent dimerization, and chromosomal fusions (KIF5B-RET, CCDC6-RET, NCOA4-RET) that confer ligand-independent kinase activation and drive transformation, migration and EMT (PMID:7824936, PMID:8570194, PMID:22327624, PMID:22327623, PMID:27626672). RET is essential for tumor maintenance in these contexts, and inhibition reverses oncogenic signaling and tumor growth (PMID:15316058). Acquired resistance to selective RET inhibitors arises from G810 solvent-front mutations that sterically block drug binding and from bypass MAPK reactivation via MET amplification or EGFR signaling, motivating next-generation inhibitors that retain activity against resistance mutants (PMID:28615362, PMID:31988000, PMID:35304457, PMID:27873490, PMID:37743366). Beyond canonical signaling, caspase cleavage generates a RET ectodomain that acts as a cadherin accessory protein promoting cell aggregation, a ligand-independent adhesion role (PMID:21357690).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1987 High

    Established the molecular identity of RET as a transmembrane receptor tyrosine kinase, defining the protein class whose dysregulation underlies its oncogenic and developmental roles.

    Evidence cDNA cloning and sequencing of the ret transforming gene

    PMID:3037315

    Open questions at the time
    • Did not identify the physiological ligand or co-receptor
    • No downstream signaling characterized
  2. 1996 High

    Identified GDNF as the activating ligand and demonstrated RET is genetically required for kidney and peripheral nervous system development, linking RET signaling to organogenesis.

    Evidence Xenopus embryo bioassay and Ret-knockout mouse explant cultures

    PMID:8657282

    Open questions at the time
    • Mechanism of ligand binding (co-receptor requirement) not yet defined
    • Downstream effectors of developmental signaling unknown
  3. 1997 High

    Resolved how RET achieves ligand selectivity, showing that distinct GPI-anchored GFRα co-receptors set the ligand preference of the RET complex.

    Evidence Receptor reconstitution in fibroblasts with quantitative ligand sensitivity measurements

    PMID:9182803

    Open questions at the time
    • Structural basis of GFRα-RET-ligand assembly not resolved
    • In vivo consequences of co-receptor switching not addressed
  4. 1995 High

    Defined two mechanistically distinct routes to oncogenic RET activation — extracellular cysteine mutations forcing dimerization versus a kinase-domain mutation altering catalytic specificity — explaining MEN2A versus MEN2B.

    Evidence NIH 3T3 transformation assay, dimerization and kinase activity biochemistry, mutagenesis

    PMID:7824936 PMID:8570194

    Open questions at the time
    • Did not map full set of downstream effectors driving transformation
    • Tissue specificity of phenotypes not explained
  5. 1997 High

    Showed that oncogenic activation can be isoform-restricted, with FMTC kinase-domain mutations transforming RET51 but not RET9, providing a biochemical basis for tissue-restricted phenotypes.

    Evidence Site-directed mutagenesis with autophosphorylation, fibroblast transformation, and PC12 differentiation assays

    PMID:9242375

    Open questions at the time
    • Molecular reason for differential isoform sensitivity not defined
    • In vivo relevance to C-cell restriction inferred but not tested
  6. 1999 High

    Identified c-Src as a required effector of RET mitogenic signaling, extending the RET pathway beyond canonical adaptor recruitment.

    Evidence Src kinase activity assay, SH2 pull-down, and dominant-negative Src microinjection

    PMID:10070972

    Open questions at the time
    • Direct RET tyrosine docking site for Src not mapped
    • Relationship to other RET pathways not integrated
  7. 2000 High

    Pinpointed Y1062 as the docking site coupling RET to PI3K/AKT and demonstrated this axis is essential for RET-driven transformation.

    Evidence PI3K/AKT kinase assays, Y1062F mutagenesis, dominant-negative PI3K, soft agar transformation

    PMID:10652352

    Open questions at the time
    • Did not separate AKT from other Y1062-dependent outputs
    • In vivo tumor dependence not tested in this study
  8. 2001 Medium

    Expanded the RET signaling map to STAT3 (via Y752/Y928) and ERK5/BMK1-MEF2C (via Y1062), defining additional proliferative and transcriptional outputs.

    Evidence Cell-line phosphorylation assays, docking-site mutagenesis, and luciferase/cyclin-D1 reporter assays

    PMID:11237712 PMID:11536047

    Open questions at the time
    • Single-lab cell-based evidence without in vivo confirmation
    • Crosstalk between these parallel pathways not resolved
  9. 2002 High

    Characterized Dok1 as a bifunctional RET scaffold that simultaneously suppresses Ras/ERK and enables JNK/c-Jun, revealing how a single adaptor can balance opposing RET outputs.

    Evidence Yeast two-hybrid identification with Dok1 tyrosine mutagenesis and pathway activation assays

    PMID:12087092

    Open questions at the time
    • Physiological consequences of Dok1 balancing in normal development not tested
    • Preferential MEN2B binding mechanism not structurally explained
  10. 2004 High

    Demonstrated that RET kinase activity is required for medullary thyroid carcinoma maintenance, validating RET as a therapeutic target in vivo.

    Evidence Adenoviral dominant-negative RET in MTC cells and transgenic orthotopic mouse tumor model with signaling, cell cycle, and apoptosis readouts

    PMID:15316058

    Open questions at the time
    • Did not test small-molecule inhibition
    • Effector(s) most critical for survival not isolated
  11. 2004 Medium

    Identified TTF-1 as a direct transcriptional activator of RET and linked HSCR-associated promoter variants to reduced RET expression, connecting RET dosage to disease.

    Evidence Luciferase reporter assays, TTF-1 binding site analysis, and functional characterization of a patient TTF-1 mutation

    PMID:15548547

    Open questions at the time
    • Single-lab reporter-based evidence
    • Endogenous chromatin occupancy not directly shown
  12. 2009 High

    Placed Etv4/Etv5 as essential downstream effectors of GDNF-Ret signaling in renal branching morphogenesis, identifying the transcriptional output of the developmental pathway.

    Evidence Compound Etv4/Etv5 knockout mice with ureteric bud gene expression analysis

    PMID:19898483

    Open questions at the time
    • Direct versus indirect regulation of target genes not fully separated
    • How RET kinase output converts to Etv induction not mechanistically traced
  13. 2010 Medium

    Mapped a RET51-specific phosphotyrosine (Y905) required for FKBP52 recruitment, adding an isoform-selective interaction to the RET signaling repertoire.

    Evidence Co-immunoprecipitation with Y905 mutagenesis and patient mutation screening

    PMID:20442138

    Open questions at the time
    • Single Co-IP-based interaction without reciprocal structural validation
    • Functional consequence of the RET51-FKBP52 complex not defined
  14. 2011 Medium

    Uncovered a non-canonical, ligand-independent RET function in which caspase cleavage yields an ectodomain acting as a cadherin accessory protein in cell adhesion.

    Evidence Caspase cleavage and cleavage-site mutagenesis assays with sympathetic neuron aggregation assays

    PMID:21357690

    Open questions at the time
    • Single-lab evidence; in vivo relevance not established
    • Physiological trigger for caspase cleavage of RET unclear
  15. 2012 High

    Linked RET9/RET51 splice isoforms to distinct trafficking itineraries and signaling kinetics, explaining how isoform choice tunes the duration of ERK/MAPK output.

    Evidence Subcellular fractionation, live-cell imaging, FRAP, internalization assays, and ERK/MAPK time-courses

    PMID:22875993

    Open questions at the time
    • Trafficking machinery not yet identified at this stage
    • Consequences for in vivo physiology not tested
  16. 2012 High

    Established RET gene fusion (KIF5B-RET) as an oncogenic driver in lung adenocarcinoma, extending the spectrum of RET activation beyond point mutations.

    Evidence Whole-transcriptome sequencing, NIH3T3 transformation assay, and vandetanib inhibition

    PMID:22327623 PMID:22327624

    Open questions at the time
    • Did not detail downstream signaling differences from other fusions
    • Patient response data not addressed
  17. 2015 High

    Identified clathrin/AP2-mediated endocytosis as the route of RET internalization and showed faster RET51 recruitment to coated pits underlies isoform-specific signaling durations.

    Evidence TIRF microscopy, AP2 μ-subunit interaction assay, and AP2 siRNA knockdown

    PMID:26304132

    Open questions at the time
    • Downstream sorting fate (degradation versus recycling) not fully resolved here
    • How endocytic rate quantitatively sets signal duration not modeled
  18. 2016 Medium

    Demonstrated RET51 is the functionally dominant isoform driving thyroid carcinoma survival, proliferation, migration and invasion, prioritizing it as the disease-relevant species.

    Evidence Isoform-specific shRNA knockdown with viability, migration, invasion, anoikis, and EMT-marker readouts

    PMID:27872141

    Open questions at the time
    • Single-lab study
    • Mechanistic basis of isoform dominance in these phenotypes not dissected
  19. 2016 Medium

    Showed that different RET fusion partners (CCDC6-RET vs NCOA4-RET) signal through distinct networks with divergent drug sensitivities, revealing fusion-specific therapeutic vulnerabilities.

    Evidence Drosophila transgenic cancer models with kinome RNAi and drug-combination synergy screens

    PMID:27626672

    Open questions at the time
    • Findings in Drosophila model require human validation
    • Molecular basis for partner-specific signaling networks not defined
  20. 2017 High

    Defined DFG-out (type II) inhibitor binding as an effective strategy against RET-rearranged tumors and identified MAPK reactivation and a gatekeeper-region mutation as resistance routes.

    Evidence DFG-out inhibitor characterization, chemical genomics, and phosphoproteomics in RET-rearranged cells

    PMID:28615362

    Open questions at the time
    • Did not anticipate solvent-front resistance to selective inhibitors
    • Clinical durability of type II inhibitors not assessed
  21. 2017 Medium

    Established EGFR bypass signaling through ERK and AKT as a resistance mechanism to RET inhibitors that is reversible by EGFR-TKI co-treatment, defining an actionable combination strategy.

    Evidence Cell viability with RET inhibitors ± EGF, EGFR siRNA, and EGFR-TKI combination in CCDC6-RET lung cells

    PMID:27873490

    Open questions at the time
    • Single-lab cell-line evidence
    • In vivo and clinical relevance of the combination not tested here
  22. 2017 Medium

    Showed that secreted GFRα1 enables ligand-driven RET transformation and perineural invasion in prostate cancer, with p70S6K as a convergent required effector, extending RET oncogenic biology beyond mutation/fusion.

    Evidence RET and p70S6K knockdown, anti-GFRα1 antibody, dorsal root ganglion perineural invasion assay, and xenografts

    PMID:28490466

    Open questions at the time
    • Single-lab study
    • Source and regulation of tumor-microenvironment GFRα1 not fully defined
  23. 2019 High

    Identified FAT4 as a juxtacrine negative regulator that restrains RET signaling during kidney development by perturbing RET-GFRα1-GDNF complex assembly.

    Evidence Fat4 conditional knockout mice with Gdnf heterozygous genetic rescue and FAT4-RET co-immunoprecipitation

    PMID:30853441

    Open questions at the time
    • Structural mechanism of FAT4 interference with complex assembly not resolved
    • Role outside kidney development not addressed
  24. 2020 High

    Defined the molecular basis of acquired resistance to selective RET inhibitor selpercatinib, identifying G810 solvent-front mutations and off-target MET amplification.

    Evidence ctDNA and post-mortem tissue analysis, patient-derived xenografts, kinase/cell-based assays, and structural modeling

    PMID:31988000 PMID:35304457

    Open questions at the time
    • Strategies to overcome G810 mutations not provided in this study
    • Frequency and co-occurrence of resistance routes not fully quantified
  25. 2023 Medium

    Provided a next-generation RET inhibitor (vepafestinib) that retains activity against on-target resistance mutations and improves CNS penetration, addressing the resistance liabilities of prior inhibitors.

    Evidence RET kinase selectivity panel, resistance-mutant cell assays, brain-penetration pharmacokinetics, and intracranial xenograft model

    PMID:37743366

    Open questions at the time
    • Single-study; clinical efficacy not yet established
    • Full structural basis of the unique binding mode not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse RET tyrosine docking codes, isoform trafficking, and fusion-partner-specific networks integrate to produce context-specific physiological versus oncogenic outcomes remains incompletely resolved.
  • No unified structural model linking phospho-site usage to pathway selection across cell types
  • Predictive rules for which resistance route emerges under each inhibitor are lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005794 Golgi apparatus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
AP2M1DOK1FAT4FKBP52GDNFGFRA1GFRA2SRC
Complex memberships
RET-GFRα1-GDNF signaling complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 The RET transforming gene encodes a fusion protein with a carboxy-terminal domain homologous to tyrosine kinases (40-50% homology), preceded by a hydrophobic transmembrane domain sequence, establishing RET as a transmembrane receptor tyrosine kinase. cDNA cloning and sequencing of ret transforming gene Molecular and cellular biology High 3037315
1995 MEN2A mutations in extracellular cysteine residues of RET result in constitutive RET dimerization and ligand-independent kinase activation, while the MEN2B mutation (M918T in the kinase domain) activates RET kinase constitutively without covalent dimerization but alters catalytic properties both quantitatively and qualitatively. Both convert RET into a dominant transforming gene in NIH 3T3 cells. NIH 3T3 transformation assay, biochemical analysis of RET dimerization and kinase activity, mutagenesis Science High 7824936 8570194
1996 GDNF signals through the Ret receptor tyrosine kinase: a Xenopus embryo bioassay demonstrated GDNF activates Ret, and explant cultures from Ret-deficient mouse embryos showed that normal Ret function is necessary for GDNF signaling in the peripheral nervous system, establishing Ret as a functional receptor for GDNF essential for kidney organogenesis and peripheral nervous system development. Xenopus embryo bioassay, Ret-knockout mouse explant cultures Nature High 8657282
1997 TrnR2 (GFRα2) is a GPI-anchored co-receptor that mediates both neurturin and GDNF signaling through Ret. Fibroblasts expressing TrnR2 and Ret are ~30-fold more sensitive to neurturin than to GDNF, whereas TrnR1 (GFRα1)-Ret complexes respond equivalently to both, establishing that distinct GFRα-Ret complexes confer differential ligand selectivity. Receptor reconstitution in fibroblasts, cell-based signaling assay, expression analysis Neuron High 9182803
1997 FMTC mutations E768D and V804L in the RET kinase domain are gain-of-function mutations that confer autophosphorylation and transforming activity selectively to the RET51 long isoform (1114 aa) but not to the RET9 short isoform, demonstrating isoform-specific oncogenic activation and providing a biochemical basis for phenotype restriction to thyroid C-cells. Site-directed mutagenesis, autophosphorylation assay, Rat1 fibroblast transformation assay, PC12 neuronal differentiation assay Oncogene High 9242375
1999 Ret stimulation activates c-Src kinase, and Ret associates with the SH2 domain of Src in a phosphotyrosine-dependent manner. Microinjection of a kinase-inactive c-Src mutant blocks Ret-mediated mitogenic effect, establishing that Src kinase activity is required for Ret-mediated mitogenesis. c-Src kinase activity assay, SH2 domain pull-down, microinjection of dominant-negative c-Src Cancer research High 10070972
2000 MEN2A-RET (Cys634) activates PI3K and its downstream effector AKT/PKB. Mutation of Tyr-1062 (docking site for Shc and p85 regulatory subunit of PI3K) abrogates PI3K/AKT activation and abolishes transforming activity. A dominant-interfering PI3K suppresses RET-MEN2A transformation, while AKT overexpression enhances it, establishing PI3K/AKT as essential for RET-mediated transformation. PI3K activity assay, AKT phosphorylation assay, site-directed mutagenesis (Y1062F), retroviral dominant-negative PI3K expression, soft agar transformation assay The Journal of biological chemistry High 10652352
2001 MEN2A-RET activates STAT3 via two YxxV/Q STAT3 docking sites at Tyr752 and Tyr928, inducing both Tyr705 and Ser727 phosphorylation of STAT3. STAT3α (but not STAT3β) mediates enhanced proliferation and cyclin-D1 promoter activity downstream of MEN2A-RET, establishing STAT3 as a component of MEN2A-RET oncogenic signaling. Stable NIH3T3 cell lines, STAT3 phosphorylation assay, cyclin-D1 promoter reporter assay, soft agar growth assay, mutagenesis of docking sites Oncogene Medium 11536047
2001 GDNF activates BMK1 (ERK5) through RET tyrosine kinase via phosphorylation of tyrosine 1062. BMK1 activation is not significantly impaired by MEK1 or PI3K inhibitors, indicating a distinct signaling pathway from Y1062. RET-MEN2A activates MEF2C transcription factor in a Y1062-dependent manner via MEK5. BMK1 kinase activation assay, Y1062F mutagenesis, pharmacological pathway inhibitors, luciferase reporter assay Biochemical and biophysical research communications Medium 11237712
2002 Dok1 is a docking protein for RET tyrosine kinase (identified by yeast two-hybrid). Dok1 binds RET-MEN2B more strongly than RET-MEN2A. Dok1 (via Ras-GAP binding at multiple tyrosines) suppresses Ras/Erk activation by GDNF/RET-MEN2B, while Dok1 (via Nck binding at Y361) is required for JNK/c-Jun activation, establishing Dok1 as a bifunctional scaffold with opposing effects on RET downstream pathways. Yeast two-hybrid screen, site-directed mutagenesis of Dok1 tyrosines, Ras/Erk and JNK/c-Jun activation assays The Journal of biological chemistry High 12087092
2004 Dominant-negative RET(ΔTK) disrupts oncogenic RET autophosphorylation in MTC cells, abolishing downstream Akt and ERK phosphorylation, decreasing cyclin D1 expression, increasing p21 and p27, stimulating apoptosis with decreased BCL-2, reducing cell cycle progression, and suppressing tumor growth in transgenic mice with orthotopic MTC. Adenoviral dominant-negative RET expression, Western blotting of signaling proteins, cell cycle analysis, apoptosis assay, in vivo transgenic mouse tumor model Journal of the National Cancer Institute High 15316058
2009 ETS transcription factors Etv4 and Etv5 are positively regulated downstream of GDNF-Ret signaling in ureteric bud tips. Double knockout mice lacking both Etv4 alleles and one Etv5 allele show renal agenesis or severe hypodysplasia; complete double homozygous knockout causes total kidney development failure. Downstream Etv4/Etv5 targets include Cxcr4, Myb, Met, and Mmp14, establishing Etv4/Etv5 as key effectors in the Ret-dependent gene network for renal branching morphogenesis. Genetic mouse knockouts (Etv4/Etv5 compound mutants), gene expression analysis in ureteric bud Nature genetics High 19898483
2010 RET51 activation by GDNF or NGF triggers formation of a RET51/FKBP52 complex. Substitution of tyrosine 905 of RET51 (phosphorylated by both GDNF and NGF) disrupts this complex, establishing Y905 phosphorylation as required for RET51-FKBP52 interaction. Co-immunoprecipitation, site-directed mutagenesis (Y905 substitution), patient mutation screening Human molecular genetics Medium 20442138
2011 Caspase cleavage of RET generates two fragments: an intracellular domain capable of triggering apoptosis, and a membrane-anchored N-terminal ectodomain (containing cadherin domains) that functions as a cadherin accessory protein, enhancing cadherin-mediated cell aggregation in sympathetic neurons. This establishes a non-canonical ligand-independent role for RET in cell adhesion regulation. Caspase cleavage assay, cell aggregation assay in sympathetic neurons, mutagenesis of caspase cleavage site The Journal of biological chemistry Medium 21357690
2012 RET is alternatively spliced to encode isoforms (primarily RET9 and RET51) with distinct trafficking properties: RET9 accumulates in the Golgi intracellularly while RET51 is efficiently matured and present at higher levels on the plasma membrane. RET51 is internalized faster after ligand binding and undergoes recycling back to the plasma membrane. This differential trafficking produces more rapid and longer ERK/MAPK signaling from RET51 versus RET9. Subcellular fractionation, live-cell imaging, FRAP, internalization assays, ERK/MAPK signaling time-course Molecular biology of the cell High 22875993
2012 KIF5B-RET fusion leads to aberrant constitutive activation of RET kinase and functions as an oncogenic driver in lung adenocarcinoma, as demonstrated by anchorage-independent growth of NIH3T3 cells that is suppressible by the RET tyrosine kinase inhibitor vandetanib. Whole-transcriptome sequencing to identify fusion, NIH3T3 transformation assay, RET kinase inhibitor treatment Nature medicine High 22327623 22327624
2014 GM1 ganglioside enhances Ret kinase activity in striatal tissue via GFRα1, increasing binding of endogenous GDNF to GFRα1. GM1-induced Ret activation leads to Tyr1062 phosphorylation and PI3K/Akt and Erk and Src signaling recruitment. Src kinase (PP1/PP2 sensitive) is required for GM1-induced Ret activation. Neutralization of released GDNF does not inhibit the Ret response, indicating GM1 acts upstream at the GFRα1 level. Striatal slice preparation, kinase activity assay, Src inhibitor treatment, GDNF neutralization, co-receptor dependence assays Journal of neurochemistry Medium 24821093
2015 RET internalization occurs primarily through clathrin-coated pits (not caveolin). The AP2 μ subunit interacts directly with both RET isoforms and is required for RET internalization via clathrin-mediated endocytosis. RET51 is rapidly and robustly recruited to clathrin-coated pits upon GDNF stimulation, while RET9 recruitment is slower and less pronounced, contributing to their distinct signaling durations. TIRF microscopy, co-localization with clathrin/caveolin, AP2 interaction assay, siRNA knockdown of AP2 Traffic High 26304132
2016 RET51 isoform depletion has significantly greater effects than RET9 depletion on medullary thyroid carcinoma (MTC) cell survival, proliferation, anoikis resistance, and on papillary thyroid carcinoma (PTC) cell migration, mesenchymal marker expression, matrix metalloproteinase expression, and invasive potential, establishing RET51 as the functionally dominant isoform in thyroid carcinoma contexts. shRNA-mediated isoform-specific knockdown, cell viability assay, migration assay, invasion assay, anoikis assay, immunoblotting of EMT markers Endocrine-related cancer Medium 27872141
2016 Drosophila models of CCDC6-RET and NCOA4-RET fusions show that both drive cell migration, delamination, and EMT, but NCOA4-RET produces more severe phenotypes than CCDC6-RET mirroring clinical behavior. A kinome/drug screen revealed CCDC6-RET and NCOA4-RET act through different signaling networks with distinct drug sensitivities, and WEE1 inhibitor plus sorafenib is synergistically specific for NCOA4-RET. Drosophila transgenic cancer model, kinome RNAi screen, drug library screen, combination drug synergy assay Cell reports Medium 27626672
2017 Potent RET inhibitors (AD80, ponatinib) that bind RET in the DFG-out (catalytically inactive) conformation selectively kill RET-rearranged tumor cells. Chemical genomics and phosphoproteomics identified the CCDC6-RET I788N mutation and MAPK pathway reactivation as resistance mechanisms to RET inhibitors. DFG-out conformation binding (type II inhibitors), chemical genomics screen, phosphoproteomics in RET-rearranged cells, drug sensitivity assays Science translational medicine High 28615362
2019 FAT4 (atypical cadherin) interacts with RET through extracellular cadherin repeats and perturbs assembly of the RET-GFRα1-GDNF signaling complex, reducing RET signaling. Loss of Fat4 in mice causes excessive RET signaling and abnormal ureteric budding; removing one copy of Gdnf rescues the Fat4-knockout kidney phenotype, establishing FAT4 as a juxtacrine negative regulator of RET signaling during kidney development. Fat4 conditional knockout mice, Gdnf genetic rescue experiment, co-immunoprecipitation of FAT4-RET interaction, kidney developmental analysis Developmental cell High 30853441
2020 Acquired resistance to selpercatinib (selective RET inhibitor) is driven by RET G810 solvent front mutations (G810R, G810S, G810C) that sterically hinder selpercatinib binding, as predicted by structural modeling and confirmed by in vitro kinase and cell-based assays. In addition, MET amplification and rare RET-wildtype tumor cell populations driven by alternative mitogenic drivers represent off-target resistance routes. Circulating tumor DNA analysis, post-mortem biopsy, patient-derived xenograft model of acquired resistance, enzyme assay, cell-based assay, structural modeling Journal of thoracic oncology High 31988000 35304457
2023 Vepafestinib (TAS0953/HM06) has a unique binding mode to RET with best-in-class selectivity, retains activity against RETL730, RETV804, and RETG810 on-target resistance mutations, and shows superior CNS pharmacokinetics compared to approved RET inhibitors, translating to improved tumor control in an intracranial RET-driven cancer model. In vitro RET kinase selectivity panel, cell-based assays with resistance mutants, pharmacokinetic brain penetration studies, intracranial xenograft model Nature cancer Medium 37743366
2017 EGF/EGFR activation triggers resistance to RET inhibitors (sunitinib, E7080, vandetanib, sorafenib) in CCDC6-RET lung cancer cells by transducing bypass survival signaling through ERK and AKT. EGFR-TKI treatment resensitizes cells to RET inhibitors, establishing EGFR bypass as a mechanism of RET inhibitor resistance. Cell viability assay with RET inhibitors ± EGF, ERK/AKT phosphorylation Western blot, EGFR siRNA, EGFR-TKI combination Yonsei medical journal Medium 27873490
2004 TTF-1 (thyroid transcription factor-1) directly binds the RET promoter and activates RET transcription. HSCR-associated RET promoter SNPs overlap TTF-1 binding sites and decrease RET transcription in functional reporter assays. A TTF-1 missense mutation (Gly322Ser) in an HSCR patient compromises activation from HSCR-associated RET promoter haplotypes, establishing TTF-1 as a direct transcriptional regulator of RET. Luciferase reporter assay, TTF-1 binding site analysis, patient mutation functional characterization, chromatin context analysis Human molecular genetics Medium 15548547
2017 GDNF plus GFRα1 (but not GDNF alone) promotes RET-dependent perineural invasion, proliferation, and soft agar colony formation in prostate cancer cells. Conditioned medium from dorsal root ganglia (containing secreted GFRα1) promotes these transformed phenotypes, blocked by anti-GFRα1 antibody. RET signaling activates ERK or AKT depending on context, but p70S6 kinase phosphorylation is markedly increased in all cases; p70S6K knockdown markedly decreases RET-induced transformed phenotypes. RET knockdown, anti-GFRα1 antibody, dorsal root ganglion perineural invasion assay, p70S6K siRNA, Western blotting, in vivo tumor xenograft Clinical cancer research Medium 28490466

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 RET, ROS1 and ALK fusions in lung cancer. Nature medicine 1068 22327623
1995 Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science (New York, N.Y.) 727 7824936
1996 GDNF signalling through the Ret receptor tyrosine kinase. Nature 711 8657282
2012 KIF5B-RET fusions in lung adenocarcinoma. Nature medicine 673 22327624
2014 RET revisited: expanding the oncogenic portfolio. Nature reviews. Cancer 398 24561444
2002 RET/PTC rearrangement in thyroid tumors. Endocrine pathology 355 12114746
1987 ret transforming gene encodes a fusion protein homologous to tyrosine kinases. Molecular and cellular biology 351 3037315
2018 Selective RET kinase inhibition for patients with RET-altered cancers. Annals of oncology : official journal of the European Society for Medical Oncology 347 29912274
1997 TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Neuron 305 9182803
1999 RET proto-oncogene in the development of human cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 263 10458257
2000 The RET proto-oncogene in human cancers. Oncogene 242 11114739
2001 The RET receptor: function in development and dysfunction in congenital malformation. Trends in genetics : TIG 234 11585664
2020 RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 227 31988000
2019 RET fusions in solid tumors. Cancer treatment reviews 196 31715421
2000 Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway. The Journal of biological chemistry 186 10652352
2009 Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nature genetics 179 19898483
2001 RET oncogene activation in papillary thyroid carcinoma. Advances in anatomic pathology 155 11707626
2004 RET and neuroendocrine tumors. Cancer letters 151 15013219
1996 RET mutations in human disease. Trends in genetics : TIG 147 8901418
2004 Minireview: RET: normal and abnormal functions. Endocrinology 137 15331579
2009 Targeting the RET pathway in thyroid cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 135 19934298
2021 Precision therapy for RET-altered cancers with RET inhibitors. Trends in cancer 130 34391699
2020 Advances in Targeting RET-Dependent Cancers. Cancer discovery 122 32094155
1995 RET activation by germline MEN2A and MEN2B mutations. Oncogene 121 8570194
2003 RET and NTRK1 proto-oncogenes in human diseases. Journal of cellular physiology 113 12652644
2018 RET rearrangements are actionable alterations in breast cancer. Nature communications 103 30446652
2014 Comprehensive analysis of RET and ROS1 rearrangement in lung adenocarcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 102 25234288
2022 The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers. Nature communications 100 35304457
2020 RET Gene Fusions in Malignancies of the Thyroid and Other Tissues. Genes 99 32326537
2004 Cellular effects and antitumor activity of RET inhibitor RPI-1 on MEN2A-associated medullary thyroid carcinoma. Journal of the National Cancer Institute 99 15240784
2013 Central role of RET in thyroid cancer. Cold Spring Harbor perspectives in biology 98 24296167
2006 Current concepts in RET-related genetics, signaling and therapeutics. Trends in genetics : TIG 92 16979782
2017 Role of RET protein-tyrosine kinase inhibitors in the treatment RET-driven thyroid and lung cancers. Pharmacological research 89 29284153
1997 Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene 89 9242375
2018 Cabozantinib: Multi-kinase Inhibitor of MET, AXL, RET, and VEGFR2. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 82 30069760
2022 RET signaling pathway and RET inhibitors in human cancer. Frontiers in oncology 79 35957881
2011 RET in breast cancer: functional and therapeutic implications. Trends in molecular medicine 79 21251878
2015 The RET oncogene in papillary thyroid carcinoma. Cancer 74 25731779
2004 TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease. Human molecular genetics 74 15548547
2001 MEN2A-RET-induced cellular transformation by activation of STAT3. Oncogene 74 11536047
2004 Dysfunction of the RET receptor in human cancer. Cellular and molecular life sciences : CMLS 69 15583857
2016 A subpopulation of itch-sensing neurons marked by Ret and somatostatin expression. EMBO reports 67 26929027
2018 Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 66 29018141
2016 Preclinical Modeling of KIF5B-RET Fusion Lung Adenocarcinoma. Molecular cancer therapeutics 66 27496134
2014 Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 66 24756794
1997 RET in human development and oncogenesis. BioEssays : news and reviews in molecular, cellular and developmental biology 63 9174404
2015 Design, Synthesis and Inhibitory Activity of Photoswitchable RET Kinase Inhibitors. Scientific reports 62 25944708
2020 Intracellular RET signaling pathways activated by GDNF. Cell and tissue research 58 32816064
2002 Role of Dok1 in cell signaling mediated by RET tyrosine kinase. The Journal of biological chemistry 58 12087092
2014 To bud or not to bud: the RET perspective in CAKUT. Pediatric nephrology (Berlin, Germany) 57 24022366
2004 Role of MEN2A-derived RET in maintenance and proliferation of medullary thyroid carcinoma. Journal of the National Cancer Institute 57 15316058
2006 Inhibition of RET tyrosine kinase by SU5416. Journal of molecular endocrinology 56 17032739
1998 Signal transduction by the receptor tyrosine kinase Ret. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 56 10027007
2017 Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Science translational medicine 54 28615362
1998 RET/PTC and RET tyrosine kinase expression in adult papillary thyroid carcinomas. The Journal of clinical endocrinology and metabolism 51 9768676
2022 RET kinase inhibitors for RET-altered thyroid cancers. Therapeutic advances in medical oncology 49 35756966
2020 Roles of the RET Proto-oncogene in Cancer and Development. JMA journal 49 33150251
2004 The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation. Oncogene 49 14712226
2017 Medullary Thyroid Carcinoma in MEN2A: ATA Moderate- or High-Risk RET Mutations Do Not Predict Disease Aggressiveness. The Journal of clinical endocrinology and metabolism 48 28609830
2016 Drosophila Cancer Models Identify Functional Differences between Ret Fusions. Cell reports 48 27626672
2012 Alternative splicing results in RET isoforms with distinct trafficking properties. Molecular biology of the cell 48 22875993
2011 Development of RET kinase inhibitors for targeted cancer therapy. Current medicinal chemistry 45 21110809
2017 RET Signaling in Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 44 28490466
2014 RET mutation and expression in small-cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 44 25122427
1995 Oncogenic activation of the ret protooncogene in thyroid cancer. Critical reviews in oncogenesis 44 8573606
2020 Targeting RET Kinase in Neuroendocrine Prostate Cancer. Molecular cancer research : MCR 43 32461304
1995 RET gene and its implications for cancer. Journal of the National Cancer Institute 43 7563185
2013 RET and NRG1 interplay in Hirschsprung disease. Human genetics 41 23400839
2001 Activation of BMK1 via tyrosine 1062 in RET by GDNF and MEN2A mutation. Biochemical and biophysical research communications 41 11237712
1999 Ret-mediated mitogenesis requires Src kinase activity. Cancer research 41 10070972
2021 Hallmarks of RET and Co-occuring Genomic Alterations in RET-aberrant Cancers. Molecular cancer therapeutics 37 34493590
2013 RET inhibition: implications in cancer therapy. Expert opinion on therapeutic targets 37 23461584
2020 RET-independent signaling by GDNF ligands and GFRα receptors. Cell and tissue research 35 32737575
2017 EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells. Yonsei medical journal 35 27873490
2023 RET aberrant cancers and RET inhibitor therapies: Current state-of-the-art and future perspectives. Pharmacology & therapeutics 34 36632846
2016 Differential roles of RET isoforms in medullary and papillary thyroid carcinomas. Endocrine-related cancer 34 27872141
2001 Conservation of RET proto-oncogene splicing variants and implications for RET isoform function. Cytogenetics and cell genetics 33 12063395
2019 FAT4 Fine-Tunes Kidney Development by Regulating RET Signaling. Developmental cell 32 30853441
2012 RET expression and detection of KIF5B/RET gene rearrangements in Japanese lung cancer. Cancer medicine 32 23342255
2023 Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations. Nature cancer 30 37743366
2006 RET and neuroendocrine tumors. Pituitary 30 17036197
1995 The RET proto-oncogene and cancer. Journal of internal medicine 30 7595167
2006 Molecular mechanisms of RET-induced Hirschsprung pathogenesis. Annals of medicine 29 16448984
2007 RET signaling in endocrine tumors: delving deeper into molecular mechanisms. Endocrine pathology 27 17916994
2000 Relative expression of the RET9 and RET51 isoforms in human pheochromocytomas. Oncology 27 10838497
2011 Ret-dependent and Ret-independent mechanisms of Gfl-induced sensitization. Molecular pain 26 21450093
2016 RET mutation and increased angiogenesis in medullary thyroid carcinomas. Endocrine-related cancer 25 27402614
2004 The RET receptor is linked to stress response pathways. Cancer research 24 15231654
2020 RET kinase alterations in targeted cancer therapy. Cancer drug resistance (Alhambra, Calif.) 23 35582449
2014 GM1 ganglioside enhances Ret signaling in striatum. Journal of neurochemistry 23 24821093
2009 CXCR2 and RET single nucleotide polymorphisms in pancreatic cancer. World journal of surgery 23 19057948
2023 Strategies for mitigating adverse events related to selective RET inhibitors in patients with RET-altered cancers. Cell reports. Medicine 22 38118420
2010 The RET51/FKBP52 complex and its involvement in Parkinson disease. Human molecular genetics 21 20442138
2012 AZD1480 blocks growth and tumorigenesis of RET- activated thyroid cancer cell lines. PloS one 20 23056499
2015 Distinct Temporal Regulation of RET Isoform Internalization: Roles of Clathrin and AP2. Traffic (Copenhagen, Denmark) 19 26304132
2011 RET modulates cell adhesion via its cleavage by caspase in sympathetic neurons. The Journal of biological chemistry 19 21357690
1996 RET oncogene. Current opinion in genetics & development 19 8791480
2016 miRNA Profiling Reveals Dysregulation of RET and RET-Regulating Pathways in Hirschsprung's Disease. PloS one 18 26933947
1997 Altered RET gene mRNA expression in Hirschsprung's disease. Journal of pediatric surgery 18 9126763
2023 Precision oncology with selective RET inhibitor selpercatinib in RET-rearranged cancers. Therapeutic advances in medical oncology 17 37360768

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