{"gene":"AXL","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2005,"finding":"Crystal structure of the Gas6/AXL complex at 3.3 Å resolution reveals a 2:2 stoichiometric assembly in which two immunoglobulin-like domains of the AXL ectodomain are crosslinked by the first laminin G-like domain of Gas6, with no direct AXL/AXL or Gas6/Gas6 contacts. Structure-based mutagenesis and receptor activation experiments demonstrate that both major and minor Gas6-binding sites are required for productive transmembrane signaling.","method":"X-ray crystallography, structure-based mutagenesis, protein binding assays, receptor activation experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and functional validation in one study","pmids":["16362042"],"is_preprint":false},{"year":1995,"finding":"AXL is post-translationally processed by proteolytic cleavage in a 14-amino acid region immediately N-terminal to the transmembrane domain, generating a soluble extracellular domain and a membrane-bound kinase domain. This cleavage is augmented by phorbol ester treatment and does not require protein synthesis or transport. Proteolytic processing enhances receptor turnover at the cell surface, thereby down-regulating AXL kinase activity.","method":"Biochemical characterization, phorbol ester stimulation assays, cell surface receptor turnover assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct mechanistic characterization with multiple experimental conditions and controls","pmids":["7822279"],"is_preprint":false},{"year":2005,"finding":"Gas6-induced downregulation of AXL is blocked by inhibitors of endocytosis and lysosomal degradation but not by proteasomal inhibitors. Gas6 binding induces AXL phosphorylation, ubiquitination, and interaction with the ubiquitin ligase c-Cbl. Hydrogen peroxide induces AXL tyrosine phosphorylation but not ubiquitination, thereby inhibiting AXL downregulation.","method":"In vitro pharmacological inhibition, immunoprecipitation, Western blotting, ubiquitination assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in single study establishing ubiquitination-dependent lysosomal degradation","pmids":["15958209"],"is_preprint":false},{"year":2014,"finding":"AXL directly phosphorylates Elmo1/2 scaffold proteins on a conserved C-terminal tyrosine residue (Tyr-713 on Elmo2) upon Gas6-dependent activation. Phosphorylated Elmo2 enters a physical complex with AXL and activates Rac1 through Dock family GEFs, promoting breast cancer cell invasion and proliferation. Elmo2 Tyr-713-Phe mutation abolishes these effects.","method":"Proteomics, mutagenesis, co-immunoprecipitation, Rac1 activation assays, siRNA knockdown, invasion assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — substrate identification with mutagenesis, functional rescue, and multiple orthogonal methods","pmids":["25332238"],"is_preprint":false},{"year":2014,"finding":"AXL forms a multiprotein complex with LDL receptor-related protein-1 (LRP-1) and RAN-binding protein 9 (RANBP9) in dendritic cells to mediate efferocytosis and antigen cross-presentation in vivo. AXL binds apoptotic cells but requires LRP-1 to trigger internalization. AXL and LRP-1 do not interact directly but rely on RANBP9 as a bridging adaptor.","method":"Targeted genetic deletion in mice, spleen efferocytosis assay, co-immunoprecipitation, antigen cross-presentation coculture assay, in vivo HSV-1 infection model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — complex identified with Co-IP, genetic deletion in vivo, and functional cross-presentation readout","pmids":["24509082"],"is_preprint":false},{"year":2014,"finding":"An engineered AXL decoy receptor with four mutations in the Gas6-binding interface binds Gas6 with ~80-fold higher affinity than wild-type AXL (femtomolar affinity as Fc fusion), sequesters Gas6, and specifically abrogates AXL signaling. Increased Gas6-binding affinity correlated with inhibition of metastasis in vivo.","method":"Rational and combinatorial protein engineering, binding affinity measurements, in vivo tumor/metastasis models","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 — structure-guided mutagenesis with quantitative binding and in vivo functional validation","pmids":["25242553"],"is_preprint":false},{"year":2010,"finding":"AXL enhances macropinocytosis of Zaire ebolavirus glycoprotein-dependent entry; RNAi knockdown of AXL reduced ZEBOV entry via macropinocytosis but had no effect on clathrin-dependent or caveola/lipid raft-mediated endocytic pathways.","method":"Biochemical inhibitors, RNAi, dominant negative constructs, high-molecular-weight dextran uptake assay, infection assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (RNAi, dominant negatives, pathway inhibitors) with specific pathway readouts","pmids":["21047970"],"is_preprint":false},{"year":2019,"finding":"Axl receptor neutralization and its ligand Gas6 blockade strongly attenuates Zika virus entry in human Sertoli cells, while Axl kinase inhibition (without affecting entry) decreases SOCS1 and SOCS3 levels, increases interferon-stimulated gene expression, and reduces ZIKV replication, demonstrating that Axl negatively regulates the antiviral interferon response in the testis.","method":"Receptor/ligand neutralization assays, kinase inhibitor treatment, western blotting, ISG expression analysis, testicular organoid model","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — dual mechanism dissection (entry vs. signaling) with multiple cell models and mechanistic pathway readouts","pmids":["31311882"],"is_preprint":false},{"year":2003,"finding":"AXL is active in confluent vascular pericytes via endogenous Gas6 autocrine signaling. Addition of soluble AXL extracellular domain (decoy) inhibited endogenous AXL phosphorylation and enhanced osteogenic differentiation/mineralization, demonstrating that AXL activation suppresses pericyte osteogenic differentiation.","method":"Subtractive hybridization, Northern/Western blotting, immunoprecipitation with anti-phosphotyrosine antibody, recombinant protein treatment, nodule mineralization assay","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal experimental approach with decoy receptor plus direct phosphorylation measurement","pmids":["12730092"],"is_preprint":false},{"year":2006,"finding":"AXL is required for flow-dependent vascular remodeling; Axl-/- mice develop significantly smaller intima+media in response to low-flow carotid ligation, with increased apoptosis (5-fold), decreased p-Akt, and altered vascular cell composition, placing AXL upstream of Akt-mediated survival signaling in VSMC.","method":"Axl-/- knockout mouse model, carotid ligation surgery, quantitative immunohistochemistry, apoptosis assays, Western blotting for p-Akt","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with specific in vivo phenotypic readouts and mechanistic signaling analysis","pmids":["16627783"],"is_preprint":false},{"year":2013,"finding":"Gas6/AXL signaling in schwannoma cells recruits Src, FAK, and NFκB. NFκB mediates Gas6/AXL-driven overexpression of survivin, cyclin D1, and FAK, leading to enhanced cell survival, matrix adhesion, and proliferation. AXL is negatively regulated by merlin and positively regulated by E3 ubiquitin ligase CRL4DCAF1.","method":"Gas6 stimulation assays, shRNA knockdown, signaling pathway analysis, cell adhesion and proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — defined signaling pathway downstream of AXL with NFκB as mechanistic mediator, single lab","pmids":["23318455"],"is_preprint":false},{"year":1993,"finding":"The human AXL (UFO) receptor is encoded by 20 exons spanning ~44 kb, with alternative splicing of exon 10 and differential polyadenylation generating mRNA isoforms. The promoter is GC-rich, lacks TATA and CAAT boxes, and contains Sp1, AP-2, and CREB binding sites.","method":"Genomic library screening, S1 nuclease and primer extension analysis, sequencing","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — direct structural characterization of the genomic locus with transcriptional start site mapping","pmids":["8381225"],"is_preprint":false},{"year":2010,"finding":"AXL is expressed and activated in mesothelioma cells via autocrine GAS6 signaling; GAS6 knockdown modulates AXL tyrosine phosphorylation. AXL silencing suppresses mesothelioma migration and proliferation via G1 arrest, and AXL inhibition blocks PI3K/AKT/mTOR and RAF/MAPK signaling.","method":"Phosphotyrosine immunoaffinity MS, shRNA knockdown, GAS6 modulation, cell cycle analysis, pathway inhibitor studies","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased proteomics plus functional genetic knockdown with defined pathway readouts","pmids":["21132014"],"is_preprint":false},{"year":2016,"finding":"AXL dimerizes with EGFR and initiates signaling that circumvents anti-EGFR therapy effects. AXL overexpression and EGFR dimerization can overcome PI3K inhibition by activating the phospholipase C-γ-PKC cascade, which in turn sustains mTORC1 activity.","method":"Receptor co-immunoprecipitation, pathway signaling analysis, pharmacological inhibition","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic pathway defined in review citing primary experimental data, AXL-EGFR interaction established by co-IP","pmids":["26763248"],"is_preprint":false},{"year":2019,"finding":"Osimertinib stimulates AXL by inhibiting a negative feedback loop. Activated AXL associates with EGFR and HER3 in a complex that maintains cell survival and promotes emergence of osimertinib-tolerant cells.","method":"Co-immunoprecipitation, signaling analysis, AXL inhibitor treatment, viability assays, xenograft tumor models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — AXL-EGFR/HER3 complex identified with Co-IP plus functional inhibitor studies, single lab","pmids":["30651547"],"is_preprint":false},{"year":2016,"finding":"AXL is transcriptionally regulated by AP-1 transcription factors c-JUN and c-FOS; AXL expression correlates with c-JUN, and silencing c-JUN/c-FOS downregulates AXL and restores sensitivity to PI3Kα inhibition.","method":"siRNA silencing of c-JUN/c-FOS, qPCR, Western blotting, JNK inhibitor studies, in vivo xenograft models","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — direct transcription factor silencing with AXL as readout, multiple models","pmids":["30860495"],"is_preprint":false},{"year":2019,"finding":"AXL expression is regulated post-transcriptionally by RNA-binding protein PTBP1, which directly targets the 5'-UTR of AXL mRNA and decreases AXL mRNA stability without affecting transcription rate.","method":"RNA-IP, in vitro and in vivo PTBP1-AXL mRNA binding assays, mRNA stability assays, qRT-PCR, tumor xenograft models","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct RNA-protein interaction demonstrated with functional mRNA stability readout","pmids":["31729427"],"is_preprint":false},{"year":2023,"finding":"NAT10-mediated N4-acetylcytidine (ac4C) modification of AXL mRNA promotes its stability, leading to increased AXL protein expression and enhanced pancreatic cancer cell proliferation and metastasis.","method":"ac4C-seq, mRNA stability assays, NAT10 knockdown/overexpression, in vitro and in vivo functional assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — direct epitranscriptomic modification of AXL mRNA established with functional consequences","pmids":["37156457"],"is_preprint":false},{"year":2020,"finding":"p85β (PIK3R2) prevents autophagic degradation of AXL protein by altering phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), thereby upregulating AXL protein levels and activating downstream AKT-independent PDK1/SGK3 signaling in ovarian cancer.","method":"Co-immunoprecipitation, siRNA/overexpression, phospho-proteomics, autophagy flux assays, in vivo tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway from p85β to AXL protein stability defined with multiple orthogonal methods","pmids":["32385243"],"is_preprint":false},{"year":2023,"finding":"LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase that targets AXL (and EGFR) for ubiquitin-dependent lysosomal degradation. Pathogenic cancer-associated LZTR1 mutations fail to promote AXL degradation, resulting in AXL protein accumulation and dysregulated signaling.","method":"Unbiased biochemical screens, co-immunoprecipitation, genetic mouse models (conditional Lztr1/Cdkn2a knockout), ubiquitination assays, tumor formation assays","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1-2 — substrate-adaptor relationship identified by unbiased screens with genetic in vivo validation and mechanistic ubiquitination assays","pmids":["36445254"],"is_preprint":false},{"year":2016,"finding":"Gas6-Axl interaction mediates endothelial uptake of platelet-derived microparticles (PMPs) via Axl on endothelial cells; TAM-blocking antibodies or siRNA knockdown of individual TAMs confirmed Axl and Gas6 as the specific mediators of PMP phagocytosis.","method":"Flow cytometry, confocal/electron microscopy, Western blotting, siRNA knockdown, TAM-blocking antibodies, Gas6-/- mouse model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — specific receptor identified by siRNA and antibody blockade with multiple imaging modalities","pmids":["27006397"],"is_preprint":false},{"year":2018,"finding":"Protein S (PROS1) secreted by tumor-associated macrophages/microglia activates AXL in mesenchymal glioblastoma stem cells, inducing NFκB activation. PROS1-driven AXL phosphorylation is inhibited by the AXL inhibitor BGB324.","method":"Co-immunoprecipitation, phospho-AXL detection, NFκB reporter assays, pharmacological inhibition, in vivo survival studies","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — ligand-receptor activation confirmed by Co-IP and phosphorylation with functional NFκB readout","pmids":["29531161"],"is_preprint":false},{"year":2022,"finding":"Gas6/Axl/Rac1 signaling promotes microglia efferocytosis of apoptotic neurons following subarachnoid hemorrhage; beneficial effects of recombinant Gas6 are abrogated by inhibiting or knocking down Axl or Rac1, placing Rac1 downstream of Axl in this efferocytosis pathway.","method":"In vivo mouse SAH model, intraventricular injection, siRNA knockdown, specific inhibitors, in vitro efferocytosis assays","journal":"Translational stroke research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological epistasis in both in vivo and in vitro models","pmids":["36324028"],"is_preprint":false},{"year":2015,"finding":"AXL is a sensor of local spatial heterogeneity in Gas6 ligand concentration, a property arising from reaction-diffusion interactions. Quantitative experiments and mathematical modeling demonstrate AXL operates distinctly from other RTK families in ligand-sensing mechanism.","method":"Quantitative cell-based assays, mathematical/computational modeling, ligand gradient experiments","journal":"Cell systems","confidence":"Medium","confidence_rationale":"Tier 2 — integrated experimental and computational modeling with quantitative mechanistic interpretation","pmids":["26236777"],"is_preprint":false},{"year":2020,"finding":"Axl regulates apolipoprotein E (apoE) homeostasis in human astrocytes; AXL-deficient cells have significantly attenuated apoE expression and secretion, and reconstitution with either wild-type or kinase-dead Axl restores apoE baseline levels, demonstrating a kinase-independent scaffolding role for Axl in apoE regulation.","method":"AXL-/- cell line generation, pharmacological Axl inhibition, reconstitution with WT and kinase-dead Axl, ELISA, Western blotting","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 — kinase-dead rescue experiment distinguishing kinase-dependent vs. scaffolding functions","pmids":["32366277"],"is_preprint":false},{"year":2017,"finding":"YAP transcriptionally regulates AXL expression in EGFR TKI-resistant lung cancer cells; YAP silencing reduces AXL expression, pharmacological or genetic AXL inhibition restores drug sensitivity, placing AXL downstream of YAP in resistance.","method":"YAP siRNA/overexpression, ChIP-seq/reporter assay inference, AXL inhibitor treatment, drug sensitivity assays","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2-3 — YAP-AXL transcriptional axis established by genetic knockdown/overexpression with functional drug resistance readout","pmids":["29136529"],"is_preprint":false},{"year":2020,"finding":"Phosphatidylethanolamine (PE) synergizes with phosphatidylserine (PS) to enhance GAS6 recognition, leading to increased AXL-mediated efferocytosis and virus entry. Liposomes containing both PE and PS bound GAS6 and were engulfed by AXL-expressing cells more efficiently than PS alone.","method":"Liposome binding assays, AXL-expressing cell efferocytosis assays, virus pseudotype infection assays, flow cytometry","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — defined lipid requirement for AXL ligand recognition using reconstituted liposome system","pmids":["33115868"],"is_preprint":false},{"year":2018,"finding":"AXL binds to the initial 600 bp sequence at the 5' end of the TP53 promoter (demonstrated by ChIP-qPCR and sequencing), suppressing TP53 transcription; AXL knockdown induces p53 expression and AXL nuclear colocalization with p53 is observed by immunofluorescence, establishing a feedback regulatory loop.","method":"ChIP-qPCR, ChIP-seq, TP53 promoter luciferase assay, qRT-PCR, immunofluorescence, shRNA knockdown","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrates direct AXL-promoter binding with functional transcriptional readout","pmids":["32992696"],"is_preprint":false},{"year":2020,"finding":"AXL mediates cancer cell invasion in esophageal adenocarcinoma through regulation of lysosome peripheral distribution and cathepsin B secretion; this process is mediated by AXL-dependent extracellular acidification through AKT-NFκB-dependent regulation of lactate transporter MCT-1.","method":"siRNA knockdown, pharmacological AXL inhibition, lysosome trafficking assays, cathepsin B secretion assays, pH measurements, Western blotting","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 — defined mechanistic pathway from AXL to lysosome trafficking with multiple functional readouts","pmids":["30189359"],"is_preprint":false},{"year":2022,"finding":"GALNT2 modifies O-glycans on AXL and regulates AXL protein levels via the proteasome-dependent pathway; GALNT2-promoted cancer cell invasiveness is significantly reversed by AXL siRNA.","method":"GALNT2 overexpression/knockout (CRISPR/Cas9), co-immunoprecipitation, glycan modification assays, AXL protein level analysis, invasion assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — direct O-glycosylation of AXL identified with functional consequence on protein stability and invasion","pmids":["36409270"],"is_preprint":false},{"year":2018,"finding":"Axl and Tyro3, but not Mertk, are required for platelet activation and thrombus formation; Axl-/- platelets show decreased Syk and PLCγ2 tyrosine phosphorylation upon GPVI agonist stimulation; anti-Axl neutralizing antibodies and recombinant Axl extracellular domain inhibit platelet aggregation in a Gas6-independent manner.","method":"TAM single-receptor knockout mice, platelet aggregation assays, in vivo laser-induced thrombosis model, phosphorylation analysis, neutralizing antibody and recombinant ECD experiments","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO plus multiple pharmacological approaches with in vivo functional validation","pmids":["30541554"],"is_preprint":false},{"year":1999,"finding":"E1A negatively regulates AXL expression at the transcriptional level; Gas6-triggered AXL signaling counteracts E1A-mediated growth suppression and protects cells from serum deprivation-induced apoptosis, placing AXL as a downstream effector of survival signaling opposing E1A tumor suppression.","method":"Degenerate RT-PCR kinase profiling, AXL cDNA transfection, Gas6 stimulation, serum deprivation apoptosis assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptional regulation and functional rescue established by genetic and biochemical approaches","pmids":["10567533"],"is_preprint":false}],"current_model":"AXL is a TAM-family receptor tyrosine kinase activated primarily by Gas6 (and Protein S) binding to its two immunoglobulin-like extracellular domains, forming a 2:2 ligand-receptor complex that drives receptor dimerization and autophosphorylation; downstream signaling proceeds through PI3K/AKT, MAPK, Src/FAK/NFκB, and Rac1 (via direct phosphorylation of Elmo scaffold proteins), promoting cell survival, migration, invasion, efferocytosis, and immune suppression. AXL protein levels are regulated by Gas6-induced c-Cbl-dependent ubiquitination and lysosomal degradation, proteolytic ectodomain shedding, LZTR1-CUL3 ubiquitin ligase-mediated degradation, autophagic clearance controlled by p85β/TRIM2/optineurin, O-glycosylation by GALNT2, and mRNA stability regulated by PTBP1 and NAT10-mediated ac4C modification, while transcription is driven by AP-1 (c-JUN/c-FOS) and suppressed by E1A; AXL also forms functional complexes with EGFR/HER3 to mediate drug resistance, interacts with LRP-1/RANBP9 to mediate DC efferocytosis, and suppresses TP53 transcription through direct promoter binding."},"narrative":{"teleology":[{"year":1993,"claim":"Characterization of the AXL genomic locus revealed a GC-rich, TATA-less promoter with Sp1/AP-2/CREB sites and alternative splicing of exon 10, establishing the basic transcriptional architecture of the gene.","evidence":"Genomic library screening, S1 nuclease/primer extension mapping of the human AXL locus","pmids":["8381225"],"confidence":"Medium","gaps":["Functional significance of individual promoter elements not tested by mutagenesis","Role of alternative splicing isoforms undefined"]},{"year":1995,"claim":"Discovery that AXL undergoes proteolytic ectodomain shedding near its transmembrane domain established a first mechanism for downregulating surface AXL and generating soluble receptor.","evidence":"Biochemical characterization of AXL cleavage products with phorbol ester stimulation and turnover assays","pmids":["7822279"],"confidence":"High","gaps":["Identity of the responsible protease not determined","Physiological stimuli beyond phorbol esters not explored"]},{"year":1999,"claim":"Identification of E1A as a transcriptional repressor of AXL, with Gas6/AXL signaling opposing E1A-mediated growth suppression, linked AXL to survival signaling for the first time.","evidence":"Degenerate RT-PCR kinase profiling, AXL cDNA rescue, Gas6 stimulation, and serum deprivation apoptosis assay","pmids":["10567533"],"confidence":"Medium","gaps":["Mechanism of E1A-mediated transcriptional repression of AXL not defined","Downstream survival pathway not specified beyond anti-apoptosis"]},{"year":2003,"claim":"Demonstration that autocrine Gas6 activates AXL in vascular pericytes and that decoy receptor blockade promotes osteogenic differentiation established AXL as a tonic suppressor of cell fate transitions.","evidence":"Soluble AXL ectodomain treatment with phospho-AXL and mineralization readouts in pericyte cultures","pmids":["12730092"],"confidence":"Medium","gaps":["Downstream pathway connecting AXL to osteogenic transcription not identified","Single cell type studied"]},{"year":2005,"claim":"The 3.3 Å crystal structure of Gas6/AXL resolved how two AXL Ig-like domains are crosslinked by Gas6 LG1 in a 2:2 complex with no direct receptor–receptor contacts, defining the unique activation mechanism of AXL.","evidence":"X-ray crystallography with structure-based mutagenesis and receptor activation assays","pmids":["16362042"],"confidence":"High","gaps":["Conformational changes in the intracellular kinase domain upon dimerization not resolved","Full-length receptor structure unavailable"]},{"year":2005,"claim":"Gas6-induced AXL ubiquitination was shown to be c-Cbl-dependent and to drive lysosomal (not proteasomal) degradation, distinguishing AXL turnover from many other RTKs.","evidence":"Pharmacological inhibition of endocytosis/lysosomes/proteasome, immunoprecipitation, and ubiquitination assays","pmids":["15958209"],"confidence":"Medium","gaps":["Direct E3 ligase assay for c-Cbl on AXL not performed","Ubiquitin chain type not determined"]},{"year":2006,"claim":"Axl−/− mice showed impaired flow-dependent vascular remodeling with increased apoptosis and reduced p-Akt, genetically placing AXL upstream of Akt-dependent survival in vascular smooth muscle cells in vivo.","evidence":"Axl knockout mice with carotid ligation, immunohistochemistry, and Western blot for p-Akt","pmids":["16627783"],"confidence":"High","gaps":["Whether AXL signals to Akt directly or through PI3K intermediates not resolved in this model","Contribution of other TAM receptors not excluded"]},{"year":2010,"claim":"AXL was identified as an enhancer of macropinocytosis-dependent Ebola virus entry, revealing a role for AXL in regulating a specific endocytic pathway exploited by enveloped viruses.","evidence":"RNAi knockdown, dominant-negative constructs, and pathway-specific inhibitors with infection assays","pmids":["21047970"],"confidence":"High","gaps":["Whether AXL acts as a direct virus receptor or enhances macropinocytosis indirectly not fully resolved","Mechanism by which AXL activates macropinocytosis not defined"]},{"year":2013,"claim":"Mapping of a Src/FAK/NFκB cascade downstream of Gas6/AXL in schwannoma cells, with merlin as a negative regulator and CRL4-DCAF1 as a positive regulator, provided the first defined multi-node signaling pathway linking AXL to NFκB-dependent gene targets (survivin, cyclin D1).","evidence":"Gas6 stimulation, shRNA knockdown, and signaling/functional assays in schwannoma cells","pmids":["23318455"],"confidence":"Medium","gaps":["Direct phosphorylation targets linking AXL to Src not identified","Whether merlin-AXL regulation is direct or indirect not established"]},{"year":2014,"claim":"Identification of Elmo1/2 as direct AXL substrates phosphorylated on Tyr-713 established the first biochemically validated AXL kinase substrate and connected AXL to Rac1 activation via Dock GEFs.","evidence":"Proteomics, mutagenesis (Y713F), co-IP, Rac1 activation, and invasion assays in breast cancer cells","pmids":["25332238"],"confidence":"High","gaps":["Whether Elmo phosphorylation is required for non-cancer AXL functions (e.g., efferocytosis) not tested","Structural basis of AXL-Elmo recognition unknown"]},{"year":2014,"claim":"Discovery that AXL forms a tripartite complex with LRP-1 and RANBP9 in dendritic cells, where AXL recognizes apoptotic cells but LRP-1 is required for internalization, defined a cooperative receptor mechanism for efferocytosis and antigen cross-presentation.","evidence":"Targeted gene deletion in mice, co-IP, in vivo efferocytosis, and antigen cross-presentation assays","pmids":["24509082"],"confidence":"High","gaps":["Signaling events downstream of AXL-LRP-1-RANBP9 complex not characterized","Whether this complex operates in non-dendritic phagocytes unknown"]},{"year":2016,"claim":"AXL heterodimerization with EGFR was shown to bypass anti-EGFR and PI3K inhibitor therapy through activation of a PLCγ–PKC–mTORC1 bypass pathway, providing a mechanistic basis for AXL-driven drug resistance.","evidence":"Receptor co-immunoprecipitation, signaling analysis, and pharmacological inhibition in cancer cell lines","pmids":["26763248"],"confidence":"Medium","gaps":["Whether AXL-EGFR heterodimer forms through direct extracellular or intracellular interaction not defined","Structural basis of heterodimerization unknown"]},{"year":2016,"claim":"AP-1 transcription factors c-JUN and c-FOS were identified as direct transcriptional activators of AXL, and their silencing restored drug sensitivity, establishing the upstream transcriptional control of AXL expression in resistant tumors.","evidence":"siRNA silencing, qPCR/Western blot, JNK inhibitor studies, and xenograft models","pmids":["30860495"],"confidence":"Medium","gaps":["Direct AP-1 binding to AXL promoter not demonstrated by ChIP in this study","Relative contribution of c-JUN vs. c-FOS not dissected"]},{"year":2018,"claim":"AXL was found to bind the TP53 promoter directly (by ChIP) and suppress p53 transcription, revealing a non-canonical nuclear function for a receptor tyrosine kinase.","evidence":"ChIP-qPCR, ChIP-seq, luciferase reporter, and immunofluorescence showing nuclear AXL","pmids":["32992696"],"confidence":"Medium","gaps":["Mechanism of AXL nuclear translocation not defined","Whether AXL binds DNA directly or through a transcription factor complex unknown","Not independently replicated"]},{"year":2018,"claim":"Axl−/− platelets showed impaired Syk and PLCγ2 phosphorylation upon GPVI stimulation, and AXL blockade inhibited aggregation in a Gas6-independent manner, establishing a ligand-independent scaffolding role for AXL in platelet activation.","evidence":"TAM single-receptor KO mice, platelet aggregation, in vivo thrombosis model, neutralizing antibodies, and recombinant ECD","pmids":["30541554"],"confidence":"High","gaps":["Molecular mechanism of Gas6-independent AXL function in platelets not defined","Whether AXL directly interacts with GPVI complex not tested"]},{"year":2019,"claim":"Dissection of AXL's dual role in Zika virus infection — mediating entry via Gas6 and suppressing the interferon response via SOCS1/3 upregulation — showed AXL functions both as a viral entry facilitator and an innate immune checkpoint.","evidence":"Receptor/ligand neutralization, kinase inhibition, ISG expression analysis in human Sertoli cells and organoids","pmids":["31311882"],"confidence":"High","gaps":["Whether AXL-dependent SOCS induction is direct or via intermediate kinases not resolved","Contribution of other TAM receptors in testis not assessed"]},{"year":2019,"claim":"PTBP1 was identified as a post-transcriptional regulator that binds AXL mRNA 5′-UTR and decreases its stability, adding an RNA-level control mechanism for AXL expression.","evidence":"RNA-IP, in vitro/in vivo binding assays, mRNA half-life measurements, and xenograft models","pmids":["31729427"],"confidence":"Medium","gaps":["Exact PTBP1 binding site on AXL 5′-UTR not mapped at nucleotide resolution","Whether other RBPs cooperate with PTBP1 not explored"]},{"year":2020,"claim":"p85β was shown to stabilize AXL protein by preventing TRIM2/optineurin-mediated autophagic degradation, defining a PI3K-independent scaffolding function for p85β that feeds into AXL-dependent PDK1/SGK3 signaling.","evidence":"Co-IP, siRNA/overexpression, phospho-proteomics, autophagy flux assays, and in vivo tumor models","pmids":["32385243"],"confidence":"High","gaps":["Direct TRIM2 ubiquitination of AXL not demonstrated in vitro","Whether this pathway operates outside ovarian cancer not tested"]},{"year":2020,"claim":"Reconstitution with kinase-dead AXL restored apoE expression in AXL-null astrocytes, demonstrating a kinase-independent scaffolding function for AXL in lipid metabolism.","evidence":"AXL-knockout and kinase-dead reconstitution in human astrocytes with ELISA/Western blot readout","pmids":["32366277"],"confidence":"Medium","gaps":["Adaptor or scaffold partner mediating AXL kinase-independent apoE regulation not identified","In vivo relevance not established"]},{"year":2022,"claim":"GALNT2-mediated O-glycosylation of AXL was shown to regulate its protein stability through the proteasome, adding glycosylation as another post-translational layer of AXL regulation.","evidence":"GALNT2 overexpression/CRISPR-KO, co-IP, glycan modification assays, and invasion assays","pmids":["36409270"],"confidence":"Medium","gaps":["Specific O-glycosylation sites on AXL not mapped","Relationship to other ubiquitin-dependent degradation pathways (c-Cbl, LZTR1) not clarified"]},{"year":2023,"claim":"LZTR1 was identified as the CUL3 adaptor targeting AXL for ubiquitin-dependent lysosomal degradation, and cancer-associated LZTR1 mutations abolished this activity, linking AXL accumulation to oncogenic signaling from loss-of-function LZTR1 mutations.","evidence":"Unbiased biochemical screen, co-IP, genetic mouse models (conditional Lztr1/Cdkn2a KO), ubiquitination assays, and tumor formation","pmids":["36445254"],"confidence":"High","gaps":["Whether LZTR1 and c-Cbl operate on AXL in the same or distinct cellular compartments not resolved","Structural basis of LZTR1-AXL recognition unknown"]},{"year":2023,"claim":"NAT10-dependent ac4C modification of AXL mRNA was shown to increase its stability and drive pancreatic cancer proliferation, adding epitranscriptomic regulation as a mechanism for AXL overexpression.","evidence":"ac4C-seq, mRNA stability assays, NAT10 knockdown/overexpression, and in vivo functional assays","pmids":["37156457"],"confidence":"Medium","gaps":["Specific ac4C sites on AXL mRNA not mapped at single-nucleotide resolution","Whether ac4C modification interacts with PTBP1-mediated mRNA destabilization not examined"]},{"year":null,"claim":"How AXL's multiple degradation pathways (c-Cbl, LZTR1-CUL3, TRIM2/optineurin autophagy, GALNT2-proteasome, ectodomain shedding) are coordinated in different cell types, and whether AXL's reported nuclear function in TP53 regulation operates through direct DNA binding or cofactor-mediated recruitment, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Integration of multiple AXL degradation pathways not studied in a single system","Mechanism of AXL nuclear translocation uncharacterized","Full-length AXL structure with intracellular domain not available"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,0,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,7,31]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[27]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5,23]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,20,30]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[27]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,9,10,12,13,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,7]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[30]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,18,19,29]}],"complexes":["AXL-LRP1-RANBP9 efferocytosis complex","Gas6-AXL 2:2 signaling complex","AXL-EGFR/HER3 heterodimer"],"partners":["GAS6","EGFR","HER3","LRP1","RANBP9","ELMO2","LZTR1","PTBP1"],"other_free_text":[]},"mechanistic_narrative":"AXL is a TAM-family receptor tyrosine kinase that functions as a key regulator of cell survival, migration, efferocytosis, and immune modulation through Gas6- and Protein S-dependent activation of PI3K/AKT, MAPK, Src/FAK/NFκB, and Rac1 signaling cascades [PMID:16362042, PMID:25332238, PMID:16627783, PMID:23318455]. Gas6 binding to the two immunoglobulin-like domains of AXL drives formation of a 2:2 ligand–receptor complex that triggers autophosphorylation, and AXL further diversifies signaling by heterodimerizing with EGFR and HER3 to sustain survival during targeted therapy [PMID:16362042, PMID:30651547]. AXL protein levels are tightly controlled through c-Cbl-mediated ubiquitination and lysosomal degradation, LZTR1-CUL3 ubiquitin ligase-directed turnover, p85β/TRIM2/optineurin-dependent autophagic clearance, GALNT2-mediated O-glycosylation, ectodomain shedding, and post-transcriptional regulation of its mRNA by PTBP1 and NAT10 [PMID:15958209, PMID:36445254, PMID:32385243, PMID:36409270, PMID:7822279, PMID:31729427, PMID:37156457]. Beyond canonical RTK signaling, AXL mediates efferocytosis through an LRP-1/RANBP9 complex in dendritic cells, facilitates endothelial uptake of platelet-derived microparticles, and suppresses TP53 transcription via direct promoter binding [PMID:24509082, PMID:27006397, PMID:32992696]."},"prefetch_data":{"uniprot":{"accession":"P30530","full_name":"Tyrosine-protein kinase receptor UFO","aliases":["AXL oncogene"],"length_aa":894,"mass_kda":98.3,"function":"Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, AXL binds and induces tyrosine phosphorylation of PI3-kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TNS2. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Also plays an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response (Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (Microbial infection) Acts as a receptor for Ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (Microbial infection) Promotes Zika virus entry in glial cells, Sertoli cells and astrocytes (PubMed:28076778, PubMed:29379210, PubMed:31311882). Additionally, Zika virus potentiates AXL kinase activity to antagonize type I interferon signaling and thereby promotes infection (PubMed:28076778). Interferon signaling inhibition occurs via an SOCS1-dependent mechanism (PubMed:29379210)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P30530/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AXL","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AXL","total_profiled":1310},"omim":[{"mim_id":"612839","title":"TET METHYLCYTOSINE DIOXYGENASE 2; TET2","url":"https://www.omim.org/entry/612839"},{"mim_id":"607717","title":"TENSIN 2; TNS2","url":"https://www.omim.org/entry/607717"},{"mim_id":"605402","title":"CD274 MOLECULE; CD274","url":"https://www.omim.org/entry/605402"},{"mim_id":"604705","title":"MER TYROSINE KINASE PROTOONCOGENE; MERTK","url":"https://www.omim.org/entry/604705"},{"mim_id":"604491","title":"CAS-BR-M MURINE ECOTROPIC RETROVIRAL TRANSFORMING SEQUENCE B; CBLB","url":"https://www.omim.org/entry/604491"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AXL"},"hgnc":{"alias_symbol":["UFO","JTK11","Tyro7","ARK"],"prev_symbol":[]},"alphafold":{"accession":"P30530","domains":[{"cath_id":"2.60.40.10","chopping":"45-136","consensus_level":"high","plddt":85.1114,"start":45,"end":136},{"cath_id":"2.60.40.10","chopping":"141-225","consensus_level":"medium","plddt":82.5841,"start":141,"end":225},{"cath_id":"2.60.40.10","chopping":"230-267_282-329","consensus_level":"medium","plddt":90.273,"start":230,"end":329},{"cath_id":"2.60.40.10","chopping":"339-426","consensus_level":"high","plddt":84.4956,"start":339,"end":426},{"cath_id":"3.30.200.20","chopping":"511-622","consensus_level":"high","plddt":76.8609,"start":511,"end":622},{"cath_id":"1.10.510.10","chopping":"627-810","consensus_level":"high","plddt":88.6354,"start":627,"end":810}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30530","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30530-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30530-F1-predicted_aligned_error_v6.png","plddt_mean":75.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AXL","jax_strain_url":"https://www.jax.org/strain/search?query=AXL"},"sequence":{"accession":"P30530","fasta_url":"https://rest.uniprot.org/uniprotkb/P30530.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30530/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30530"}},"corpus_meta":[{"pmid":"26364599","id":"PMC_26364599","title":"Targeting 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potential therapeutic target in dedifferentiated and pleomorphic liposarcomas.","date":"2015","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26573603","citation_count":29,"is_preprint":false},{"pmid":"8381225","id":"PMC_8381225","title":"The genomic structure of the human UFO receptor.","date":"1993","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8381225","citation_count":28,"is_preprint":false},{"pmid":"30567378","id":"PMC_30567378","title":"Dynamics of Axl Receptor Shedding in Hepatocellular Carcinoma and Its Implication for Theranostics.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30567378","citation_count":27,"is_preprint":false},{"pmid":"33811159","id":"PMC_33811159","title":"AXL Is a Key Factor for Cell Plasticity and Promotes Metastasis in Pancreatic Cancer.","date":"2021","source":"Molecular cancer research : 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Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28468579","citation_count":26,"is_preprint":false},{"pmid":"28627676","id":"PMC_28627676","title":"Luteolin inhibits angiogenesis by blocking Gas6/Axl signaling pathway.","date":"2017","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28627676","citation_count":25,"is_preprint":false},{"pmid":"30189359","id":"PMC_30189359","title":"AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking.","date":"2018","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30189359","citation_count":24,"is_preprint":false},{"pmid":"32174798","id":"PMC_32174798","title":"Axl-148b chimeric aptamers inhibit breast cancer and melanoma progression.","date":"2020","source":"International journal of biological 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attenuates tumour cell migration.","date":"2019","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31075180","citation_count":22,"is_preprint":false},{"pmid":"25637219","id":"PMC_25637219","title":"AXL as a modulator of sunitinib response in glioblastoma cell lines.","date":"2015","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/25637219","citation_count":22,"is_preprint":false},{"pmid":"30731400","id":"PMC_30731400","title":"Quinolone antibiotic derivatives as new selective Axl kinase inhibitors.","date":"2019","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30731400","citation_count":21,"is_preprint":false},{"pmid":"28105215","id":"PMC_28105215","title":"Role of AXL expression in non-small cell lung cancer.","date":"2016","source":"Oncology 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AXL.","date":"2022","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36409270","citation_count":20,"is_preprint":false},{"pmid":"30639615","id":"PMC_30639615","title":"Unknown fates of (brain) oxidation or UFO: Close encounters with neuronal senescence.","date":"2019","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30639615","citation_count":19,"is_preprint":false},{"pmid":"33730527","id":"PMC_33730527","title":"Targeting the AXL Receptor in Combating Smoking-related Pulmonary Fibrosis.","date":"2021","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33730527","citation_count":19,"is_preprint":false},{"pmid":"31528256","id":"PMC_31528256","title":"Macrophage phenotypes and Gas6/Axl signaling in apical lesions.","date":"2019","source":"Journal of dental sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31528256","citation_count":19,"is_preprint":false},{"pmid":"36445254","id":"PMC_36445254","title":"LZTR1 Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL.","date":"2023","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36445254","citation_count":18,"is_preprint":false},{"pmid":"33954117","id":"PMC_33954117","title":"AXL, an Important Host Factor for DENV and ZIKV Replication.","date":"2021","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33954117","citation_count":18,"is_preprint":false},{"pmid":"32366277","id":"PMC_32366277","title":"Axl receptor tyrosine kinase is a regulator of apolipoprotein E.","date":"2020","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/32366277","citation_count":17,"is_preprint":false},{"pmid":"32992696","id":"PMC_32992696","title":"AXL Inactivation Inhibits Mesothelioma Growth and Migration via Regulation of p53 Expression.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32992696","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46212,"output_tokens":7371,"usd":0.124601},"stage2":{"model":"claude-opus-4-6","input_tokens":11132,"output_tokens":5128,"usd":0.27579},"total_usd":0.400391,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of the Gas6/AXL complex at 3.3 Å resolution reveals a 2:2 stoichiometric assembly in which two immunoglobulin-like domains of the AXL ectodomain are crosslinked by the first laminin G-like domain of Gas6, with no direct AXL/AXL or Gas6/Gas6 contacts. Structure-based mutagenesis and receptor activation experiments demonstrate that both major and minor Gas6-binding sites are required for productive transmembrane signaling.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, protein binding assays, receptor activation experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and functional validation in one study\",\n      \"pmids\": [\"16362042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"AXL is post-translationally processed by proteolytic cleavage in a 14-amino acid region immediately N-terminal to the transmembrane domain, generating a soluble extracellular domain and a membrane-bound kinase domain. This cleavage is augmented by phorbol ester treatment and does not require protein synthesis or transport. Proteolytic processing enhances receptor turnover at the cell surface, thereby down-regulating AXL kinase activity.\",\n      \"method\": \"Biochemical characterization, phorbol ester stimulation assays, cell surface receptor turnover assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct mechanistic characterization with multiple experimental conditions and controls\",\n      \"pmids\": [\"7822279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Gas6-induced downregulation of AXL is blocked by inhibitors of endocytosis and lysosomal degradation but not by proteasomal inhibitors. Gas6 binding induces AXL phosphorylation, ubiquitination, and interaction with the ubiquitin ligase c-Cbl. Hydrogen peroxide induces AXL tyrosine phosphorylation but not ubiquitination, thereby inhibiting AXL downregulation.\",\n      \"method\": \"In vitro pharmacological inhibition, immunoprecipitation, Western blotting, ubiquitination assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in single study establishing ubiquitination-dependent lysosomal degradation\",\n      \"pmids\": [\"15958209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AXL directly phosphorylates Elmo1/2 scaffold proteins on a conserved C-terminal tyrosine residue (Tyr-713 on Elmo2) upon Gas6-dependent activation. Phosphorylated Elmo2 enters a physical complex with AXL and activates Rac1 through Dock family GEFs, promoting breast cancer cell invasion and proliferation. Elmo2 Tyr-713-Phe mutation abolishes these effects.\",\n      \"method\": \"Proteomics, mutagenesis, co-immunoprecipitation, Rac1 activation assays, siRNA knockdown, invasion assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — substrate identification with mutagenesis, functional rescue, and multiple orthogonal methods\",\n      \"pmids\": [\"25332238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AXL forms a multiprotein complex with LDL receptor-related protein-1 (LRP-1) and RAN-binding protein 9 (RANBP9) in dendritic cells to mediate efferocytosis and antigen cross-presentation in vivo. AXL binds apoptotic cells but requires LRP-1 to trigger internalization. AXL and LRP-1 do not interact directly but rely on RANBP9 as a bridging adaptor.\",\n      \"method\": \"Targeted genetic deletion in mice, spleen efferocytosis assay, co-immunoprecipitation, antigen cross-presentation coculture assay, in vivo HSV-1 infection model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — complex identified with Co-IP, genetic deletion in vivo, and functional cross-presentation readout\",\n      \"pmids\": [\"24509082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"An engineered AXL decoy receptor with four mutations in the Gas6-binding interface binds Gas6 with ~80-fold higher affinity than wild-type AXL (femtomolar affinity as Fc fusion), sequesters Gas6, and specifically abrogates AXL signaling. Increased Gas6-binding affinity correlated with inhibition of metastasis in vivo.\",\n      \"method\": \"Rational and combinatorial protein engineering, binding affinity measurements, in vivo tumor/metastasis models\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structure-guided mutagenesis with quantitative binding and in vivo functional validation\",\n      \"pmids\": [\"25242553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AXL enhances macropinocytosis of Zaire ebolavirus glycoprotein-dependent entry; RNAi knockdown of AXL reduced ZEBOV entry via macropinocytosis but had no effect on clathrin-dependent or caveola/lipid raft-mediated endocytic pathways.\",\n      \"method\": \"Biochemical inhibitors, RNAi, dominant negative constructs, high-molecular-weight dextran uptake assay, infection assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (RNAi, dominant negatives, pathway inhibitors) with specific pathway readouts\",\n      \"pmids\": [\"21047970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Axl receptor neutralization and its ligand Gas6 blockade strongly attenuates Zika virus entry in human Sertoli cells, while Axl kinase inhibition (without affecting entry) decreases SOCS1 and SOCS3 levels, increases interferon-stimulated gene expression, and reduces ZIKV replication, demonstrating that Axl negatively regulates the antiviral interferon response in the testis.\",\n      \"method\": \"Receptor/ligand neutralization assays, kinase inhibitor treatment, western blotting, ISG expression analysis, testicular organoid model\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dual mechanism dissection (entry vs. signaling) with multiple cell models and mechanistic pathway readouts\",\n      \"pmids\": [\"31311882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"AXL is active in confluent vascular pericytes via endogenous Gas6 autocrine signaling. Addition of soluble AXL extracellular domain (decoy) inhibited endogenous AXL phosphorylation and enhanced osteogenic differentiation/mineralization, demonstrating that AXL activation suppresses pericyte osteogenic differentiation.\",\n      \"method\": \"Subtractive hybridization, Northern/Western blotting, immunoprecipitation with anti-phosphotyrosine antibody, recombinant protein treatment, nodule mineralization assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal experimental approach with decoy receptor plus direct phosphorylation measurement\",\n      \"pmids\": [\"12730092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AXL is required for flow-dependent vascular remodeling; Axl-/- mice develop significantly smaller intima+media in response to low-flow carotid ligation, with increased apoptosis (5-fold), decreased p-Akt, and altered vascular cell composition, placing AXL upstream of Akt-mediated survival signaling in VSMC.\",\n      \"method\": \"Axl-/- knockout mouse model, carotid ligation surgery, quantitative immunohistochemistry, apoptosis assays, Western blotting for p-Akt\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with specific in vivo phenotypic readouts and mechanistic signaling analysis\",\n      \"pmids\": [\"16627783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Gas6/AXL signaling in schwannoma cells recruits Src, FAK, and NFκB. NFκB mediates Gas6/AXL-driven overexpression of survivin, cyclin D1, and FAK, leading to enhanced cell survival, matrix adhesion, and proliferation. AXL is negatively regulated by merlin and positively regulated by E3 ubiquitin ligase CRL4DCAF1.\",\n      \"method\": \"Gas6 stimulation assays, shRNA knockdown, signaling pathway analysis, cell adhesion and proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — defined signaling pathway downstream of AXL with NFκB as mechanistic mediator, single lab\",\n      \"pmids\": [\"23318455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The human AXL (UFO) receptor is encoded by 20 exons spanning ~44 kb, with alternative splicing of exon 10 and differential polyadenylation generating mRNA isoforms. The promoter is GC-rich, lacks TATA and CAAT boxes, and contains Sp1, AP-2, and CREB binding sites.\",\n      \"method\": \"Genomic library screening, S1 nuclease and primer extension analysis, sequencing\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct structural characterization of the genomic locus with transcriptional start site mapping\",\n      \"pmids\": [\"8381225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AXL is expressed and activated in mesothelioma cells via autocrine GAS6 signaling; GAS6 knockdown modulates AXL tyrosine phosphorylation. AXL silencing suppresses mesothelioma migration and proliferation via G1 arrest, and AXL inhibition blocks PI3K/AKT/mTOR and RAF/MAPK signaling.\",\n      \"method\": \"Phosphotyrosine immunoaffinity MS, shRNA knockdown, GAS6 modulation, cell cycle analysis, pathway inhibitor studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased proteomics plus functional genetic knockdown with defined pathway readouts\",\n      \"pmids\": [\"21132014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AXL dimerizes with EGFR and initiates signaling that circumvents anti-EGFR therapy effects. AXL overexpression and EGFR dimerization can overcome PI3K inhibition by activating the phospholipase C-γ-PKC cascade, which in turn sustains mTORC1 activity.\",\n      \"method\": \"Receptor co-immunoprecipitation, pathway signaling analysis, pharmacological inhibition\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic pathway defined in review citing primary experimental data, AXL-EGFR interaction established by co-IP\",\n      \"pmids\": [\"26763248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Osimertinib stimulates AXL by inhibiting a negative feedback loop. Activated AXL associates with EGFR and HER3 in a complex that maintains cell survival and promotes emergence of osimertinib-tolerant cells.\",\n      \"method\": \"Co-immunoprecipitation, signaling analysis, AXL inhibitor treatment, viability assays, xenograft tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — AXL-EGFR/HER3 complex identified with Co-IP plus functional inhibitor studies, single lab\",\n      \"pmids\": [\"30651547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AXL is transcriptionally regulated by AP-1 transcription factors c-JUN and c-FOS; AXL expression correlates with c-JUN, and silencing c-JUN/c-FOS downregulates AXL and restores sensitivity to PI3Kα inhibition.\",\n      \"method\": \"siRNA silencing of c-JUN/c-FOS, qPCR, Western blotting, JNK inhibitor studies, in vivo xenograft models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct transcription factor silencing with AXL as readout, multiple models\",\n      \"pmids\": [\"30860495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AXL expression is regulated post-transcriptionally by RNA-binding protein PTBP1, which directly targets the 5'-UTR of AXL mRNA and decreases AXL mRNA stability without affecting transcription rate.\",\n      \"method\": \"RNA-IP, in vitro and in vivo PTBP1-AXL mRNA binding assays, mRNA stability assays, qRT-PCR, tumor xenograft models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA-protein interaction demonstrated with functional mRNA stability readout\",\n      \"pmids\": [\"31729427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NAT10-mediated N4-acetylcytidine (ac4C) modification of AXL mRNA promotes its stability, leading to increased AXL protein expression and enhanced pancreatic cancer cell proliferation and metastasis.\",\n      \"method\": \"ac4C-seq, mRNA stability assays, NAT10 knockdown/overexpression, in vitro and in vivo functional assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct epitranscriptomic modification of AXL mRNA established with functional consequences\",\n      \"pmids\": [\"37156457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"p85β (PIK3R2) prevents autophagic degradation of AXL protein by altering phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), thereby upregulating AXL protein levels and activating downstream AKT-independent PDK1/SGK3 signaling in ovarian cancer.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/overexpression, phospho-proteomics, autophagy flux assays, in vivo tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway from p85β to AXL protein stability defined with multiple orthogonal methods\",\n      \"pmids\": [\"32385243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase that targets AXL (and EGFR) for ubiquitin-dependent lysosomal degradation. Pathogenic cancer-associated LZTR1 mutations fail to promote AXL degradation, resulting in AXL protein accumulation and dysregulated signaling.\",\n      \"method\": \"Unbiased biochemical screens, co-immunoprecipitation, genetic mouse models (conditional Lztr1/Cdkn2a knockout), ubiquitination assays, tumor formation assays\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — substrate-adaptor relationship identified by unbiased screens with genetic in vivo validation and mechanistic ubiquitination assays\",\n      \"pmids\": [\"36445254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Gas6-Axl interaction mediates endothelial uptake of platelet-derived microparticles (PMPs) via Axl on endothelial cells; TAM-blocking antibodies or siRNA knockdown of individual TAMs confirmed Axl and Gas6 as the specific mediators of PMP phagocytosis.\",\n      \"method\": \"Flow cytometry, confocal/electron microscopy, Western blotting, siRNA knockdown, TAM-blocking antibodies, Gas6-/- mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — specific receptor identified by siRNA and antibody blockade with multiple imaging modalities\",\n      \"pmids\": [\"27006397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Protein S (PROS1) secreted by tumor-associated macrophages/microglia activates AXL in mesenchymal glioblastoma stem cells, inducing NFκB activation. PROS1-driven AXL phosphorylation is inhibited by the AXL inhibitor BGB324.\",\n      \"method\": \"Co-immunoprecipitation, phospho-AXL detection, NFκB reporter assays, pharmacological inhibition, in vivo survival studies\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ligand-receptor activation confirmed by Co-IP and phosphorylation with functional NFκB readout\",\n      \"pmids\": [\"29531161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Gas6/Axl/Rac1 signaling promotes microglia efferocytosis of apoptotic neurons following subarachnoid hemorrhage; beneficial effects of recombinant Gas6 are abrogated by inhibiting or knocking down Axl or Rac1, placing Rac1 downstream of Axl in this efferocytosis pathway.\",\n      \"method\": \"In vivo mouse SAH model, intraventricular injection, siRNA knockdown, specific inhibitors, in vitro efferocytosis assays\",\n      \"journal\": \"Translational stroke research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological epistasis in both in vivo and in vitro models\",\n      \"pmids\": [\"36324028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AXL is a sensor of local spatial heterogeneity in Gas6 ligand concentration, a property arising from reaction-diffusion interactions. Quantitative experiments and mathematical modeling demonstrate AXL operates distinctly from other RTK families in ligand-sensing mechanism.\",\n      \"method\": \"Quantitative cell-based assays, mathematical/computational modeling, ligand gradient experiments\",\n      \"journal\": \"Cell systems\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — integrated experimental and computational modeling with quantitative mechanistic interpretation\",\n      \"pmids\": [\"26236777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Axl regulates apolipoprotein E (apoE) homeostasis in human astrocytes; AXL-deficient cells have significantly attenuated apoE expression and secretion, and reconstitution with either wild-type or kinase-dead Axl restores apoE baseline levels, demonstrating a kinase-independent scaffolding role for Axl in apoE regulation.\",\n      \"method\": \"AXL-/- cell line generation, pharmacological Axl inhibition, reconstitution with WT and kinase-dead Axl, ELISA, Western blotting\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinase-dead rescue experiment distinguishing kinase-dependent vs. scaffolding functions\",\n      \"pmids\": [\"32366277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YAP transcriptionally regulates AXL expression in EGFR TKI-resistant lung cancer cells; YAP silencing reduces AXL expression, pharmacological or genetic AXL inhibition restores drug sensitivity, placing AXL downstream of YAP in resistance.\",\n      \"method\": \"YAP siRNA/overexpression, ChIP-seq/reporter assay inference, AXL inhibitor treatment, drug sensitivity assays\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — YAP-AXL transcriptional axis established by genetic knockdown/overexpression with functional drug resistance readout\",\n      \"pmids\": [\"29136529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Phosphatidylethanolamine (PE) synergizes with phosphatidylserine (PS) to enhance GAS6 recognition, leading to increased AXL-mediated efferocytosis and virus entry. Liposomes containing both PE and PS bound GAS6 and were engulfed by AXL-expressing cells more efficiently than PS alone.\",\n      \"method\": \"Liposome binding assays, AXL-expressing cell efferocytosis assays, virus pseudotype infection assays, flow cytometry\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined lipid requirement for AXL ligand recognition using reconstituted liposome system\",\n      \"pmids\": [\"33115868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AXL binds to the initial 600 bp sequence at the 5' end of the TP53 promoter (demonstrated by ChIP-qPCR and sequencing), suppressing TP53 transcription; AXL knockdown induces p53 expression and AXL nuclear colocalization with p53 is observed by immunofluorescence, establishing a feedback regulatory loop.\",\n      \"method\": \"ChIP-qPCR, ChIP-seq, TP53 promoter luciferase assay, qRT-PCR, immunofluorescence, shRNA knockdown\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates direct AXL-promoter binding with functional transcriptional readout\",\n      \"pmids\": [\"32992696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AXL mediates cancer cell invasion in esophageal adenocarcinoma through regulation of lysosome peripheral distribution and cathepsin B secretion; this process is mediated by AXL-dependent extracellular acidification through AKT-NFκB-dependent regulation of lactate transporter MCT-1.\",\n      \"method\": \"siRNA knockdown, pharmacological AXL inhibition, lysosome trafficking assays, cathepsin B secretion assays, pH measurements, Western blotting\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined mechanistic pathway from AXL to lysosome trafficking with multiple functional readouts\",\n      \"pmids\": [\"30189359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GALNT2 modifies O-glycans on AXL and regulates AXL protein levels via the proteasome-dependent pathway; GALNT2-promoted cancer cell invasiveness is significantly reversed by AXL siRNA.\",\n      \"method\": \"GALNT2 overexpression/knockout (CRISPR/Cas9), co-immunoprecipitation, glycan modification assays, AXL protein level analysis, invasion assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct O-glycosylation of AXL identified with functional consequence on protein stability and invasion\",\n      \"pmids\": [\"36409270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Axl and Tyro3, but not Mertk, are required for platelet activation and thrombus formation; Axl-/- platelets show decreased Syk and PLCγ2 tyrosine phosphorylation upon GPVI agonist stimulation; anti-Axl neutralizing antibodies and recombinant Axl extracellular domain inhibit platelet aggregation in a Gas6-independent manner.\",\n      \"method\": \"TAM single-receptor knockout mice, platelet aggregation assays, in vivo laser-induced thrombosis model, phosphorylation analysis, neutralizing antibody and recombinant ECD experiments\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO plus multiple pharmacological approaches with in vivo functional validation\",\n      \"pmids\": [\"30541554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"E1A negatively regulates AXL expression at the transcriptional level; Gas6-triggered AXL signaling counteracts E1A-mediated growth suppression and protects cells from serum deprivation-induced apoptosis, placing AXL as a downstream effector of survival signaling opposing E1A tumor suppression.\",\n      \"method\": \"Degenerate RT-PCR kinase profiling, AXL cDNA transfection, Gas6 stimulation, serum deprivation apoptosis assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional regulation and functional rescue established by genetic and biochemical approaches\",\n      \"pmids\": [\"10567533\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AXL is a TAM-family receptor tyrosine kinase activated primarily by Gas6 (and Protein S) binding to its two immunoglobulin-like extracellular domains, forming a 2:2 ligand-receptor complex that drives receptor dimerization and autophosphorylation; downstream signaling proceeds through PI3K/AKT, MAPK, Src/FAK/NFκB, and Rac1 (via direct phosphorylation of Elmo scaffold proteins), promoting cell survival, migration, invasion, efferocytosis, and immune suppression. AXL protein levels are regulated by Gas6-induced c-Cbl-dependent ubiquitination and lysosomal degradation, proteolytic ectodomain shedding, LZTR1-CUL3 ubiquitin ligase-mediated degradation, autophagic clearance controlled by p85β/TRIM2/optineurin, O-glycosylation by GALNT2, and mRNA stability regulated by PTBP1 and NAT10-mediated ac4C modification, while transcription is driven by AP-1 (c-JUN/c-FOS) and suppressed by E1A; AXL also forms functional complexes with EGFR/HER3 to mediate drug resistance, interacts with LRP-1/RANBP9 to mediate DC efferocytosis, and suppresses TP53 transcription through direct promoter binding.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AXL is a TAM-family receptor tyrosine kinase that functions as a key regulator of cell survival, migration, efferocytosis, and immune modulation through Gas6- and Protein S-dependent activation of PI3K/AKT, MAPK, Src/FAK/NFκB, and Rac1 signaling cascades [PMID:16362042, PMID:25332238, PMID:16627783, PMID:23318455]. Gas6 binding to the two immunoglobulin-like domains of AXL drives formation of a 2:2 ligand–receptor complex that triggers autophosphorylation, and AXL further diversifies signaling by heterodimerizing with EGFR and HER3 to sustain survival during targeted therapy [PMID:16362042, PMID:30651547]. AXL protein levels are tightly controlled through c-Cbl-mediated ubiquitination and lysosomal degradation, LZTR1-CUL3 ubiquitin ligase-directed turnover, p85β/TRIM2/optineurin-dependent autophagic clearance, GALNT2-mediated O-glycosylation, ectodomain shedding, and post-transcriptional regulation of its mRNA by PTBP1 and NAT10 [PMID:15958209, PMID:36445254, PMID:32385243, PMID:36409270, PMID:7822279, PMID:31729427, PMID:37156457]. Beyond canonical RTK signaling, AXL mediates efferocytosis through an LRP-1/RANBP9 complex in dendritic cells, facilitates endothelial uptake of platelet-derived microparticles, and suppresses TP53 transcription via direct promoter binding [PMID:24509082, PMID:27006397, PMID:32992696].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Characterization of the AXL genomic locus revealed a GC-rich, TATA-less promoter with Sp1/AP-2/CREB sites and alternative splicing of exon 10, establishing the basic transcriptional architecture of the gene.\",\n      \"evidence\": \"Genomic library screening, S1 nuclease/primer extension mapping of the human AXL locus\",\n      \"pmids\": [\"8381225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of individual promoter elements not tested by mutagenesis\", \"Role of alternative splicing isoforms undefined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Discovery that AXL undergoes proteolytic ectodomain shedding near its transmembrane domain established a first mechanism for downregulating surface AXL and generating soluble receptor.\",\n      \"evidence\": \"Biochemical characterization of AXL cleavage products with phorbol ester stimulation and turnover assays\",\n      \"pmids\": [\"7822279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the responsible protease not determined\", \"Physiological stimuli beyond phorbol esters not explored\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of E1A as a transcriptional repressor of AXL, with Gas6/AXL signaling opposing E1A-mediated growth suppression, linked AXL to survival signaling for the first time.\",\n      \"evidence\": \"Degenerate RT-PCR kinase profiling, AXL cDNA rescue, Gas6 stimulation, and serum deprivation apoptosis assay\",\n      \"pmids\": [\"10567533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of E1A-mediated transcriptional repression of AXL not defined\", \"Downstream survival pathway not specified beyond anti-apoptosis\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstration that autocrine Gas6 activates AXL in vascular pericytes and that decoy receptor blockade promotes osteogenic differentiation established AXL as a tonic suppressor of cell fate transitions.\",\n      \"evidence\": \"Soluble AXL ectodomain treatment with phospho-AXL and mineralization readouts in pericyte cultures\",\n      \"pmids\": [\"12730092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream pathway connecting AXL to osteogenic transcription not identified\", \"Single cell type studied\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The 3.3 Å crystal structure of Gas6/AXL resolved how two AXL Ig-like domains are crosslinked by Gas6 LG1 in a 2:2 complex with no direct receptor–receptor contacts, defining the unique activation mechanism of AXL.\",\n      \"evidence\": \"X-ray crystallography with structure-based mutagenesis and receptor activation assays\",\n      \"pmids\": [\"16362042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational changes in the intracellular kinase domain upon dimerization not resolved\", \"Full-length receptor structure unavailable\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Gas6-induced AXL ubiquitination was shown to be c-Cbl-dependent and to drive lysosomal (not proteasomal) degradation, distinguishing AXL turnover from many other RTKs.\",\n      \"evidence\": \"Pharmacological inhibition of endocytosis/lysosomes/proteasome, immunoprecipitation, and ubiquitination assays\",\n      \"pmids\": [\"15958209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct E3 ligase assay for c-Cbl on AXL not performed\", \"Ubiquitin chain type not determined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Axl−/− mice showed impaired flow-dependent vascular remodeling with increased apoptosis and reduced p-Akt, genetically placing AXL upstream of Akt-dependent survival in vascular smooth muscle cells in vivo.\",\n      \"evidence\": \"Axl knockout mice with carotid ligation, immunohistochemistry, and Western blot for p-Akt\",\n      \"pmids\": [\"16627783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AXL signals to Akt directly or through PI3K intermediates not resolved in this model\", \"Contribution of other TAM receptors not excluded\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"AXL was identified as an enhancer of macropinocytosis-dependent Ebola virus entry, revealing a role for AXL in regulating a specific endocytic pathway exploited by enveloped viruses.\",\n      \"evidence\": \"RNAi knockdown, dominant-negative constructs, and pathway-specific inhibitors with infection assays\",\n      \"pmids\": [\"21047970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AXL acts as a direct virus receptor or enhances macropinocytosis indirectly not fully resolved\", \"Mechanism by which AXL activates macropinocytosis not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping of a Src/FAK/NFκB cascade downstream of Gas6/AXL in schwannoma cells, with merlin as a negative regulator and CRL4-DCAF1 as a positive regulator, provided the first defined multi-node signaling pathway linking AXL to NFκB-dependent gene targets (survivin, cyclin D1).\",\n      \"evidence\": \"Gas6 stimulation, shRNA knockdown, and signaling/functional assays in schwannoma cells\",\n      \"pmids\": [\"23318455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation targets linking AXL to Src not identified\", \"Whether merlin-AXL regulation is direct or indirect not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of Elmo1/2 as direct AXL substrates phosphorylated on Tyr-713 established the first biochemically validated AXL kinase substrate and connected AXL to Rac1 activation via Dock GEFs.\",\n      \"evidence\": \"Proteomics, mutagenesis (Y713F), co-IP, Rac1 activation, and invasion assays in breast cancer cells\",\n      \"pmids\": [\"25332238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Elmo phosphorylation is required for non-cancer AXL functions (e.g., efferocytosis) not tested\", \"Structural basis of AXL-Elmo recognition unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that AXL forms a tripartite complex with LRP-1 and RANBP9 in dendritic cells, where AXL recognizes apoptotic cells but LRP-1 is required for internalization, defined a cooperative receptor mechanism for efferocytosis and antigen cross-presentation.\",\n      \"evidence\": \"Targeted gene deletion in mice, co-IP, in vivo efferocytosis, and antigen cross-presentation assays\",\n      \"pmids\": [\"24509082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling events downstream of AXL-LRP-1-RANBP9 complex not characterized\", \"Whether this complex operates in non-dendritic phagocytes unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"AXL heterodimerization with EGFR was shown to bypass anti-EGFR and PI3K inhibitor therapy through activation of a PLCγ–PKC–mTORC1 bypass pathway, providing a mechanistic basis for AXL-driven drug resistance.\",\n      \"evidence\": \"Receptor co-immunoprecipitation, signaling analysis, and pharmacological inhibition in cancer cell lines\",\n      \"pmids\": [\"26763248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AXL-EGFR heterodimer forms through direct extracellular or intracellular interaction not defined\", \"Structural basis of heterodimerization unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"AP-1 transcription factors c-JUN and c-FOS were identified as direct transcriptional activators of AXL, and their silencing restored drug sensitivity, establishing the upstream transcriptional control of AXL expression in resistant tumors.\",\n      \"evidence\": \"siRNA silencing, qPCR/Western blot, JNK inhibitor studies, and xenograft models\",\n      \"pmids\": [\"30860495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AP-1 binding to AXL promoter not demonstrated by ChIP in this study\", \"Relative contribution of c-JUN vs. c-FOS not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"AXL was found to bind the TP53 promoter directly (by ChIP) and suppress p53 transcription, revealing a non-canonical nuclear function for a receptor tyrosine kinase.\",\n      \"evidence\": \"ChIP-qPCR, ChIP-seq, luciferase reporter, and immunofluorescence showing nuclear AXL\",\n      \"pmids\": [\"32992696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of AXL nuclear translocation not defined\", \"Whether AXL binds DNA directly or through a transcription factor complex unknown\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Axl−/− platelets showed impaired Syk and PLCγ2 phosphorylation upon GPVI stimulation, and AXL blockade inhibited aggregation in a Gas6-independent manner, establishing a ligand-independent scaffolding role for AXL in platelet activation.\",\n      \"evidence\": \"TAM single-receptor KO mice, platelet aggregation, in vivo thrombosis model, neutralizing antibodies, and recombinant ECD\",\n      \"pmids\": [\"30541554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of Gas6-independent AXL function in platelets not defined\", \"Whether AXL directly interacts with GPVI complex not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissection of AXL's dual role in Zika virus infection — mediating entry via Gas6 and suppressing the interferon response via SOCS1/3 upregulation — showed AXL functions both as a viral entry facilitator and an innate immune checkpoint.\",\n      \"evidence\": \"Receptor/ligand neutralization, kinase inhibition, ISG expression analysis in human Sertoli cells and organoids\",\n      \"pmids\": [\"31311882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AXL-dependent SOCS induction is direct or via intermediate kinases not resolved\", \"Contribution of other TAM receptors in testis not assessed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"PTBP1 was identified as a post-transcriptional regulator that binds AXL mRNA 5′-UTR and decreases its stability, adding an RNA-level control mechanism for AXL expression.\",\n      \"evidence\": \"RNA-IP, in vitro/in vivo binding assays, mRNA half-life measurements, and xenograft models\",\n      \"pmids\": [\"31729427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Exact PTBP1 binding site on AXL 5′-UTR not mapped at nucleotide resolution\", \"Whether other RBPs cooperate with PTBP1 not explored\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"p85β was shown to stabilize AXL protein by preventing TRIM2/optineurin-mediated autophagic degradation, defining a PI3K-independent scaffolding function for p85β that feeds into AXL-dependent PDK1/SGK3 signaling.\",\n      \"evidence\": \"Co-IP, siRNA/overexpression, phospho-proteomics, autophagy flux assays, and in vivo tumor models\",\n      \"pmids\": [\"32385243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TRIM2 ubiquitination of AXL not demonstrated in vitro\", \"Whether this pathway operates outside ovarian cancer not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reconstitution with kinase-dead AXL restored apoE expression in AXL-null astrocytes, demonstrating a kinase-independent scaffolding function for AXL in lipid metabolism.\",\n      \"evidence\": \"AXL-knockout and kinase-dead reconstitution in human astrocytes with ELISA/Western blot readout\",\n      \"pmids\": [\"32366277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adaptor or scaffold partner mediating AXL kinase-independent apoE regulation not identified\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"GALNT2-mediated O-glycosylation of AXL was shown to regulate its protein stability through the proteasome, adding glycosylation as another post-translational layer of AXL regulation.\",\n      \"evidence\": \"GALNT2 overexpression/CRISPR-KO, co-IP, glycan modification assays, and invasion assays\",\n      \"pmids\": [\"36409270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific O-glycosylation sites on AXL not mapped\", \"Relationship to other ubiquitin-dependent degradation pathways (c-Cbl, LZTR1) not clarified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"LZTR1 was identified as the CUL3 adaptor targeting AXL for ubiquitin-dependent lysosomal degradation, and cancer-associated LZTR1 mutations abolished this activity, linking AXL accumulation to oncogenic signaling from loss-of-function LZTR1 mutations.\",\n      \"evidence\": \"Unbiased biochemical screen, co-IP, genetic mouse models (conditional Lztr1/Cdkn2a KO), ubiquitination assays, and tumor formation\",\n      \"pmids\": [\"36445254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LZTR1 and c-Cbl operate on AXL in the same or distinct cellular compartments not resolved\", \"Structural basis of LZTR1-AXL recognition unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"NAT10-dependent ac4C modification of AXL mRNA was shown to increase its stability and drive pancreatic cancer proliferation, adding epitranscriptomic regulation as a mechanism for AXL overexpression.\",\n      \"evidence\": \"ac4C-seq, mRNA stability assays, NAT10 knockdown/overexpression, and in vivo functional assays\",\n      \"pmids\": [\"37156457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ac4C sites on AXL mRNA not mapped at single-nucleotide resolution\", \"Whether ac4C modification interacts with PTBP1-mediated mRNA destabilization not examined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AXL's multiple degradation pathways (c-Cbl, LZTR1-CUL3, TRIM2/optineurin autophagy, GALNT2-proteasome, ectodomain shedding) are coordinated in different cell types, and whether AXL's reported nuclear function in TP53 regulation operates through direct DNA binding or cofactor-mediated recruitment, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Integration of multiple AXL degradation pathways not studied in a single system\", \"Mechanism of AXL nuclear translocation uncharacterized\", \"Full-length AXL structure with intracellular domain not available\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 0, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 7, 31]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 20, 30]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 9, 10, 12, 13, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 18, 19, 29]}\n    ],\n    \"complexes\": [\n      \"AXL-LRP1-RANBP9 efferocytosis complex\",\n      \"Gas6-AXL 2:2 signaling complex\",\n      \"AXL-EGFR/HER3 heterodimer\"\n    ],\n    \"partners\": [\n      \"GAS6\",\n      \"EGFR\",\n      \"HER3\",\n      \"LRP1\",\n      \"RANBP9\",\n      \"ELMO2\",\n      \"LZTR1\",\n      \"PTBP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}