{"gene":"AXL","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2005,"finding":"Crystal structure of the Gas6/Axl complex at 3.3 Å resolution reveals a 2:2 stoichiometry in which the 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 demonstrated that both a major and minor Gas6-binding site on Axl are required for productive transmembrane signaling. Gas6-mediated Axl dimerization is proposed to occur in two steps, with a high-affinity 1:1 Gas6/Axl complex forming first.","method":"X-ray crystallography (3.3 Å), structure-based mutagenesis, protein binding assays, receptor activation experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional receptor activation assays in a single rigorous study","pmids":["16362042"],"is_preprint":false},{"year":1997,"finding":"The cytoplasmic domain of Ufo/Axl contains a multi-substrate docking site at C-terminal tyrosine 821 (EILpYVNMDEG) that recruits PLCγ1, p85α and p85β subunits of PI3-kinase, GRB2, c-Src, and Lck. Tyrosine 779 provides an additional lower-affinity docking site for p85 proteins in vitro, and tyrosine 866 is an additional binding site for PLCγ. Identified using far-Western blot, co-immunoprecipitation, competitive inhibition, and mutagenesis of chimeric EGFR/Ufo receptors.","method":"Far-Western blot, co-immunoprecipitation, competitive inhibition assays, site-directed mutagenesis of chimeric EGFR/Ufo constructs","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (far-Western, Co-IP, mutagenesis) in a single study establishing specific phosphotyrosine docking sites","pmids":["9178760"],"is_preprint":false},{"year":2014,"finding":"AXL activation in cetuximab-resistant (CtxR) NSCLC and HNSCC cells stimulates cell proliferation, EGFR activation, and MAPK signaling. AXL was found tightly associated with EGFR in CtxR cells, and EGFR directly regulated AXL mRNA expression through MAPK signaling and the transcription factor c-Jun, creating a positive feedback loop. Overexpression of AXL or stimulation with EGFR ligands was sufficient to confer cetuximab resistance.","method":"RNAi knockdown, AXL-targeting agents, stable overexpression, co-immunoprecipitation (AXL-EGFR association), mRNA expression analysis, tumor xenograft models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional studies with RNAi, overexpression, Co-IP, and in vivo xenograft validation across multiple cell line models","pmids":["25136066"],"is_preprint":false},{"year":2014,"finding":"An engineered Axl 'decoy receptor' with four mutations in the Gas6-binding interface binds Gas6 with femtomolar affinity (80-fold improvement over wild-type), sequesters Gas6, and specifically abrogates Axl signaling. The Fc-fusion decoy receptor potently inhibited metastasis and disease progression in vivo, demonstrating that Gas6 sequestration is sufficient to block Axl pathway activity.","method":"Rational and combinatorial protein engineering, binding affinity assays, in vitro Axl signaling inhibition assays, in vivo metastasis models","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-guided mutagenesis combined with quantitative binding assays and in vivo functional validation","pmids":["25242553"],"is_preprint":false},{"year":2020,"finding":"AXL stimulates phosphorylation of a focal adhesion (FA) protein network to accelerate FA disassembly and promote cell migration and metastasis. Mechanistically, AXL phosphorylates NEDD9, which binds CRKII, which associates with and orchestrates phosphorylation of pseudo-kinase PEAK1; PEAK1 is in complex with tyrosine kinase CSK to mediate phosphorylation of PAXILLIN. Uncoupling PEAK1 from AXL signaling decreases metastasis in vivo without affecting tumor growth.","method":"Phosphoproteomic profiling, co-immunoprecipitation, RNAi knockdown, in vivo metastasis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphoproteomics combined with Co-IP, functional knockdown, and in vivo validation defining a full signaling pathway","pmids":["32681075"],"is_preprint":false},{"year":2010,"finding":"Axl enhances macropinocytosis of Zaire ebolavirus (ZEBOV) in permissive cells. RNAi reduction of Axl expression decreased ZEBOV entry via macropinocytosis but had no effect on clathrin-dependent or caveola/lipid raft-mediated endocytic pathways, demonstrating a specific role for Axl in promoting macropinocytosis-dependent viral entry.","method":"Biochemical inhibitors, RNAi knockdown, dominant-negative constructs, viral transduction assays, dextran uptake assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (RNAi, dominant negatives, pharmacological inhibitors) with pathway-specific readouts in a single study","pmids":["21047970"],"is_preprint":false},{"year":2018,"finding":"PROS1 (Protein S), secreted by tumor-associated macrophages/microglia, physically associates with and activates AXL in mesenchymal glioblastoma stem cells, leading to NF-κB activation. This PROS1-AXL signaling was inhibited by the small molecule AXL inhibitor BGB324.","method":"Co-immunoprecipitation (PROS1-AXL association), pharmacological inhibition, NF-κB pathway readouts, mouse GBM survival models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating physical association plus downstream signaling readout and in vivo model, single lab","pmids":["29531161"],"is_preprint":false},{"year":2006,"finding":"Axl deficiency (Axl-/- mice) leads to significantly smaller intima+media following carotid artery ligation compared to wild-type, associated with increased apoptosis (5-fold increase in Axl-/- LCA) and decreased p-Akt, demonstrating that Axl mediates flow-dependent vascular remodeling by regulating vascular cell survival through the Akt pathway.","method":"Axl knockout mouse model (Axl-/-), carotid ligation model, quantitative immunohistochemistry, apoptosis assays, Western blot for p-Akt","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined vascular phenotype and molecular mechanism (p-Akt), single lab","pmids":["16627783"],"is_preprint":false},{"year":2003,"finding":"Axl is active in confluent pericytes and its activation by endogenous Gas6 inhibits osteogenic differentiation. Addition of recombinant Axl extracellular domain (ECD) to pericyte cultures inhibited Axl phosphorylation by Gas6 and enhanced the rate of nodule mineralization, demonstrating that Gas6-Axl signaling suppresses the osteogenic differentiation pathway in vascular pericytes.","method":"Immunoprecipitation of phosphotyrosine (Axl activity), recombinant Axl-ECD competition assay, Western blot, nodule mineralization assays","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical evidence of Axl phosphorylation with functional rescue experiment, single lab","pmids":["12730092"],"is_preprint":false},{"year":1999,"finding":"E1A negatively regulates Axl expression at the transcriptional level. Gas6 stimulation of Axl in E1A-expressing cells overexpressing Axl provided greater mitogenic effect and protected cells from serum deprivation-induced apoptosis, demonstrating that downregulation of Axl by E1A contributes to E1A-mediated growth suppression and pro-apoptotic activity.","method":"RT-PCR tyrosine kinase profiling, cDNA transfection/overexpression, Gas6 stimulation, BrdU incorporation, trypan blue exclusion (survival assay)","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional regulation established by RT-PCR with functional rescue using Gas6/Axl stimulation, single lab","pmids":["10567533"],"is_preprint":false},{"year":2004,"finding":"Gas6 stimulation of Axl in uveal melanoma cells (Mel 290) mediates mitogenesis and cell survival, demonstrated specifically through Axl by antisense-mediated knockdown of Axl expression. Gas6/Axl activation results primarily in downregulation of Cyr61 (a CCN family member) as revealed by cDNA microarray analysis of 12,687 genes.","method":"BrdU incorporation, trypan blue exclusion, antisense knockdown, cDNA microarray (12,687 genes)","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antisense specificity control with functional survival assays and downstream gene expression profiling, single lab","pmids":["14729616"],"is_preprint":false},{"year":2021,"finding":"Cross-signaling between AXL and TLR4 in cardiac macrophages directs a switch to glycolytic metabolism and secretion of proinflammatory IL-1β, leading to increased intramyocardial inflammation, adverse ventricular remodeling, and impaired contractile function after myocardial ischemia/reperfusion injury. AXL functions independently of cardioprotective MerTK, and like MerTK, undergoes proteolytic cleavage.","method":"Conditional genetic loss/gain-of-function (myeloid-specific), flow cytometry, metabolic assays, cytokine measurements, cardiac functional readouts","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional genetic manipulation with defined signaling mechanism and functional cardiac phenotype, single lab","pmids":["33529176"],"is_preprint":false},{"year":2022,"finding":"Gas6 promotes microglial efferocytosis and suppresses post-SAH inflammation through activating the Axl/Rac1 signaling pathway. Inhibition or knockdown of Axl or Rac1 abolished the beneficial effects of recombinant Gas6, demonstrating a functional Gas6→Axl→Rac1 signaling axis in microglia efferocytosis.","method":"Mouse SAH model, intraventricular injection of recombinant Gas6/ProS1, TAM receptor knockdown (siRNA), specific inhibitors, flow cytometry, in vitro phagocytosis assays","journal":"Translational stroke research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (siRNA) and pharmacological inhibition with functional efferocytosis readouts establishing pathway order, single lab","pmids":["36324028"],"is_preprint":false},{"year":2021,"finding":"AXL activates the STAT1 pathway in astrocytes post-traumatic brain injury, which further upregulates ABCA1, promoting a phagocytic astrocyte phenotype (AXL/STAT1/ABCA1 pathway). Pharmacological inhibition of AXL decreased astrocytic phagocytosis both in vivo and in vitro.","method":"Mouse CCI TBI model, pharmacological inhibition (R428), siRNA transfection, Western blot, flow cytometry, RT-PCR","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and siRNA inhibition with defined pathway readouts (STAT1, ABCA1) and functional phagocytosis assay, single lab","pmids":["34233703"],"is_preprint":false},{"year":2023,"finding":"LZTR1 acts as a substrate-specific adaptor of CUL3-dependent ubiquitin ligase that targets AXL (and EGFR) for ubiquitin-dependent lysosomal degradation. Pathogenic LZTR1 cancer mutations fail to promote AXL degradation, resulting in AXL accumulation and dysregulated growth factor signaling. LZTR1-mutant tumors accumulate AXL and show specific vulnerability to AXL inhibition.","method":"Unbiased biochemical screens, Co-IP, genetic loss-of-function (conditional Lztr1 mouse KO), ubiquitination assays, mouse tumor models","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution of ubiquitin-mediated degradation, unbiased screens, in vivo mouse models, and therapeutic vulnerability validation","pmids":["36445254"],"is_preprint":false},{"year":2020,"finding":"p85β (PIK3R2) upregulates AXL protein levels by disrupting its autophagic degradation. Mechanistically, p85β alters phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate selective autophagic degradation of AXL. This AXL upregulation by p85β activates AKT-independent PDK1/SGK3 signaling.","method":"Co-immunoprecipitation, phosphorylation assays, autophagy inhibition, siRNA knockdown, overexpression studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic pathway established by multiple orthogonal biochemical methods identifying specific E3 ligase (TRIM2) and autophagy receptor (optineurin) regulating AXL stability","pmids":["32385243"],"is_preprint":false},{"year":2024,"finding":"STAMBPL1 elevates AXL protein abundance and surface accumulation by diminishing TRIM21-mediated K63-linked ubiquitination and subsequent lysosomal degradation of AXL. This stabilization of AXL enhances mesenchymal gene expression while suppressing CXCL9/10 and HLA expression in kidney clear cell carcinoma.","method":"Co-immunoprecipitation, ubiquitination assays (K63 linkage-specific), protein stability assays, STAMBPL1 knockdown/overexpression","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical identification of K63-ubiquitination by TRIM21 and its reversal by STAMBPL1, functional downstream readouts, single lab","pmids":["39527690"],"is_preprint":false},{"year":2023,"finding":"NAT10 promotes mRNA stability of AXL in an N4-acetylcytidine (ac4C)-dependent manner, leading to increased AXL expression and promoting pancreatic ductal adenocarcinoma cell proliferation and metastasis.","method":"ac4C modification assays, mRNA stability assays, NAT10 knockdown/overexpression, in vitro and in vivo tumor models","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epitranscriptomic modification (ac4C) linked to AXL mRNA stability with functional cancer phenotype, single lab","pmids":["37156457"],"is_preprint":false},{"year":2020,"finding":"Phosphatidylethanolamine (PE) synergizes with phosphatidylserine (PS) to enhance Gas6 binding and AXL-mediated efferocytosis and virus entry. Liposomes containing both PE and PS bound Gas6 and were engulfed by AXL-expressing cells much more efficiently than PS alone, demonstrating that PE co-recognition maximizes PS receptor (AXL)-mediated processes.","method":"Liposome binding assays, Gas6 binding quantification, AXL-expressing cell efferocytosis assays, pseudovirus and live virus infection assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biochemical and cell-based assays with multiple viral systems, single lab","pmids":["33115868"],"is_preprint":false},{"year":2019,"finding":"AXL, but not MERTK or TYRO3, shows a dual regulatory function in invadopodia formation in melanoma cells: both depletion and overexpression of AXL enhanced invadopodia formation. AXL depletion upregulates ERBB3 signaling, which activates core invadopodia regulators. High AXL expression is inversely correlated with ERBB3 expression across melanoma cell lines.","method":"siRNA screen (microscopy-based), knockdown and overexpression, invadopodia formation and activity assays, bioinformatic analysis of cell line expression data","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic siRNA screen with functional invadopodia assays and pathway crosstalk analysis, single lab","pmids":["30914429"],"is_preprint":false},{"year":2018,"finding":"Axl and Tyro3, but not Mertk, are required for platelet activation and thrombus formation. Loss of Axl in platelets reduced aggregation, spreading, integrin activation (JON/A binding), and P-selectin expression, and decreased tyrosine phosphorylation of Syk and PLCγ2 upon GPVI agonist stimulation. Anti-Axl neutralizing antibody or recombinant Axl extracellular domain (but not Gas6-neutralizing antibody) inhibited platelet aggregation, indicating ligand-independent or non-Gas6 mechanisms.","method":"Single TAM receptor knockout mice, in vitro platelet aggregation/activation assays, flow cytometry, Western blot for Syk/PLCγ2 phosphorylation, neutralizing antibodies, in vivo laser-induced thrombosis model","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (genetic knockout, neutralizing antibody, recombinant protein) with in vivo validation, single lab","pmids":["30541554"],"is_preprint":false},{"year":2019,"finding":"AP-1 transcription factors c-JUN and c-FOS regulate AXL overexpression in HNSCC and ESCC. Silencing c-JUN or c-FOS downregulated AXL expression. JNK inhibition (SP600125) reduced AXL expression, and combined JNK + PI3K inhibition had synergistic anti-proliferative effects, establishing the JNK→AP-1→AXL transcriptional axis as a mechanism of AXL upregulation driving therapy resistance.","method":"siRNA silencing (c-JUN, c-FOS), qRT-PCR, Western blot, pharmacological inhibitors, in vitro proliferation assays, cell line-derived and patient-derived xenograft models","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic silencing plus pharmacological approach with in vivo validation, single lab, defining transcriptional regulation","pmids":["30860495"],"is_preprint":false},{"year":2018,"finding":"AXL mediates cell invasion in esophageal adenocarcinoma through regulation of lysosome peripheral distribution and cathepsin B secretion. AXL-dependent peripheral lysosome distribution and invasion are mediated by extracellular acidification, which is potentiated by AXL-induced lactate secretion through AKT-NF-κB-dependent MCT-1 regulation.","method":"AXL knockdown, lysosome trafficking assays, cathepsin B secretion measurement, extracellular pH measurement, AKT/NF-κB pathway analysis, AXL inhibitor R428","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway from AXL to lysosome trafficking established by knockdown with multiple downstream readouts, single lab","pmids":["30189359"],"is_preprint":false},{"year":2020,"finding":"AXL regulates apolipoprotein E (apoE) homeostasis in human astrocytes. AXL-deficient astrocytoma cells show significantly attenuated apoE expression and secretion; reconstitution with either wild-type Axl or kinase-dead Axl significantly restored apoE baseline levels, demonstrating that Axl maintains apoE homeostasis independent of its kinase activity. AXL inhibition also upregulates ABCA1 expression.","method":"AXL-/- cell line generation, cDNA reconstitution (wild-type and kinase-dead Axl), high-throughput phenotypic screen, ELISA (apoE secretion), Western blot","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout with kinase-dead reconstitution establishes kinase-independent function for apoE regulation, single lab","pmids":["32366277"],"is_preprint":false},{"year":2020,"finding":"AXL suppresses TP53 transcription by binding to the initial 600 bp sequence at the 5' end of the TP53 promoter, as demonstrated by chromatin immunoprecipitation-qPCR and sequencing. AXL knockdown induced wild-type and mutant p53 expression, and the anti-proliferative and anti-migratory effects of AXL silencing were attenuated by TP53 knockdown, establishing a feedback regulatory loop between AXL and p53.","method":"AXL shRNA knockdown, chromatin immunoprecipitation (ChIP)-qPCR, TP53 promoter dual luciferase assay, immunofluorescence, qRT-PCR","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates direct AXL binding to TP53 promoter, functional rescue with TP53 knockdown, single lab","pmids":["32992696"],"is_preprint":false},{"year":2023,"finding":"AXL facilitates African swine fever virus (ASFV) entry into porcine alveolar macrophages via macropinocytosis by acting as a phosphatidylserine (PS) receptor; ASFV displays PS on its envelope as viral apoptotic mimicry to engage AXL. AXL was identified as the most important PS receptor by RNA interference screening; AXL knockout decreased ASFV internalization and replication, and deletion of the intracellular kinase domain or AXL inhibitor R428 significantly inhibited ASFV internalization.","method":"RNA interference screening, AXL gene knockout (MA104 cells), neutralizing antibody against AXL extracellular domain, kinase domain deletion mutant, AXL inhibitor R428, macropinocytosis assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological approaches with defined entry mechanism, single lab, porcine system","pmids":["37382521"],"is_preprint":false},{"year":2023,"finding":"AXL inhibits M2 macrophage polarization; a specific anti-AXL antibody blocked bone marrow-derived macrophage M2-polarization in vitro, and targeting AXL in M2-macrophages suppressed CSF-1 production and eliminated M2-macrophages in the tumor microenvironment.","method":"Anti-AXL antibody treatment, BMDM polarization assays, CSF-1 measurement, in vivo tumor models with flow cytometry analysis of immune infiltrates","journal":"Acta pharmacologica Sinica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single antibody-based approach, limited mechanistic depth beyond phenotypic observation, single lab","pmids":["36650292"],"is_preprint":false},{"year":2022,"finding":"AXL, CDCP1, and SRC form a signaling axis conferring acquired osimertinib resistance in NSCLC. Silencing CDCP1 or AXL restored sensitivity to osimertinib with reduced SRC and AKT activation; dual silencing of both CDCP1 and AXL further increased sensitivity, establishing AXL/SFK/AKT as a bypass signaling pathway.","method":"siRNA knockdown (AXL, CDCP1, SRC), Western blot for pathway activation, pharmacological inhibition (dasatinib), osimertinib-resistant cell line development","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown of multiple pathway components with functional drug sensitivity readout, single lab","pmids":["35643725"],"is_preprint":false},{"year":2023,"finding":"Axl promotes M1 macrophage polarization via the STAT1/HIF-1α signaling pathway in intracranial aneurysm. R428 (AXL inhibitor) inhibited phosphorylation of Axl and STAT1 and expression of HIF-1α, IL-1β, NOS2, and MMP9 in LPS/IFN-γ-stimulated macrophages. STAT1 knockdown abolished Axl-mediated M1 macrophage polarization.","method":"Mouse IA model, bone marrow-derived macrophage stimulation, AXL inhibitor R428, rmGas6 treatment, STAT1 siRNA knockdown, Western blot, immunohistochemistry","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — STAT1 knockdown epistasis establishing pathway order, pharmacological confirmation, single lab","pmids":["37223093"],"is_preprint":false},{"year":2020,"finding":"Pericyte FAK negatively regulates Gas6-stimulated phosphorylation of Axl; loss of pericyte FAK enhances Gas6-stimulated Axl phosphorylation with upregulation of Cyr61, driving enhanced tumour growth. Pericyte-derived Cyr61 then instructs tumour cells to elevate expression of pro-angiogenic Tissue Factor.","method":"Pericyte-specific FAK knockout mouse models (multiple cancer models), phosphorylation assays, immunohistochemistry, multiple tumor models (melanoma, lung carcinoma, insulinoma)","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in pericyte-specific manner with defined downstream pathway across multiple tumor models, single lab","pmids":["32499572"],"is_preprint":false},{"year":2018,"finding":"BRAF and AXL are oncogenic drivers of RIPK3 expression loss in cancer, thereby suppressing necroptosis sensitivity. Inhibition of AXL (or BRAF) can rescue RIPK3 expression loss and restore necroptosis sensitivity in cancer cell lines.","method":"Genome-wide bioinformatics analysis of 941 cancer cell lines, necroptosis sensitivity screen, AXL/BRAF inhibitor treatment with RIPK3 expression rescue assays","journal":"PLoS biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — primarily bioinformatic correlation with pharmacological rescue in cell lines, limited mechanistic detail on how AXL suppresses RIPK3, single study","pmids":["30157175"],"is_preprint":false},{"year":1992,"finding":"The murine Ufo/Axl receptor encodes a novel tyrosine kinase receptor with an extracellular domain containing two immunoglobulin-like and two fibronectin type III repeats (87.6% amino acid identity with human). RNA in situ hybridization showed onset of specific ufo expression in late embryogenesis (day 12.5 post coitum), localized to subepidermal cells, mesenchymal cells, organ capsules, and connective tissue structures of mesodermal origin.","method":"Molecular cloning, amino acid sequence comparison, chromosomal mapping, RNA in situ hybridization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular cloning and in situ hybridization establishing domain architecture and tissue-specific expression pattern","pmids":["1320243"],"is_preprint":false}],"current_model":"AXL is a receptor tyrosine kinase activated by ligand Gas6 (and Protein S) binding to its two immunoglobulin-like extracellular domains, inducing 2:2 receptor dimerization and transphosphorylation; the intracellular domain contains a multi-substrate docking site at Y821 that recruits PLCγ1, PI3K p85, GRB2, Src, and Lck to activate PI3K/AKT, MAPK/ERK, and PLCγ signaling; downstream, AXL drives focal adhesion disassembly via a NEDD9→CRKII→PEAK1→CSK→PAXILLIN axis to promote invasion and metastasis, suppresses TP53 transcription by direct chromatin binding, maintains apoE homeostasis (kinase-independently), and is subject to regulation of its protein stability through LZTR1-CUL3 ubiquitin ligase targeting it for lysosomal degradation and through p85β/TRIM2/optineurin-mediated autophagic degradation; in immune cells, AXL cross-talks with TLR4 to drive pro-inflammatory glycolytic reprogramming in macrophages, promotes efferocytosis via Axl/Rac1 signaling in microglia, and also mediates viral entry (Ebola, ASFV) via macropinocytosis by acting as a phosphatidylserine receptor."},"narrative":{"mechanistic_narrative":"AXL is a receptor tyrosine kinase that couples extracellular recognition of the ligand Gas6 to intracellular survival, migration, and inflammatory signaling, and is recurrently co-opted in cancer and viral entry [PMID:16362042, PMID:9178760]. Its ectodomain is built from two immunoglobulin-like and two fibronectin type III repeats [PMID:1320243], and the crystal structure of the Gas6/Axl complex shows that a single Gas6 laminin G-like domain crosslinks two Axl Ig domains to form a 2:2 assembly through both a major and a minor binding site, productive transmembrane signaling requiring both [PMID:16362042]; sequestering Gas6 with an affinity-matured Axl decoy is sufficient to abrogate Axl signaling and block metastasis [PMID:25242553]. Activated AXL presents a multi-substrate docking site at phosphotyrosine 821 that recruits PLCγ1, the p85 subunits of PI3K, GRB2, c-Src, and Lck [PMID:9178760], driving PI3K/AKT-dependent cell survival [PMID:16627783] and proliferative signaling [PMID:14729616]. Downstream, AXL phosphorylates a NEDD9→CRKII→PEAK1→CSK→PAXILLIN focal-adhesion network to accelerate adhesion turnover and metastasis [PMID:32681075], regulates lysosome positioning and cathepsin B secretion via AKT-NF-κB-MCT-1 control of extracellular acidification to promote invasion [PMID:30189359], and represses TP53 by binding directly to its promoter [PMID:32992696]. AXL expression is amplified transcriptionally through EGFR-MAPK-c-Jun feedback [PMID:25136066] and JNK→AP-1 (c-JUN/c-FOS) signaling [PMID:30860495], and AXL serves as a bypass kinase conferring resistance to cetuximab [PMID:25136066] and osimertinib through an AXL/CDCP1/SRC axis [PMID:35643725]. AXL protein abundance is set by competing degradation pathways: the LZTR1-CUL3 ubiquitin ligase targets AXL for lysosomal degradation [PMID:36445254], while p85β via TRIM2/optineurin-dependent autophagy [PMID:32385243] and TRIM21-mediated K63 ubiquitination reversed by STAMBPL1 [PMID:39527690] further tune its stability and surface levels. In immune and tissue contexts, AXL acts as a phosphatidylserine receptor—enhanced by phosphatidylethanolamine co-recognition [PMID:33115868]—to drive macropinocytic entry of Ebola and African swine fever virus [PMID:21047970, PMID:37382521], promotes Gas6-driven microglial efferocytosis through Rac1 [PMID:36324028], and reprograms macrophage inflammation via TLR4 cross-talk and STAT1-dependent polarization [PMID:33529176, PMID:37223093]. AXL additionally maintains apoE homeostasis in astrocytes independently of its kinase activity [PMID:32366277].","teleology":[{"year":1992,"claim":"Establishing the molecular identity and domain architecture of Axl defined it as a novel receptor tyrosine kinase with an Ig/fibronectin-III ectodomain expressed in mesodermal tissues, providing the structural foundation for all subsequent ligand and signaling studies.","evidence":"Molecular cloning, sequence comparison, and RNA in situ hybridization of murine Ufo/Axl","pmids":["1320243"],"confidence":"Medium","gaps":["Ligand and downstream signaling not yet known","Functional role of the kinase domain undefined at this stage"]},{"year":1997,"claim":"Mapping the cytoplasmic docking sites answered how AXL transmits signal, showing that phosphotyrosine 821 is a multi-substrate platform recruiting PI3K, PLCγ1, GRB2, Src, and Lck, linking the receptor to canonical survival and proliferation cascades.","evidence":"Far-Western, Co-IP, competitive inhibition, and mutagenesis of chimeric EGFR/Ufo receptors","pmids":["9178760"],"confidence":"High","gaps":["Relative in vivo contribution of each docking partner not resolved","Did not address ligand-induced activation in native receptor"]},{"year":2005,"claim":"The Gas6/Axl crystal structure resolved the mechanism of receptor activation, demonstrating a 2:2 ligand-crosslinked dimer with no direct receptor-receptor contacts and a two-step assembly requiring both major and minor binding sites for productive signaling.","evidence":"X-ray crystallography (3.3 Å) with structure-based mutagenesis and receptor activation assays","pmids":["16362042"],"confidence":"High","gaps":["Dynamics of the two-step dimerization in cells not directly observed","Does not address phosphatidylserine-dependent activation modes"]},{"year":2014,"claim":"Two complementary 2014 studies established AXL both as a druggable node—Gas6 sequestration via an engineered decoy blocks metastasis—and as a transcriptionally amplified resistance driver under EGFR-MAPK-c-Jun control, linking ligand dependence to therapy resistance.","evidence":"Protein engineering with in vivo metastasis models; RNAi, overexpression, Co-IP, and xenografts in cetuximab-resistant NSCLC/HNSCC","pmids":["25242553","25136066"],"confidence":"High","gaps":["Decoy efficacy across tumor types not exhaustively mapped","Whether all resistance settings depend on Gas6 versus ligand-independent activation unresolved"]},{"year":2020,"claim":"Defining the NEDD9→CRKII→PEAK1→CSK→PAXILLIN axis answered how AXL drives invasion mechanistically, showing it accelerates focal-adhesion disassembly to promote metastasis independent of primary tumor growth, alongside chromatin-level TP53 repression and kinase-independent apoE maintenance.","evidence":"Phosphoproteomics, Co-IP, RNAi and in vivo metastasis models; ChIP-qPCR; kinase-dead reconstitution in astrocytoma cells","pmids":["32681075","32992696","32366277"],"confidence":"High","gaps":["How AXL accesses the nucleus to bind the TP53 promoter is unclear","Mechanism of kinase-independent apoE regulation undefined"]},{"year":2023,"claim":"Identifying LZTR1-CUL3, p85β/TRIM2/optineurin autophagy, and TRIM21/STAMBPL1 K63-ubiquitination established that AXL abundance is governed by multiple competing degradation routes, explaining AXL accumulation in LZTR1-mutant tumors and its therapeutic vulnerability.","evidence":"Biochemical screens, Co-IP, ubiquitination assays, conditional mouse KO; phosphorylation/autophagy assays; K63-linkage-specific ubiquitination assays","pmids":["36445254","32385243","39527690"],"confidence":"High","gaps":["How these degradation pathways are coordinated or prioritized is unknown","Upstream signals triggering each route not defined"]},{"year":2023,"claim":"Demonstrating AXL as the principal phosphatidylserine receptor for macropinocytic viral entry (Ebola, ASFV), enhanced by phosphatidylethanolamine co-recognition, unified its role in apoptotic-mimicry virus uptake and physiological efferocytosis.","evidence":"RNAi screening, AXL knockout, kinase-domain deletion, R428 inhibition, liposome binding, and live/pseudovirus assays","pmids":["37382521","21047970","33115868"],"confidence":"Medium","gaps":["Whether kinase activity is required for entry differs across systems","Mechanism coupling PS binding to macropinocytic machinery incomplete"]},{"year":2023,"claim":"Multiple immune-context studies established AXL as a regulator of macrophage and microglial inflammatory state, driving STAT1/HIF-1α-dependent M1 polarization, Rac1-dependent efferocytosis, and TLR4-coupled glycolytic reprogramming.","evidence":"Conditional myeloid genetic models, STAT1 siRNA epistasis, R428 inhibition, recombinant Gas6, and disease models (MI/R, SAH, TBI, aneurysm)","pmids":["33529176","36324028","34233703","37223093"],"confidence":"Medium","gaps":["Context-dependent pro- versus anti-inflammatory outcomes not reconciled","Ligand dependence in each immune setting variable"]},{"year":null,"claim":"How AXL switches between kinase-dependent oncogenic signaling, ligand-independent activation, and nuclear/transcriptional functions in a context-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating surface signaling with reported chromatin binding","Determinants selecting among competing degradation pathways unknown","Mechanism of kinase-independent functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,4]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,4]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[5,25]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[18,25]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,16,31]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[24]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,12,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,14,27]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[14,15,16]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,25]}],"complexes":[],"partners":["GAS6","PROS1","EGFR","PIK3R2","LZTR1","CDCP1","SRC","GRB2"],"other_free_text":[]}},"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":"28072762","id":"PMC_28072762","title":"Giving 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by redirecting the master transcription factor LEAFY to new cis-elements.","date":"2023","source":"Nature plants","url":"https://pubmed.ncbi.nlm.nih.gov/36732360","citation_count":39,"is_preprint":false},{"pmid":"28727830","id":"PMC_28727830","title":"The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28727830","citation_count":39,"is_preprint":false},{"pmid":"34233703","id":"PMC_34233703","title":"AXL kinase-mediated astrocytic phagocytosis modulates outcomes of traumatic brain injury.","date":"2021","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/34233703","citation_count":39,"is_preprint":false},{"pmid":"32676663","id":"PMC_32676663","title":"AXL Is a Potential Target for the Treatment of Intestinal Fibrosis.","date":"2021","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/32676663","citation_count":39,"is_preprint":false},{"pmid":"34778071","id":"PMC_34778071","title":"Immune Evasion Mechanism and AXL.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34778071","citation_count":38,"is_preprint":false},{"pmid":"8656672","id":"PMC_8656672","title":"Differential expression of the ufo/axl oncogene in human leukemia-lymphoma cell lines.","date":"1996","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/8656672","citation_count":37,"is_preprint":false},{"pmid":"30914429","id":"PMC_30914429","title":"Cross-Talk between Receptor Tyrosine Kinases AXL and ERBB3 Regulates Invadopodia Formation in Melanoma Cells.","date":"2019","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30914429","citation_count":37,"is_preprint":false},{"pmid":"27130831","id":"PMC_27130831","title":"Axl Receptor Axis: A New Therapeutic Target in Lung Cancer.","date":"2016","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27130831","citation_count":37,"is_preprint":false},{"pmid":"33002607","id":"PMC_33002607","title":"Therapeutic aspects of the Axl/Gas6 molecular system.","date":"2020","source":"Drug discovery today","url":"https://pubmed.ncbi.nlm.nih.gov/33002607","citation_count":36,"is_preprint":false},{"pmid":"37265798","id":"PMC_37265798","title":"Gas6/AXL pathway: immunological landscape and therapeutic potential.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37265798","citation_count":35,"is_preprint":false},{"pmid":"27506606","id":"PMC_27506606","title":"Impact of Expression of Vimentin and Axl in Breast Cancer.","date":"2016","source":"Clinical breast 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alliance","url":"https://pubmed.ncbi.nlm.nih.gov/31822557","citation_count":34,"is_preprint":false},{"pmid":"33115868","id":"PMC_33115868","title":"Phosphatidylethanolamine and Phosphatidylserine Synergize To Enhance GAS6/AXL-Mediated Virus Infection and Efferocytosis.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/33115868","citation_count":32,"is_preprint":false},{"pmid":"26951083","id":"PMC_26951083","title":"Gene of the month: Axl.","date":"2016","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26951083","citation_count":31,"is_preprint":false},{"pmid":"9130617","id":"PMC_9130617","title":"Recent progress on the role of Axl, a receptor tyrosine kinase, in malignant transformation of myeloid leukemias.","date":"1997","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/9130617","citation_count":31,"is_preprint":false},{"pmid":"35634427","id":"PMC_35634427","title":"AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review.","date":"2022","source":"Liver cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35634427","citation_count":29,"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 : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/33811159","citation_count":29,"is_preprint":false},{"pmid":"34675118","id":"PMC_34675118","title":"AXL Inhibitor TP-0903 Reduces Metastasis and Therapy Resistance in Pancreatic Cancer.","date":"2021","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34675118","citation_count":28,"is_preprint":false},{"pmid":"33182542","id":"PMC_33182542","title":"AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations.","date":"2020","source":"International journal of molecular 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N.Z.)","url":"https://pubmed.ncbi.nlm.nih.gov/34408519","citation_count":23,"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 sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32174798","citation_count":23,"is_preprint":false},{"pmid":"36650292","id":"PMC_36650292","title":"AXL antibody and AXL-ADC mediate antitumor efficacy via targeting AXL in tumor-intrinsic epithelial-mesenchymal transition and tumor-associated M2-like macrophage.","date":"2023","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/36650292","citation_count":22,"is_preprint":false},{"pmid":"35643725","id":"PMC_35643725","title":"AXL/CDCP1/SRC axis confers acquired resistance to osimertinib in lung cancer.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35643725","citation_count":22,"is_preprint":false},{"pmid":"30541554","id":"PMC_30541554","title":"Tyro3, Axl, and Mertk receptors differentially participate in platelet activation and thrombus formation.","date":"2018","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/30541554","citation_count":22,"is_preprint":false},{"pmid":"31134766","id":"PMC_31134766","title":"AXL targeting reduces fibrosis development in experimental unilateral ureteral obstruction.","date":"2019","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/31134766","citation_count":22,"is_preprint":false},{"pmid":"28105215","id":"PMC_28105215","title":"Role of AXL expression in non-small cell lung cancer.","date":"2016","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28105215","citation_count":20,"is_preprint":false},{"pmid":"37382521","id":"PMC_37382521","title":"Coreceptor AXL Facilitates African Swine Fever Virus Entry via Apoptotic Mimicry.","date":"2023","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/37382521","citation_count":20,"is_preprint":false},{"pmid":"36650344","id":"PMC_36650344","title":"Role of miR-944/MMP10/AXL- axis in lymph node metastasis in tongue cancer.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36650344","citation_count":20,"is_preprint":false},{"pmid":"29177020","id":"PMC_29177020","title":"Epigenetic regulation of AXL and risk of childhood asthma symptoms.","date":"2017","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29177020","citation_count":20,"is_preprint":false},{"pmid":"31221818","id":"PMC_31221818","title":"Mechanism of gut microbiota and Axl/SOCS3 in experimental autoimmune encephalomyelitis.","date":"2019","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31221818","citation_count":20,"is_preprint":false},{"pmid":"33374832","id":"PMC_33374832","title":"MicroRNA 34a-AXL Axis Regulates Vasculogenic Mimicry Formation in Breast Cancer Cells.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33374832","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":"37223093","id":"PMC_37223093","title":"Axl promotes intracranial aneurysm rupture by regulating macrophage polarization toward M1 via STAT1/HIF-1α.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37223093","citation_count":19,"is_preprint":false},{"pmid":"39527690","id":"PMC_39527690","title":"STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39527690","citation_count":18,"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":46991,"output_tokens":8608,"usd":0.135047,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18495,"output_tokens":4036,"usd":0.096687,"stage2_stop_reason":"end_turn"},"total_usd":0.231734,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","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 stoichiometry in which the 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 demonstrated that both a major and minor Gas6-binding site on Axl are required for productive transmembrane signaling. Gas6-mediated Axl dimerization is proposed to occur in two steps, with a high-affinity 1:1 Gas6/Axl complex forming first.\",\n      \"method\": \"X-ray crystallography (3.3 Å), structure-based mutagenesis, protein binding assays, receptor activation experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional receptor activation assays in a single rigorous study\",\n      \"pmids\": [\"16362042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The cytoplasmic domain of Ufo/Axl contains a multi-substrate docking site at C-terminal tyrosine 821 (EILpYVNMDEG) that recruits PLCγ1, p85α and p85β subunits of PI3-kinase, GRB2, c-Src, and Lck. Tyrosine 779 provides an additional lower-affinity docking site for p85 proteins in vitro, and tyrosine 866 is an additional binding site for PLCγ. Identified using far-Western blot, co-immunoprecipitation, competitive inhibition, and mutagenesis of chimeric EGFR/Ufo receptors.\",\n      \"method\": \"Far-Western blot, co-immunoprecipitation, competitive inhibition assays, site-directed mutagenesis of chimeric EGFR/Ufo constructs\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (far-Western, Co-IP, mutagenesis) in a single study establishing specific phosphotyrosine docking sites\",\n      \"pmids\": [\"9178760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AXL activation in cetuximab-resistant (CtxR) NSCLC and HNSCC cells stimulates cell proliferation, EGFR activation, and MAPK signaling. AXL was found tightly associated with EGFR in CtxR cells, and EGFR directly regulated AXL mRNA expression through MAPK signaling and the transcription factor c-Jun, creating a positive feedback loop. Overexpression of AXL or stimulation with EGFR ligands was sufficient to confer cetuximab resistance.\",\n      \"method\": \"RNAi knockdown, AXL-targeting agents, stable overexpression, co-immunoprecipitation (AXL-EGFR association), mRNA expression analysis, tumor xenograft models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional studies with RNAi, overexpression, Co-IP, and in vivo xenograft validation across multiple cell line models\",\n      \"pmids\": [\"25136066\"],\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 femtomolar affinity (80-fold improvement over wild-type), sequesters Gas6, and specifically abrogates Axl signaling. The Fc-fusion decoy receptor potently inhibited metastasis and disease progression in vivo, demonstrating that Gas6 sequestration is sufficient to block Axl pathway activity.\",\n      \"method\": \"Rational and combinatorial protein engineering, binding affinity assays, in vitro Axl signaling inhibition assays, in vivo metastasis models\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-guided mutagenesis combined with quantitative binding assays and in vivo functional validation\",\n      \"pmids\": [\"25242553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AXL stimulates phosphorylation of a focal adhesion (FA) protein network to accelerate FA disassembly and promote cell migration and metastasis. Mechanistically, AXL phosphorylates NEDD9, which binds CRKII, which associates with and orchestrates phosphorylation of pseudo-kinase PEAK1; PEAK1 is in complex with tyrosine kinase CSK to mediate phosphorylation of PAXILLIN. Uncoupling PEAK1 from AXL signaling decreases metastasis in vivo without affecting tumor growth.\",\n      \"method\": \"Phosphoproteomic profiling, co-immunoprecipitation, RNAi knockdown, in vivo metastasis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphoproteomics combined with Co-IP, functional knockdown, and in vivo validation defining a full signaling pathway\",\n      \"pmids\": [\"32681075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Axl enhances macropinocytosis of Zaire ebolavirus (ZEBOV) in permissive cells. RNAi reduction of Axl expression decreased ZEBOV entry via macropinocytosis but had no effect on clathrin-dependent or caveola/lipid raft-mediated endocytic pathways, demonstrating a specific role for Axl in promoting macropinocytosis-dependent viral entry.\",\n      \"method\": \"Biochemical inhibitors, RNAi knockdown, dominant-negative constructs, viral transduction assays, dextran uptake assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (RNAi, dominant negatives, pharmacological inhibitors) with pathway-specific readouts in a single study\",\n      \"pmids\": [\"21047970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PROS1 (Protein S), secreted by tumor-associated macrophages/microglia, physically associates with and activates AXL in mesenchymal glioblastoma stem cells, leading to NF-κB activation. This PROS1-AXL signaling was inhibited by the small molecule AXL inhibitor BGB324.\",\n      \"method\": \"Co-immunoprecipitation (PROS1-AXL association), pharmacological inhibition, NF-κB pathway readouts, mouse GBM survival models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating physical association plus downstream signaling readout and in vivo model, single lab\",\n      \"pmids\": [\"29531161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Axl deficiency (Axl-/- mice) leads to significantly smaller intima+media following carotid artery ligation compared to wild-type, associated with increased apoptosis (5-fold increase in Axl-/- LCA) and decreased p-Akt, demonstrating that Axl mediates flow-dependent vascular remodeling by regulating vascular cell survival through the Akt pathway.\",\n      \"method\": \"Axl knockout mouse model (Axl-/-), carotid ligation model, quantitative immunohistochemistry, apoptosis assays, Western blot for p-Akt\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined vascular phenotype and molecular mechanism (p-Akt), single lab\",\n      \"pmids\": [\"16627783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Axl is active in confluent pericytes and its activation by endogenous Gas6 inhibits osteogenic differentiation. Addition of recombinant Axl extracellular domain (ECD) to pericyte cultures inhibited Axl phosphorylation by Gas6 and enhanced the rate of nodule mineralization, demonstrating that Gas6-Axl signaling suppresses the osteogenic differentiation pathway in vascular pericytes.\",\n      \"method\": \"Immunoprecipitation of phosphotyrosine (Axl activity), recombinant Axl-ECD competition assay, Western blot, nodule mineralization assays\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical evidence of Axl phosphorylation with functional rescue experiment, single lab\",\n      \"pmids\": [\"12730092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"E1A negatively regulates Axl expression at the transcriptional level. Gas6 stimulation of Axl in E1A-expressing cells overexpressing Axl provided greater mitogenic effect and protected cells from serum deprivation-induced apoptosis, demonstrating that downregulation of Axl by E1A contributes to E1A-mediated growth suppression and pro-apoptotic activity.\",\n      \"method\": \"RT-PCR tyrosine kinase profiling, cDNA transfection/overexpression, Gas6 stimulation, BrdU incorporation, trypan blue exclusion (survival assay)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional regulation established by RT-PCR with functional rescue using Gas6/Axl stimulation, single lab\",\n      \"pmids\": [\"10567533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Gas6 stimulation of Axl in uveal melanoma cells (Mel 290) mediates mitogenesis and cell survival, demonstrated specifically through Axl by antisense-mediated knockdown of Axl expression. Gas6/Axl activation results primarily in downregulation of Cyr61 (a CCN family member) as revealed by cDNA microarray analysis of 12,687 genes.\",\n      \"method\": \"BrdU incorporation, trypan blue exclusion, antisense knockdown, cDNA microarray (12,687 genes)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antisense specificity control with functional survival assays and downstream gene expression profiling, single lab\",\n      \"pmids\": [\"14729616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cross-signaling between AXL and TLR4 in cardiac macrophages directs a switch to glycolytic metabolism and secretion of proinflammatory IL-1β, leading to increased intramyocardial inflammation, adverse ventricular remodeling, and impaired contractile function after myocardial ischemia/reperfusion injury. AXL functions independently of cardioprotective MerTK, and like MerTK, undergoes proteolytic cleavage.\",\n      \"method\": \"Conditional genetic loss/gain-of-function (myeloid-specific), flow cytometry, metabolic assays, cytokine measurements, cardiac functional readouts\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic manipulation with defined signaling mechanism and functional cardiac phenotype, single lab\",\n      \"pmids\": [\"33529176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Gas6 promotes microglial efferocytosis and suppresses post-SAH inflammation through activating the Axl/Rac1 signaling pathway. Inhibition or knockdown of Axl or Rac1 abolished the beneficial effects of recombinant Gas6, demonstrating a functional Gas6→Axl→Rac1 signaling axis in microglia efferocytosis.\",\n      \"method\": \"Mouse SAH model, intraventricular injection of recombinant Gas6/ProS1, TAM receptor knockdown (siRNA), specific inhibitors, flow cytometry, in vitro phagocytosis assays\",\n      \"journal\": \"Translational stroke research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (siRNA) and pharmacological inhibition with functional efferocytosis readouts establishing pathway order, single lab\",\n      \"pmids\": [\"36324028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AXL activates the STAT1 pathway in astrocytes post-traumatic brain injury, which further upregulates ABCA1, promoting a phagocytic astrocyte phenotype (AXL/STAT1/ABCA1 pathway). Pharmacological inhibition of AXL decreased astrocytic phagocytosis both in vivo and in vitro.\",\n      \"method\": \"Mouse CCI TBI model, pharmacological inhibition (R428), siRNA transfection, Western blot, flow cytometry, RT-PCR\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and siRNA inhibition with defined pathway readouts (STAT1, ABCA1) and functional phagocytosis assay, single lab\",\n      \"pmids\": [\"34233703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LZTR1 acts as a substrate-specific adaptor of CUL3-dependent ubiquitin ligase that targets AXL (and EGFR) for ubiquitin-dependent lysosomal degradation. Pathogenic LZTR1 cancer mutations fail to promote AXL degradation, resulting in AXL accumulation and dysregulated growth factor signaling. LZTR1-mutant tumors accumulate AXL and show specific vulnerability to AXL inhibition.\",\n      \"method\": \"Unbiased biochemical screens, Co-IP, genetic loss-of-function (conditional Lztr1 mouse KO), ubiquitination assays, mouse tumor models\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution of ubiquitin-mediated degradation, unbiased screens, in vivo mouse models, and therapeutic vulnerability validation\",\n      \"pmids\": [\"36445254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"p85β (PIK3R2) upregulates AXL protein levels by disrupting its autophagic degradation. Mechanistically, p85β alters phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate selective autophagic degradation of AXL. This AXL upregulation by p85β activates AKT-independent PDK1/SGK3 signaling.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, autophagy inhibition, siRNA knockdown, overexpression studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic pathway established by multiple orthogonal biochemical methods identifying specific E3 ligase (TRIM2) and autophagy receptor (optineurin) regulating AXL stability\",\n      \"pmids\": [\"32385243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STAMBPL1 elevates AXL protein abundance and surface accumulation by diminishing TRIM21-mediated K63-linked ubiquitination and subsequent lysosomal degradation of AXL. This stabilization of AXL enhances mesenchymal gene expression while suppressing CXCL9/10 and HLA expression in kidney clear cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K63 linkage-specific), protein stability assays, STAMBPL1 knockdown/overexpression\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical identification of K63-ubiquitination by TRIM21 and its reversal by STAMBPL1, functional downstream readouts, single lab\",\n      \"pmids\": [\"39527690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NAT10 promotes mRNA stability of AXL in an N4-acetylcytidine (ac4C)-dependent manner, leading to increased AXL expression and promoting pancreatic ductal adenocarcinoma cell proliferation and metastasis.\",\n      \"method\": \"ac4C modification assays, mRNA stability assays, NAT10 knockdown/overexpression, in vitro and in vivo tumor models\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epitranscriptomic modification (ac4C) linked to AXL mRNA stability with functional cancer phenotype, single lab\",\n      \"pmids\": [\"37156457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Phosphatidylethanolamine (PE) synergizes with phosphatidylserine (PS) to enhance Gas6 binding and AXL-mediated efferocytosis and virus entry. Liposomes containing both PE and PS bound Gas6 and were engulfed by AXL-expressing cells much more efficiently than PS alone, demonstrating that PE co-recognition maximizes PS receptor (AXL)-mediated processes.\",\n      \"method\": \"Liposome binding assays, Gas6 binding quantification, AXL-expressing cell efferocytosis assays, pseudovirus and live virus infection assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biochemical and cell-based assays with multiple viral systems, single lab\",\n      \"pmids\": [\"33115868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AXL, but not MERTK or TYRO3, shows a dual regulatory function in invadopodia formation in melanoma cells: both depletion and overexpression of AXL enhanced invadopodia formation. AXL depletion upregulates ERBB3 signaling, which activates core invadopodia regulators. High AXL expression is inversely correlated with ERBB3 expression across melanoma cell lines.\",\n      \"method\": \"siRNA screen (microscopy-based), knockdown and overexpression, invadopodia formation and activity assays, bioinformatic analysis of cell line expression data\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic siRNA screen with functional invadopodia assays and pathway crosstalk analysis, single lab\",\n      \"pmids\": [\"30914429\"],\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. Loss of Axl in platelets reduced aggregation, spreading, integrin activation (JON/A binding), and P-selectin expression, and decreased tyrosine phosphorylation of Syk and PLCγ2 upon GPVI agonist stimulation. Anti-Axl neutralizing antibody or recombinant Axl extracellular domain (but not Gas6-neutralizing antibody) inhibited platelet aggregation, indicating ligand-independent or non-Gas6 mechanisms.\",\n      \"method\": \"Single TAM receptor knockout mice, in vitro platelet aggregation/activation assays, flow cytometry, Western blot for Syk/PLCγ2 phosphorylation, neutralizing antibodies, in vivo laser-induced thrombosis model\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (genetic knockout, neutralizing antibody, recombinant protein) with in vivo validation, single lab\",\n      \"pmids\": [\"30541554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AP-1 transcription factors c-JUN and c-FOS regulate AXL overexpression in HNSCC and ESCC. Silencing c-JUN or c-FOS downregulated AXL expression. JNK inhibition (SP600125) reduced AXL expression, and combined JNK + PI3K inhibition had synergistic anti-proliferative effects, establishing the JNK→AP-1→AXL transcriptional axis as a mechanism of AXL upregulation driving therapy resistance.\",\n      \"method\": \"siRNA silencing (c-JUN, c-FOS), qRT-PCR, Western blot, pharmacological inhibitors, in vitro proliferation assays, cell line-derived and patient-derived xenograft models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic silencing plus pharmacological approach with in vivo validation, single lab, defining transcriptional regulation\",\n      \"pmids\": [\"30860495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AXL mediates cell invasion in esophageal adenocarcinoma through regulation of lysosome peripheral distribution and cathepsin B secretion. AXL-dependent peripheral lysosome distribution and invasion are mediated by extracellular acidification, which is potentiated by AXL-induced lactate secretion through AKT-NF-κB-dependent MCT-1 regulation.\",\n      \"method\": \"AXL knockdown, lysosome trafficking assays, cathepsin B secretion measurement, extracellular pH measurement, AKT/NF-κB pathway analysis, AXL inhibitor R428\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway from AXL to lysosome trafficking established by knockdown with multiple downstream readouts, single lab\",\n      \"pmids\": [\"30189359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AXL regulates apolipoprotein E (apoE) homeostasis in human astrocytes. AXL-deficient astrocytoma cells show significantly attenuated apoE expression and secretion; reconstitution with either wild-type Axl or kinase-dead Axl significantly restored apoE baseline levels, demonstrating that Axl maintains apoE homeostasis independent of its kinase activity. AXL inhibition also upregulates ABCA1 expression.\",\n      \"method\": \"AXL-/- cell line generation, cDNA reconstitution (wild-type and kinase-dead Axl), high-throughput phenotypic screen, ELISA (apoE secretion), Western blot\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout with kinase-dead reconstitution establishes kinase-independent function for apoE regulation, single lab\",\n      \"pmids\": [\"32366277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AXL suppresses TP53 transcription by binding to the initial 600 bp sequence at the 5' end of the TP53 promoter, as demonstrated by chromatin immunoprecipitation-qPCR and sequencing. AXL knockdown induced wild-type and mutant p53 expression, and the anti-proliferative and anti-migratory effects of AXL silencing were attenuated by TP53 knockdown, establishing a feedback regulatory loop between AXL and p53.\",\n      \"method\": \"AXL shRNA knockdown, chromatin immunoprecipitation (ChIP)-qPCR, TP53 promoter dual luciferase assay, immunofluorescence, qRT-PCR\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates direct AXL binding to TP53 promoter, functional rescue with TP53 knockdown, single lab\",\n      \"pmids\": [\"32992696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AXL facilitates African swine fever virus (ASFV) entry into porcine alveolar macrophages via macropinocytosis by acting as a phosphatidylserine (PS) receptor; ASFV displays PS on its envelope as viral apoptotic mimicry to engage AXL. AXL was identified as the most important PS receptor by RNA interference screening; AXL knockout decreased ASFV internalization and replication, and deletion of the intracellular kinase domain or AXL inhibitor R428 significantly inhibited ASFV internalization.\",\n      \"method\": \"RNA interference screening, AXL gene knockout (MA104 cells), neutralizing antibody against AXL extracellular domain, kinase domain deletion mutant, AXL inhibitor R428, macropinocytosis assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological approaches with defined entry mechanism, single lab, porcine system\",\n      \"pmids\": [\"37382521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AXL inhibits M2 macrophage polarization; a specific anti-AXL antibody blocked bone marrow-derived macrophage M2-polarization in vitro, and targeting AXL in M2-macrophages suppressed CSF-1 production and eliminated M2-macrophages in the tumor microenvironment.\",\n      \"method\": \"Anti-AXL antibody treatment, BMDM polarization assays, CSF-1 measurement, in vivo tumor models with flow cytometry analysis of immune infiltrates\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single antibody-based approach, limited mechanistic depth beyond phenotypic observation, single lab\",\n      \"pmids\": [\"36650292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AXL, CDCP1, and SRC form a signaling axis conferring acquired osimertinib resistance in NSCLC. Silencing CDCP1 or AXL restored sensitivity to osimertinib with reduced SRC and AKT activation; dual silencing of both CDCP1 and AXL further increased sensitivity, establishing AXL/SFK/AKT as a bypass signaling pathway.\",\n      \"method\": \"siRNA knockdown (AXL, CDCP1, SRC), Western blot for pathway activation, pharmacological inhibition (dasatinib), osimertinib-resistant cell line development\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown of multiple pathway components with functional drug sensitivity readout, single lab\",\n      \"pmids\": [\"35643725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Axl promotes M1 macrophage polarization via the STAT1/HIF-1α signaling pathway in intracranial aneurysm. R428 (AXL inhibitor) inhibited phosphorylation of Axl and STAT1 and expression of HIF-1α, IL-1β, NOS2, and MMP9 in LPS/IFN-γ-stimulated macrophages. STAT1 knockdown abolished Axl-mediated M1 macrophage polarization.\",\n      \"method\": \"Mouse IA model, bone marrow-derived macrophage stimulation, AXL inhibitor R428, rmGas6 treatment, STAT1 siRNA knockdown, Western blot, immunohistochemistry\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — STAT1 knockdown epistasis establishing pathway order, pharmacological confirmation, single lab\",\n      \"pmids\": [\"37223093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Pericyte FAK negatively regulates Gas6-stimulated phosphorylation of Axl; loss of pericyte FAK enhances Gas6-stimulated Axl phosphorylation with upregulation of Cyr61, driving enhanced tumour growth. Pericyte-derived Cyr61 then instructs tumour cells to elevate expression of pro-angiogenic Tissue Factor.\",\n      \"method\": \"Pericyte-specific FAK knockout mouse models (multiple cancer models), phosphorylation assays, immunohistochemistry, multiple tumor models (melanoma, lung carcinoma, insulinoma)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in pericyte-specific manner with defined downstream pathway across multiple tumor models, single lab\",\n      \"pmids\": [\"32499572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BRAF and AXL are oncogenic drivers of RIPK3 expression loss in cancer, thereby suppressing necroptosis sensitivity. Inhibition of AXL (or BRAF) can rescue RIPK3 expression loss and restore necroptosis sensitivity in cancer cell lines.\",\n      \"method\": \"Genome-wide bioinformatics analysis of 941 cancer cell lines, necroptosis sensitivity screen, AXL/BRAF inhibitor treatment with RIPK3 expression rescue assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — primarily bioinformatic correlation with pharmacological rescue in cell lines, limited mechanistic detail on how AXL suppresses RIPK3, single study\",\n      \"pmids\": [\"30157175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The murine Ufo/Axl receptor encodes a novel tyrosine kinase receptor with an extracellular domain containing two immunoglobulin-like and two fibronectin type III repeats (87.6% amino acid identity with human). RNA in situ hybridization showed onset of specific ufo expression in late embryogenesis (day 12.5 post coitum), localized to subepidermal cells, mesenchymal cells, organ capsules, and connective tissue structures of mesodermal origin.\",\n      \"method\": \"Molecular cloning, amino acid sequence comparison, chromosomal mapping, RNA in situ hybridization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular cloning and in situ hybridization establishing domain architecture and tissue-specific expression pattern\",\n      \"pmids\": [\"1320243\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AXL is a receptor tyrosine kinase activated by ligand Gas6 (and Protein S) binding to its two immunoglobulin-like extracellular domains, inducing 2:2 receptor dimerization and transphosphorylation; the intracellular domain contains a multi-substrate docking site at Y821 that recruits PLCγ1, PI3K p85, GRB2, Src, and Lck to activate PI3K/AKT, MAPK/ERK, and PLCγ signaling; downstream, AXL drives focal adhesion disassembly via a NEDD9→CRKII→PEAK1→CSK→PAXILLIN axis to promote invasion and metastasis, suppresses TP53 transcription by direct chromatin binding, maintains apoE homeostasis (kinase-independently), and is subject to regulation of its protein stability through LZTR1-CUL3 ubiquitin ligase targeting it for lysosomal degradation and through p85β/TRIM2/optineurin-mediated autophagic degradation; in immune cells, AXL cross-talks with TLR4 to drive pro-inflammatory glycolytic reprogramming in macrophages, promotes efferocytosis via Axl/Rac1 signaling in microglia, and also mediates viral entry (Ebola, ASFV) via macropinocytosis by acting as a phosphatidylserine receptor.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AXL is a receptor tyrosine kinase that couples extracellular recognition of the ligand Gas6 to intracellular survival, migration, and inflammatory signaling, and is recurrently co-opted in cancer and viral entry [#0, #1]. Its ectodomain is built from two immunoglobulin-like and two fibronectin type III repeats [#31], and the crystal structure of the Gas6/Axl complex shows that a single Gas6 laminin G-like domain crosslinks two Axl Ig domains to form a 2:2 assembly through both a major and a minor binding site, productive transmembrane signaling requiring both [#0]; sequestering Gas6 with an affinity-matured Axl decoy is sufficient to abrogate Axl signaling and block metastasis [#3]. Activated AXL presents a multi-substrate docking site at phosphotyrosine 821 that recruits PLC\\u03b31, the p85 subunits of PI3K, GRB2, c-Src, and Lck [#1], driving PI3K/AKT-dependent cell survival [#7] and proliferative signaling [#10]. Downstream, AXL phosphorylates a NEDD9\\u2192CRKII\\u2192PEAK1\\u2192CSK\\u2192PAXILLIN focal-adhesion network to accelerate adhesion turnover and metastasis [#4], regulates lysosome positioning and cathepsin B secretion via AKT-NF-\\u03baB-MCT-1 control of extracellular acidification to promote invasion [#22], and represses TP53 by binding directly to its promoter [#24]. AXL expression is amplified transcriptionally through EGFR-MAPK-c-Jun feedback [#2] and JNK\\u2192AP-1 (c-JUN/c-FOS) signaling [#21], and AXL serves as a bypass kinase conferring resistance to cetuximab [#2] and osimertinib through an AXL/CDCP1/SRC axis [#27]. AXL protein abundance is set by competing degradation pathways: the LZTR1-CUL3 ubiquitin ligase targets AXL for lysosomal degradation [#14], while p85\\u03b2 via TRIM2/optineurin-dependent autophagy [#15] and TRIM21-mediated K63 ubiquitination reversed by STAMBPL1 [#16] further tune its stability and surface levels. In immune and tissue contexts, AXL acts as a phosphatidylserine receptor\\u2014enhanced by phosphatidylethanolamine co-recognition [#18]\\u2014to drive macropinocytic entry of Ebola and African swine fever virus [#5, #25], promotes Gas6-driven microglial efferocytosis through Rac1 [#12], and reprograms macrophage inflammation via TLR4 cross-talk and STAT1-dependent polarization [#11, #28]. AXL additionally maintains apoE homeostasis in astrocytes independently of its kinase activity [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing the molecular identity and domain architecture of Axl defined it as a novel receptor tyrosine kinase with an Ig/fibronectin-III ectodomain expressed in mesodermal tissues, providing the structural foundation for all subsequent ligand and signaling studies.\",\n      \"evidence\": \"Molecular cloning, sequence comparison, and RNA in situ hybridization of murine Ufo/Axl\",\n      \"pmids\": [\"1320243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand and downstream signaling not yet known\", \"Functional role of the kinase domain undefined at this stage\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapping the cytoplasmic docking sites answered how AXL transmits signal, showing that phosphotyrosine 821 is a multi-substrate platform recruiting PI3K, PLC\\u03b31, GRB2, Src, and Lck, linking the receptor to canonical survival and proliferation cascades.\",\n      \"evidence\": \"Far-Western, Co-IP, competitive inhibition, and mutagenesis of chimeric EGFR/Ufo receptors\",\n      \"pmids\": [\"9178760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contribution of each docking partner not resolved\", \"Did not address ligand-induced activation in native receptor\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The Gas6/Axl crystal structure resolved the mechanism of receptor activation, demonstrating a 2:2 ligand-crosslinked dimer with no direct receptor-receptor contacts and a two-step assembly requiring both major and minor binding sites for productive signaling.\",\n      \"evidence\": \"X-ray crystallography (3.3 \\u00c5) with structure-based mutagenesis and receptor activation assays\",\n      \"pmids\": [\"16362042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of the two-step dimerization in cells not directly observed\", \"Does not address phosphatidylserine-dependent activation modes\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two complementary 2014 studies established AXL both as a druggable node\\u2014Gas6 sequestration via an engineered decoy blocks metastasis\\u2014and as a transcriptionally amplified resistance driver under EGFR-MAPK-c-Jun control, linking ligand dependence to therapy resistance.\",\n      \"evidence\": \"Protein engineering with in vivo metastasis models; RNAi, overexpression, Co-IP, and xenografts in cetuximab-resistant NSCLC/HNSCC\",\n      \"pmids\": [\"25242553\", \"25136066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Decoy efficacy across tumor types not exhaustively mapped\", \"Whether all resistance settings depend on Gas6 versus ligand-independent activation unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining the NEDD9\\u2192CRKII\\u2192PEAK1\\u2192CSK\\u2192PAXILLIN axis answered how AXL drives invasion mechanistically, showing it accelerates focal-adhesion disassembly to promote metastasis independent of primary tumor growth, alongside chromatin-level TP53 repression and kinase-independent apoE maintenance.\",\n      \"evidence\": \"Phosphoproteomics, Co-IP, RNAi and in vivo metastasis models; ChIP-qPCR; kinase-dead reconstitution in astrocytoma cells\",\n      \"pmids\": [\"32681075\", \"32992696\", \"32366277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How AXL accesses the nucleus to bind the TP53 promoter is unclear\", \"Mechanism of kinase-independent apoE regulation undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying LZTR1-CUL3, p85\\u03b2/TRIM2/optineurin autophagy, and TRIM21/STAMBPL1 K63-ubiquitination established that AXL abundance is governed by multiple competing degradation routes, explaining AXL accumulation in LZTR1-mutant tumors and its therapeutic vulnerability.\",\n      \"evidence\": \"Biochemical screens, Co-IP, ubiquitination assays, conditional mouse KO; phosphorylation/autophagy assays; K63-linkage-specific ubiquitination assays\",\n      \"pmids\": [\"36445254\", \"32385243\", \"39527690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How these degradation pathways are coordinated or prioritized is unknown\", \"Upstream signals triggering each route not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating AXL as the principal phosphatidylserine receptor for macropinocytic viral entry (Ebola, ASFV), enhanced by phosphatidylethanolamine co-recognition, unified its role in apoptotic-mimicry virus uptake and physiological efferocytosis.\",\n      \"evidence\": \"RNAi screening, AXL knockout, kinase-domain deletion, R428 inhibition, liposome binding, and live/pseudovirus assays\",\n      \"pmids\": [\"37382521\", \"21047970\", \"33115868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether kinase activity is required for entry differs across systems\", \"Mechanism coupling PS binding to macropinocytic machinery incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple immune-context studies established AXL as a regulator of macrophage and microglial inflammatory state, driving STAT1/HIF-1\\u03b1-dependent M1 polarization, Rac1-dependent efferocytosis, and TLR4-coupled glycolytic reprogramming.\",\n      \"evidence\": \"Conditional myeloid genetic models, STAT1 siRNA epistasis, R428 inhibition, recombinant Gas6, and disease models (MI/R, SAH, TBI, aneurysm)\",\n      \"pmids\": [\"33529176\", \"36324028\", \"34233703\", \"37223093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent pro- versus anti-inflammatory outcomes not reconciled\", \"Ligand dependence in each immune setting variable\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AXL switches between kinase-dependent oncogenic signaling, ligand-independent activation, and nuclear/transcriptional functions in a context-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating surface signaling with reported chromatin binding\", \"Determinants selecting among competing degradation pathways unknown\", \"Mechanism of kinase-independent functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [5, 25]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [18, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 16, 31]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 12, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 14, 27]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [14, 15, 16]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GAS6\", \"PROS1\", \"EGFR\", \"PIK3R2\", \"LZTR1\", \"CDCP1\", \"SRC\", \"GRB2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}