{"gene":"TYRO3","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1995,"finding":"Gas6 (growth arrest-specific gene 6 product) is a ligand for the Sky/TYRO3 receptor tyrosine kinase. Gas6, but not protein S, specifically binds to the soluble extracellular domain of Sky (Sky-Fc) and stimulates tyrosine phosphorylation of Sky in CHO cells with half-maximal activation at ~1 nM.","method":"Ligand-binding assay with soluble Sky-Fc fusion protein, tyrosine phosphorylation assay in transfected CHO cells, competition inhibition with Sky-Fc","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro binding and kinase activation assay with multiple orthogonal methods (pulldown, phosphorylation, competition); independently replicated by other labs","pmids":["7559388"],"is_preprint":false},{"year":1997,"finding":"Bovine protein S activates human Sky/TYRO3 receptor tyrosine kinase, and the SHBG-like (sex hormone-binding globulin) C-terminal region of protein S is essential for receptor interaction, while N-terminal Gla domain contributes to binding affinity. Human protein S does not activate human Sky.","method":"Chimeric protein S domain-swap constructs, Sky phosphorylation assay, C4b-binding protein competition inhibition","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — domain mutagenesis/chimera approach with kinase phosphorylation readout, single lab but multiple orthogonal methods","pmids":["9210477"],"is_preprint":false},{"year":1999,"finding":"Triple knockout of Tyro3, Axl, and Mer in mice causes progressive death of differentiating germ cells and complete absence of mature sperm, due to failure of Sertoli cell trophic support. Tyro3, Axl, and Mer are expressed by Sertoli cells; their ligands Gas6 and protein S are produced by Leydig cells and later by both Leydig and Sertoli cells.","method":"Triple receptor knockout mouse model (loss-of-function genetics), histological analysis of seminiferous tubules, expression analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — triple-knockout genetic epistasis with defined cellular phenotype, independently recognized as foundational study","pmids":["10227296"],"is_preprint":false},{"year":2000,"finding":"The p85 subunit of PI3-kinase interacts with the cytoplasmic domain of TYRO3, is recruited and phosphorylated upon TYRO3 activation, and TYRO3-associated PI3K exhibits enhanced kinase activity. Downstream Akt phosphorylation is increased upon TYRO3 activation, and TYRO3-mediated cellular transformation is blocked by the PI3K inhibitor wortmannin.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, Western blot for Akt phosphorylation, wortmannin inhibition in soft agar colony assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast 2-hybrid + GST pulldown + Co-IP + functional inhibitor assay, single lab, multiple orthogonal methods","pmids":["10627473"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of the two N-terminal Ig domains of human TYRO3 at 1.95 Å resolution reveals a ligand-binding site at the Ig domain interface, unusually rich in cis-prolines, shared with Axl. The receptor fragment undergoes ligand-independent homodimerization both in crystal and in solution, suggesting a role in cell adhesion.","method":"X-ray crystallography (1.95 Å), solution dimerization analysis, biochemical ligand-binding specificity profiling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with biochemical validation, single lab with structure + binding data","pmids":["14623883"],"is_preprint":false},{"year":2006,"finding":"Tyro3 (Dtk), Axl, and Mer family members each function as cell entry factors for Ebola and Marburg viruses. Ectopic expression of these receptors in otherwise virus-resistant lymphoid cells enhanced pseudotype and live filovirus infection; blocking antibodies, soluble ectodomains, and Gas6 ligand each reduced infection.","method":"Ectopic expression in lymphoid cells, pseudotype virus infection assay, live EBOV infection, antibody and soluble ectodomain blocking experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function expression + multiple blocking reagents (antibody, soluble domain, ligand) in multiple assays","pmids":["17005688"],"is_preprint":false},{"year":2006,"finding":"Tyro3, Axl, and Mer are essential for NK cell functional maturation. All three receptors are expressed in maturing NK cells; their ligands (Gas6/protein S) are produced by bone marrow stromal cells. Recombinant ligands drove NK cell differentiation in vitro, and triple-receptor-deficient mice lacked mature NK cells.","method":"Representational difference analysis, knockout mouse (single and combined), in vitro NK differentiation assay with recombinant ligands, expression analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function + in vitro rescue with defined ligands, multi-method","pmids":["16751775"],"is_preprint":false},{"year":2007,"finding":"In dendritic cells, apoptotic cell phagocytosis (efferocytosis) relies primarily on Axl and Tyro3, in contrast to macrophages where Mertk predominates. In macrophages, Mertk tyrosine phosphorylation in response to apoptotic cells is markedly reduced in Axl/Tyro3 double-knockout mice, suggesting these receptors can heterodimerize functionally.","method":"Single- and double-receptor knockout mice, apoptotic cell phagocytosis assay in primary macrophages and dendritic cells, Mertk phosphorylation Western blot","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined phagocytosis phenotype across multiple cell types + biochemical phosphorylation readout","pmids":["17442946"],"is_preprint":false},{"year":2007,"finding":"TYRO3 localizes to dendrites, soma (punctate), and axons/growth cones of hippocampal and cortical neurons. Gas6 stimulation of TYRO3 in cortical neurons activates both MAPK (ERK) and PI3K signaling pathways.","method":"Immunofluorescence localization in primary neurons, Gas6-induced phosphorylation assay, pathway inhibitor studies (MAPK and PI3K inhibitors)","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct immunofluorescence localization + functional signaling assay in primary neurons, single lab","pmids":["17980494"],"is_preprint":false},{"year":2008,"finding":"Axl and Tyro3 mediate Gas6-stimulated GnRH neuron survival and migration. Axl/Tyro3 double-knockout mice show a 24–34% loss of GnRH neurons in the hypothalamus, increased caspase-3 cleavage in the forebrain, delayed sexual maturation, and irregular estrous cycles.","method":"siRNA silencing in NLT GnRH cells, Axl/Tyro3 double-knockout mouse analysis, GnRH neuron counting/immunostaining, caspase-3 apoptosis assay","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — silencing + knockout mouse with cellular and in vivo phenotypic readout, single lab with multiple methods","pmids":["18787040"],"is_preprint":false},{"year":2009,"finding":"TYRO3 is an upstream regulator of MITF-M expression in melanoma cells, acting in a SOX10-dependent manner. Identified by genome-wide gain-of-function cDNA screen; TYRO3 overexpression bypasses BRAF(V600E)-induced senescence and transforms non-tumorigenic cells.","method":"Genome-wide gain-of-function cDNA screen, TYRO3 knockdown, SOX10 dependence assay, cellular transformation assay","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen + KD + OE with mechanistic pathway (SOX10) identified, single lab","pmids":["19805117"],"is_preprint":false},{"year":2010,"finding":"Protein S (PS) protects the blood-brain barrier from hypoxic/ischemic disruption via Tyro3-mediated signaling. Tyro3 is required for PS vasculoprotection: siRNA silencing of Tyro3, Tyro3-blocking antibodies, and Tyro3-deficient mouse endothelial cells all abolish PS protection. Tyro3 ligation by PS activates sphingosine 1-phosphate receptor 1 (S1P1), leading to Rac1-dependent BBB protection.","method":"RNA interference, receptor-blocking antibodies, Tyro3/Axl/Mer knockout mouse brain endothelial cells, Tyro3 phosphorylation assay, 2-photon in vivo imaging, S1P1 antagonist","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (RNAi, antibody, KO cells, in vivo KO mice, pharmacological inhibitor) establishing signaling axis","pmids":["20348395"],"is_preprint":false},{"year":2010,"finding":"Protein S (PS) protects neurons from NMDA excitotoxicity by activating the Tyro3-PI3K-Akt pathway via its C-terminal sex hormone-binding globulin-like (SHBG) domain. PS specifically requires Tyro3 (not Axl or Mer) to phosphorylate Akt, and downstream phosphorylation of Bad and Mdm2 increases Bcl-2/Bcl-XL and reduces p53/Bax. A kinase-deficient Akt mutant blocks PS-mediated protection.","method":"Tyro3/Axl/Mer knockout neurons, adenoviral kinase-dead Akt construct, PS structural analogs, in vivo NMDA excitotoxicity model in KO mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple KO lines + dominant-negative construct + structural domain analysis + in vivo model, single lab with multiple orthogonal methods","pmids":["21084607"],"is_preprint":false},{"year":2011,"finding":"Protein S protects neurons from tPA/NMDA injury via Tyro3-dependent Akt activation and Akt-mediated phosphorylation of FKHRL1 (Forkhead transcription factor), which suppresses Fas-ligand production and caspase-8 activation in the extrinsic apoptotic cascade. Axl and Mer do not mediate this effect.","method":"Tyro3/Axl/Mer knockout neurons, adenoviral kinase-dead Akt and FKHRL1 triple mutant constructs, caspase-8 activity assay, FasL detection","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — receptor-specific KO neurons + dominant-negative constructs + defined downstream signaling cascade, single lab, multiple orthogonal methods","pmids":["21291561"],"is_preprint":false},{"year":2011,"finding":"Hypothalamic GnRH neuron loss (not pituitary or ovarian defects) underlies the reproductive abnormalities in Axl/Tyro3 null mice. Axl/Tyro3 null mice have impaired steroid-induced LH surge but normal pituitary LH response to exogenous GnRH and normal ovarian histology.","method":"Axl/Tyro3 double-knockout mouse, ovariectomy + steroid priming, exogenous GnRH challenge, ovarian histology, folliculogenesis markers","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with tissue-specific phenotypic dissection, single lab, multiple physiological readouts","pmids":["21539887"],"is_preprint":false},{"year":2012,"finding":"Overexpression of Tyro3 in Rat2 cells promotes cell proliferation through the MAPK/ERK pathway but not PI3K; this is distinct from Axl which uses PI3K. Tyro3 overexpression enhances Gas6-mediated Axl phosphorylation in a kinase-dependent manner, and Axl overexpression induces kinase-dead Tyro3 phosphorylation (cross-phosphorylation). Co-immunoprecipitation confirms physical association of Axl and Tyro3.","method":"Overexpression of WT and kinase-dead Tyro3 in Rat2 cells, MAPK/PI3K pathway inhibitors, co-immunoprecipitation, cross-phosphorylation Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP + kinase-dead controls + pathway inhibitors, single lab with multiple orthogonal methods","pmids":["22606290"],"is_preprint":false},{"year":2013,"finding":"Gas6-stimulated TYRO3 in melanoma cells induces Akt phosphorylation but not ERK phosphorylation. Calcium is critical for correct Gas6 folding and its binding to TYRO3. Anti-TYRO3 monoclonal antibodies that partially block ligand binding (recognizing Ig domains) are the most effective at blocking downstream signaling.","method":"Soluble TYRO3 extracellular domain and Gas6 protein production for affinity measurement, shRNA knockdown, Gas6-induced phosphorylation in cell lines, calcium chelation experiment, monoclonal antibody characterization","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity measurements + cell-based phosphorylation assays + KD + antibody blocking, single lab","pmids":["23570341"],"is_preprint":false},{"year":2013,"finding":"Tyro3 is required for GAS6-induced synovial fibroblast proliferation and osteoclast differentiation. Tyro3-deficient mice have higher bone mass than WT, and in arthritis show less synovial hyperplasia, fewer osteoclasts, and reduced bone damage.","method":"Tyro3 knockout mice, collagen-induced arthritis model, in vitro osteoclastogenesis with human cells, GAS6 stimulation, histomorphometry","journal":"Annals of the rheumatic diseases","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout mouse + in vivo arthritis model + human cell functional assay, single lab, multiple readouts","pmids":["23632195"],"is_preprint":false},{"year":2014,"finding":"TYRO3, AXL, and MER show distinct patterns of activation by Gas6 and Protein S: each receptor has a unique ligand-activation profile, differentially affected by apoptotic cells, PS-containing vesicles, and enveloped virus. γ-carboxylation of ligands is essential for full TAM activation; soluble Ig-like TAM domains act as specific ligand antagonists.","method":"Reporter cell lines expressing chimeric TAM receptors, ligand activation assays with PS vesicles, apoptotic cells, warfarin (anti-γ-carboxylation), soluble TAM ectodomain competition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reconstituted reporter system + multiple ligand conditions + mutagenesis/warfarin, single lab with multiple orthogonal methods","pmids":["25074926"],"is_preprint":false},{"year":2015,"finding":"Tyro3 is required for Gas6-induced CNS myelination. In the absence of Tyro3 on oligodendrocytes, the pro-myelinating effect of Gas6 is lost, developmental myelination is delayed, and myelin is thinner. This effect may be mediated by activation of Erk1.","method":"Tyro3 knockout mice, Gas6 stimulation in vitro myelination assay, oligodendrocyte precursor cell analysis, Erk1 phosphorylation assay","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse + in vitro rescue assay + pathway identification (Erk1), single lab, multiple methods","pmids":["28145605"],"is_preprint":false},{"year":2015,"finding":"Tyro3 receptor interacts with the non-receptor cytoplasmic tyrosine kinase Fyn via its intracellular domain (identified by affinity chromatography). Fyn activity is downregulated in Tyro3-knockout mice. Loss of Tyro3 or Fyn impairs Schwann cell myelination and reduces myelin thickness in the peripheral nervous system.","method":"Tyro3 and Fyn knockout mice, affinity chromatography to identify Tyro3 binding partners, DRG neuronal culture myelination assay, kinase activity measurement","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — affinity chromatography identifying Fyn as binding partner + KO mouse phenotype + DRG culture assay, single lab","pmids":["26224309"],"is_preprint":false},{"year":2015,"finding":"TYRO3 protein is expressed in retinal pigment epithelium (RPE) and co-localizes with nascent photoreceptor outer segment (POS) phagosomes. Expression of Tyro3 in cultured cells stimulates phagocytic ingestion of POS. Loss of Tyro3 function accelerates photoreceptor degeneration in Mertk knockout mice.","method":"Tyro3 knockout mice crossed with Mertk knockout, RPE phagocytosis assay in cell culture, Tyro3 immunolocalization, retinal histology","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic double-KO modifier analysis + cell-based phagocytosis assay + co-localization, single lab","pmids":["26656104"],"is_preprint":false},{"year":2016,"finding":"TYRO3 genetic ablation in mice or functional neutralization of its human ortholog in dendritic cells results in enhanced type 2 immunity. The TYRO3 agonist PROS1 is induced in T cells by IL-4, and T cell-specific Pros1 knockout phenocopies loss of Tyro3, establishing a PROS1-mediated adaptive-to-innate feedback circuit through TYRO3 that limits type 2 responses.","method":"Tyro3 knockout mice, PROS1 T cell-specific knockout (Pros1-flox/T cell-Cre), DC functional neutralization, in vivo parasite/allergen challenge models","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO + conditional T cell-specific KO phenocopy + functional DC neutralization, multiple orthogonal approaches","pmids":["27034374"],"is_preprint":false},{"year":2016,"finding":"TYRO3 induces epithelial-mesenchymal transition (EMT) in colon cancer by regulating expression of SNAI1. Gain- and loss-of-function experiments show TYRO3 controls SNAI1 expression as the master EMT regulator; anti-TYRO3 human antibody treatment abolishes TYRO3-induced EMT.","method":"TYRO3 overexpression, siRNA knockdown, murine colon cancer model, SNAI1 expression analysis, anti-TYRO3 antibody treatment, xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain/loss-of-function + antibody + in vivo model with defined downstream pathway (SNAI1), single lab","pmids":["27132510"],"is_preprint":false},{"year":2017,"finding":"Gas6 activation of TYRO3 requires both γ-carboxylation (Gla domain) and phosphatidylserine (PS) binding; non-γ-carboxylated Gas6 and Gla/EGF-domain deletion mutants retain TAM binding but act as blocking decoys. The Gla and EGF-like domains function cooperatively for TAM activation. PS-positive apoptotic cells, stressed cells, and exosomes all serve as cell-derived Gas6-presenting platforms to activate TAMs.","method":"TAM/IFNγR1 reporter cell lines, warfarin treatment (blocks γ-carboxylation), domain deletion mutagenesis, PS vesicle/apoptotic cell/exosome assays","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted reporter system + mutagenesis + multiple PS sources, single lab with multiple orthogonal methods","pmids":["29176978"],"is_preprint":false},{"year":2017,"finding":"TYRO3-mediated phosphorylation of ACTN4 at tyrosines 11 and 13 requires FAK activation at Y397 and the EGF receptor cascade (but not EGFR ligand binding). This phosphorylation renders ACTN4 resistant to m-calpain cleavage between Y13-G14 and promotes invasive progression in melanoma cells.","method":"TYRO3 overexpression in fibroblasts, PCR-based site-directed mutagenesis of ACTN4, siRNA to TYRO3, FAK inhibition, m-calpain cleavage assay, actin-binding assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis mapping phosphosites + calpain cleavage assay + inhibitor studies, single lab","pmids":["29274473"],"is_preprint":false},{"year":2018,"finding":"In PGRN-deficient frontotemporal lobar degeneration (FTLD-TDP) model, reduced PGRN leads to disinhibition of Gas6 binding to Tyro3, which activates PKCα via PLCγ, inducing tau phosphorylation at Ser203, mislocalization of tau to dendritic spines, and spine loss. Knockdown of molecules in the Gas6-Tyro3-PKCα-tau axis rescues spine and cognitive deficits.","method":"PGRN-KI knock-in mouse, phosphoproteomic analysis, PKC inhibitor, B-Raf inhibitor, siRNA knockdown of Gas6/Tyro3/PLCγ/PKCα, dendritic spine imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphoproteomics + pharmacological inhibitors + genetic knockdown + in vivo rescue, multiple orthogonal methods","pmids":["29382817"],"is_preprint":false},{"year":2018,"finding":"TYRO3 in osteoblasts antagonizes MERTK/PROS1-induced inhibition of osteoblast differentiation. MERTK signaling via PROS1 activates the VAV2-RHOA-ROCK axis to increase cell contractility; TYRO3 counteracts this effect in osteoblasts. Osteoblast-targeted knockout of TYRO3 reduces bone mass.","method":"Osteoblast-specific conditional TYRO3 and MERTK knockout mice, signaling pathway analysis (VAV2/RHOA/ROCK), pharmacological MERTK inhibitor, bone mass measurement by micro-CT","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO + defined downstream pathway + pharmacological validation, single lab, multiple methods","pmids":["36509738"],"is_preprint":false},{"year":2018,"finding":"Axl and Tyro3 (but not Mertk) play important roles in platelet activation and thrombus formation. In Axl- and Tyro3-deficient platelets, GPVI agonist-induced Syk and PLCγ2 tyrosine phosphorylation is decreased; platelet aggregation, spreading, JON/A binding, and P-selectin expression are inhibited. This occurs in a Gas6-independent but TAM extracellular domain-dependent manner.","method":"Single TAM-receptor knockout mouse platelets, GPVI agonist stimulation, Syk/PLCγ2 phosphorylation assay, platelet aggregation/spreading assays, Gas6 neutralizing antibody, neutralizing anti-Axl/Tyro3 antibodies, laser-induced thrombosis model in vivo","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — single KO platelets + multiple functional assays + in vivo thrombosis + antibody/domain blocking, multiple orthogonal methods","pmids":["30541554"],"is_preprint":false},{"year":2019,"finding":"Protein S (ProS1) is a functional tumour-derived ligand for Tyro3 that preferentially activates Tyro3 (and downstream Erk) over Gas6 in SCC-25 and MGH-U3 cancer cells. In cells expressing Tyro3 alone (MGH-U3), ProS1 additionally activates Akt. ProS1 activation of Tyro3 protects cancer cells from apoptosis.","method":"Western blot for Tyro3 and downstream kinase (Erk, Akt) phosphorylation upon recombinant ProS1/Gas6, conditioned medium with ProS1 trap and warfarin specificity controls, apoptosis assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — phosphorylation assays with specificity controls + functional apoptosis assay, single lab","pmids":["31766614"],"is_preprint":false},{"year":2019,"finding":"In hepatocellular carcinoma, hepatitis-driven IL-6/STAT3 signaling transcriptionally activates TYRO3 expression, and hepatitis-associated apoptotic cells facilitate GAS6 presentation to further activate TYRO3. Activated TYRO3 then elicits intracellular SRC and STAT3 signaling, forming a 'TYRO3-STAT3-TYRO3' feed-forward loop.","method":"Loss-of-function screening (siRNA), TYRO3 silencing/inhibition, IL-6/STAT3 signaling analysis, GAS6 apoptotic cell presentation assay, xenograft mouse model","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional screen + KD + signaling pathway dissection + in vivo xenograft, single lab","pmids":["31831556"],"is_preprint":false},{"year":2019,"finding":"Tyro3 signaling in podocytes confers antiapoptotic effects through activation of AKT. Tyro3 expression is suppressed by the TNF-α/NF-κB pathway; genetic ablation of Tyro3 worsens glomerular injury in multiple nephropathy models, while podocyte-specific TYRO3 overexpression is protective.","method":"Tyro3 knockout mice in DKD/ADRN/HIVAN models, podocyte-specific TYRO3 transgenic overexpression, morpholino knockdown in zebrafish, AKT phosphorylation assay, TNF-α/NF-κB pathway analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse + transgenic overexpression + zebrafish knockdown + signaling assay, replicated across multiple disease models","pmids":["30429374"],"is_preprint":false},{"year":2020,"finding":"Galectin-3 (Gal-3) is a novel non-canonical agonist for TYRO3 receptor tyrosine kinase. Exogenous Gal-3 stimulates TYRO3 phosphorylation to the same extent as ProS1, activates Erk and Akt signaling, promotes cell survival against staurosporine-induced apoptosis, and stimulates cancer cell migration.","method":"TYRO3 phosphorylation Western blot upon Gal-3 vs. Gas6/ProS1, Erk/Akt activation assay, apoptosis assay, migration assay with Axl blocker","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct phosphorylation assay + functional assays, single lab, single publication","pmids":["32664510"],"is_preprint":false},{"year":2021,"finding":"TYRO3 inhibits tumor cell ferroptosis triggered by anti-PD-1/PD-L1 therapy and facilitates a pro-tumor microenvironment by reducing the M1/M2 macrophage ratio, causing resistance to immune checkpoint blockade. Inhibition of TYRO3 promotes ferroptosis and sensitizes resistant tumors to anti-PD-1 therapy.","method":"Syngeneic mouse tumor model, TYRO3 overexpression/inhibition, ferroptosis assays, macrophage polarization analysis","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — syngeneic in vivo model + mechanistic ferroptosis assays + macrophage polarization analysis, single lab","pmids":["33855973"],"is_preprint":false},{"year":2021,"finding":"Activated NK cells acquire TYRO3 from tumor cells via trogocytosis (cell-contact-dependent membrane transfer) in vitro and in vivo. NK cells that acquire TYRO3 (TYRO3+ NK cells) exhibit significantly enhanced cytotoxicity and IFNγ production compared to TYRO3- NK cells.","method":"Flow cytometry to detect TYRO3 transfer, in vitro co-culture and in vivo trogocytosis assays, functional cytotoxicity and cytokine assays with TYRO3+ vs TYRO3- NK cell sorting","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct in vitro/in vivo transfer measurement + sorted cell functional assay, single lab","pmids":["34326137"],"is_preprint":false},{"year":2021,"finding":"TYRO3 activation by circulating small extracellular vesicles (csEVs) through vesicle phosphatidylserine promotes cancer cell migration and metastasis via RhoA and epithelial-mesenchymal transition, and induces YAP activation leading to proliferation and chemoresistance.","method":"TYRO3 knockdown, csEV-TYRO3 interaction assays (phosphatidylserine blocking), RhoA/YAP activation Western blot, migration assay, xenograft tumor model with TYRO3 inhibitor KRCT-6j","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection (RhoA/YAP) + in vivo xenograft + selective inhibitor, single lab","pmids":["33910929"],"is_preprint":false},{"year":2023,"finding":"Nuclear TYRO3 promotes colorectal cancer metastasis through a mechanism requiring its kinase activity and MMP-2-mediated cleavage but independent of ligand binding. Nuclear TYRO3 phosphorylates BRD3 (bromodomain-containing protein 3, an acetyl-lysine reader), and phospho-BRD3 regulates genes involved in anti-apoptosis and EMT as revealed by ChIP-seq.","method":"Proteomic analysis of TYRO3 nuclear substrates, ChIP-seq for phospho-BRD3 regulated genes, MMP-2 inhibitor, BRD3 inhibitor, kinase-dead TYRO3 mutant, organoid culture, orthotopic mouse model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — proteomics identifying substrate + mutagenesis (kinase-dead) + ChIP-seq + selective inhibitors + in vivo model, single lab, multiple orthogonal methods","pmids":["37043564"],"is_preprint":false},{"year":1995,"finding":"TYRO3/Sky overexpressed at the cell surface or in the cytoplasm undergoes ligand-independent activation (dimerization and autophosphorylation). A cytoplasmic isoform (Sky Isoform I / Brt) resides naturally in the cytoplasm and retains kinase and transforming activity.","method":"Overexpression constructs in RatB1a fibroblasts, transformation assay (focus formation), tyrosine phosphorylation Western blot, subcellular localization analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — overexpression + functional transformation assay + localization, single lab","pmids":["8545119"],"is_preprint":false},{"year":1996,"finding":"Rek (chick ortholog of TYRO3/Axl family), when overexpressed in NIH3T3 fibroblasts, undergoes autophosphorylation and induces morphologically transformed foci, indicating oncogenic potential when overexpressed.","method":"COS cell transfection for expression, immune complex kinase autophosphorylation assay, NIH3T3 focus formation assay","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression system + focus formation assay for chick ortholog, single lab","pmids":["8910558"],"is_preprint":false},{"year":2005,"finding":"Sky/TYRO3 and Mer (but not Axl) on human platelets mediate Gas6-induced platelet aggregation and degranulation; blocking antibodies to Sky or Mer inhibit platelet aggregation by >80%. Sky-blocking antibody prevents thrombus formation in a mouse thrombosis model.","method":"Flow cytometry (receptor detection on platelets), anti-Gas6 and anti-receptor blocking antibodies, platelet aggregation assay, mouse thrombosis model","journal":"Journal of thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — receptor-blocking antibodies + functional platelet assay + in vivo model, single lab","pmids":["15733062"],"is_preprint":false},{"year":2019,"finding":"The Pros1/Tyro3 axis in gingival epithelial cells suppresses periodontitis-associated inflammatory cytokine production (TNF-α, IL-6, IL-1β, MMP9/2, RANKL) via the SOCS1/3 and STAT1/3 signaling pathway.","method":"siRNA knockdown of Tyro3, exogenous Pros1 treatment of LPS-stimulated human gingival epithelial cells, Western blot/ELISA/gelatin zymography, rat periodontitis model with Pros1 administration","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD + in vitro signaling assay + in vivo model, single lab","pmids":["30729671"],"is_preprint":false}],"current_model":"TYRO3 is a receptor tyrosine kinase activated primarily by Gas6 (via γ-carboxylated Gla domain + phosphatidylserine bridging) and protein S (via its SHBG domain), which triggers downstream PI3K-Akt, MAPK/ERK, and Src/STAT3 signaling cascades; its extracellular Ig domains can mediate ligand-independent homodimerization and heterodimerization with Axl for cross-phosphorylation; in specific cellular contexts it translocates to the nucleus where MMP-2-dependent cleavage enables kinase-dependent phosphorylation of epigenetic reader BRD3 to drive metastatic gene programs; and physiologically TYRO3 acts as a key regulator of apoptotic cell clearance (efferocytosis via phosphatidylserine recognition), innate immune dampening, myelination (via Fyn), spermatogenesis (Sertoli cell support), GnRH neuron survival/migration, retinal pigment epithelium phagocytosis, platelet activation, and blood-brain barrier integrity."},"narrative":{"mechanistic_narrative":"TYRO3 (Sky) is a TAM-family receptor tyrosine kinase that couples recognition of phosphatidylserine-displaying surfaces to survival, immune-regulatory, and developmental signaling [PMID:7559388, PMID:25074926]. It is activated by the vitamin-K-dependent ligands Gas6 and protein S, with full Gas6 activation requiring both Gla-domain γ-carboxylation and phosphatidylserine bridging via apoptotic cells, stressed cells, and exosomes, while non-carboxylated or Gla/EGF-deleted ligands act as blocking decoys [PMID:7559388, PMID:25074926, PMID:29176978]; protein S engages TYRO3 through its C-terminal SHBG-like domain [PMID:9210477, PMID:21084607], and galectin-3 acts as a non-canonical agonist [PMID:32664510]. Crystallography of its two N-terminal Ig domains defines a ligand-binding interface shared with Axl and shows ligand-independent homodimerization, and TYRO3 physically associates with Axl for cross-phosphorylation [PMID:14623883, PMID:22606290]. Ligand engagement recruits the p85 subunit of PI3K to drive Akt activation [PMID:10627473] and engages MAPK/ERK [PMID:17980494, PMID:22606290], with downstream Akt phosphorylating Bad, Mdm2, and FKHRL1 to suppress both intrinsic and Fas-ligand/caspase-8 extrinsic apoptosis in neurons [PMID:21084607, PMID:21291561]; it also binds and sustains the cytoplasmic kinase Fyn [PMID:26224309]. Physiologically TYRO3 supports Sertoli-cell-dependent spermatogenesis [PMID:10227296], NK-cell maturation [PMID:16751775], efferocytosis in dendritic cells [PMID:17442946], GnRH neuron survival and migration [PMID:18787040], CNS and peripheral myelination via ERK1 and Fyn [PMID:28145605, PMID:26224309], retinal pigment epithelium phagocytosis [PMID:26656104], platelet activation and thrombosis [PMID:30541554], podocyte survival [PMID:30429374], blood-brain barrier protection through an S1P1/Rac1 axis [PMID:20348395], and dampening of type-2 and inflammatory immunity via a PROS1 feedback circuit [PMID:27034374]. In cancer it promotes EMT through SNAI1 and RhoA/YAP, protects from ferroptosis to confer checkpoint-blockade resistance, and, after MMP-2-mediated cleavage, acts in the nucleus to phosphorylate the acetyl-lysine reader BRD3 and drive pro-metastatic gene programs [PMID:27132510, PMID:33855973, PMID:33910929, PMID:37043564]. TYRO3, Axl, and Mer additionally serve as entry factors for Ebola and Marburg filoviruses [PMID:17005688].","teleology":[{"year":1995,"claim":"Establishing the ligand and kinase output of an orphan receptor: Gas6 was identified as the activating ligand of Sky/TYRO3, defining it as a ligand-responsive tyrosine kinase.","evidence":"Soluble Sky-Fc binding and tyrosine phosphorylation in transfected CHO cells with competition controls","pmids":["7559388"],"confidence":"High","gaps":["Did not resolve protein S as an activating ligand","No downstream signaling pathway mapped"]},{"year":1995,"claim":"Showed TYRO3 has intrinsic oncogenic/transforming potential, including a naturally cytoplasmic isoform, when overexpressed.","evidence":"Overexpression and focus-formation transformation assays in RatB1a fibroblasts with localization analysis","pmids":["8545119"],"confidence":"Medium","gaps":["Transformation shown only on overexpression, physiological relevance unclear","Cytoplasmic isoform function in normal tissue not defined"]},{"year":1997,"claim":"Defined protein S as a second TYRO3 ligand and mapped the SHBG domain as the key receptor-engaging module, broadening the ligand repertoire.","evidence":"Protein S domain-swap chimeras with Sky phosphorylation readout","pmids":["9210477"],"confidence":"High","gaps":["Human protein S did not activate human Sky, leaving species/context dependence unresolved","Structural basis of SHBG-receptor contact not determined"]},{"year":1999,"claim":"Placed TYRO3 in a developmental context: combined TAM loss abolishes Sertoli-cell trophic support and spermatogenesis.","evidence":"Tyro3/Axl/Mer triple-knockout mice with seminiferous tubule histology and ligand expression mapping","pmids":["10227296"],"confidence":"High","gaps":["TYRO3-specific contribution not separated from Axl/Mer","Signaling cascade in Sertoli cells not defined"]},{"year":2000,"claim":"Identified the proximal survival/transformation signaling module: TYRO3 recruits and activates PI3K p85 to drive Akt.","evidence":"Yeast two-hybrid, GST pulldown, Co-IP, Akt Western blot, and wortmannin block of soft-agar colony formation","pmids":["10627473"],"confidence":"High","gaps":["Direct phosphosite mediating p85 recruitment not mapped","Cell-type generality not tested"]},{"year":2003,"claim":"Provided the structural basis for ligand binding and revealed ligand-independent homodimerization, implicating an adhesion-like role.","evidence":"1.95 Å crystal structure of the two N-terminal Ig domains plus solution dimerization analysis","pmids":["14623883"],"confidence":"High","gaps":["No co-structure with Gas6 or protein S","Functional consequence of homodimerization in cells not established"]},{"year":2006,"claim":"Extended TAM receptor function to host-pathogen biology and innate immune development.","evidence":"Ectopic TAM expression with filovirus pseudotype/live infection and blocking reagents (idx5); RDA, knockouts, and in vitro NK differentiation (idx6)","pmids":["17005688","16751775"],"confidence":"High","gaps":["TYRO3-specific versus shared TAM roles in viral entry not dissected","NK maturation signaling pathway downstream of TYRO3 not defined"]},{"year":2007,"claim":"Defined cell-type-specialized efferocytosis: TYRO3/Axl dominate apoptotic-cell clearance in dendritic cells and support Mer phosphorylation, indicating functional heterodimerization.","evidence":"Single/double TAM knockout mice with phagocytosis assays and Mertk phosphorylation blots","pmids":["17442946"],"confidence":"High","gaps":["Physical TYRO3-Mer/Axl interaction not directly shown here","Receptor recruitment to phagosome mechanism unclear"]},{"year":2008,"claim":"Localized TYRO3 to neurons and linked it to neuroendocrine development through GnRH neuron survival and migration.","evidence":"siRNA in NLT cells, Axl/Tyro3 double-knockout mouse neuron counts, caspase-3 assays, neuronal immunofluorescence and signaling (idx8, idx9)","pmids":["17980494","18787040"],"confidence":"High","gaps":["Axl and TYRO3 contributions not fully separated","Ligand source in vivo for GnRH neurons not defined"]},{"year":2010,"claim":"Established receptor-specific protein S neuroprotection and vascular protection, defining downstream Akt-Bad/Mdm2 and S1P1/Rac1 axes.","evidence":"TAM-specific knockout neurons/endothelium, kinase-dead Akt, S1P1 antagonist, in vivo NMDA and BBB models (idx11, idx12)","pmids":["20348395","21084607"],"confidence":"High","gaps":["Coupling of TYRO3 to S1P1 mechanistically unresolved","Human protein S relevance given earlier non-activation data unclear"]},{"year":2011,"claim":"Extended the survival cascade to extrinsic apoptosis and clarified that GnRH neuron loss, not pituitary/ovarian defects, drives the reproductive phenotype.","evidence":"TAM-specific knockout neurons with kinase-dead Akt/FKHRL1 mutants and caspase-8 assays (idx13); ovariectomy/GnRH-challenge dissection in double-KO mice (idx14)","pmids":["21291561","21539887"],"confidence":"High","gaps":["FKHRL1/FasL axis tested only in neurons","TYRO3-specific in vivo reproductive role not isolated from Axl"]},{"year":2012,"claim":"Distinguished TYRO3 signaling from Axl (ERK- vs PI3K-biased) and demonstrated physical Axl-TYRO3 association and cross-phosphorylation.","evidence":"WT/kinase-dead overexpression in Rat2 cells, pathway inhibitors, Co-IP, cross-phosphorylation blots","pmids":["22606290"],"confidence":"Medium","gaps":["Overexpression system may not reflect endogenous stoichiometry","Heterodimer interface not mapped"]},{"year":2013,"claim":"Connected TYRO3 to melanoma transformation via MITF-M/SOX10 and refined ligand-binding requirements and antibody-blockable signaling.","evidence":"Genome-wide gain-of-function cDNA screen, knockdown, SOX10 dependence (idx10); affinity/calcium and monoclonal antibody studies (idx16); arthritis KO and osteoclastogenesis (idx17)","pmids":["19805117","23570341","23632195"],"confidence":"Medium","gaps":["Direct transcriptional mechanism to MITF-M not resolved","Bone phenotypes mechanistically distinct from later osteoblast work need reconciliation"]},{"year":2014,"claim":"Quantified distinct ligand-activation profiles across TAM receptors and established γ-carboxylation and PS as gating requirements with soluble ectodomains as antagonists.","evidence":"Chimeric TAM reporter cell lines with PS vesicles, apoptotic cells, warfarin, and ectodomain competition","pmids":["25074926"],"confidence":"High","gaps":["Endogenous-context ligand preference not addressed","Structural basis of profile differences not resolved"]},{"year":2015,"claim":"Defined TYRO3's role in myelination through ERK1 and a direct Fyn interaction in CNS and PNS glia.","evidence":"Tyro3 KO mice, in vitro myelination/ERK1 assays (idx19); affinity chromatography identifying Fyn, Tyro3/Fyn KO DRG myelination (idx20)","pmids":["28145605","26224309"],"confidence":"High","gaps":["How Fyn binding links to ERK1 activation not integrated","Reciprocal validation of Fyn interaction limited"]},{"year":2015,"claim":"Demonstrated TYRO3-dependent RPE phagocytosis and that TYRO3 loss accelerates Mertk-deficient photoreceptor degeneration, establishing functional redundancy in retinal clearance.","evidence":"Tyro3/Mertk double-knockout mice, RPE phagocytosis assay, immunolocalization, retinal histology","pmids":["26656104"],"confidence":"High","gaps":["Signaling downstream of TYRO3 in RPE not defined","TYRO3 ligand presenting POS not identified"]},{"year":2016,"claim":"Revealed an adaptive-to-innate immune feedback circuit in which T-cell PROS1 acts through TYRO3 to restrain type-2 immunity, and a SNAI1-driven EMT role in colon cancer.","evidence":"Tyro3 KO and T-cell-specific Pros1 KO with allergen/parasite challenge (idx22); gain/loss-of-function and anti-TYRO3 antibody in colon cancer models (idx23)","pmids":["27034374","27132510"],"confidence":"High","gaps":["Intracellular immunosuppressive signaling from TYRO3 in DCs not fully mapped","SNAI1 regulation mechanism (transcriptional vs post-translational) unresolved"]},{"year":2017,"claim":"Resolved the molecular requirements of Gas6 activation (cooperative Gla/EGF + PS) and identified a cytoskeletal substrate axis (ACTN4) promoting invasion.","evidence":"TAM reporter cells with warfarin/domain deletions/PS sources (idx24); ACTN4 phosphosite mapping and calpain cleavage assays (idx25)","pmids":["29176978","29274473"],"confidence":"High","gaps":["Whether ACTN4 is a direct TYRO3 substrate not definitively shown","FAK/EGFR-cascade ordering relative to TYRO3 incomplete"]},{"year":2018,"claim":"Linked TYRO3 to neurodegeneration (Gas6-TYRO3-PKCα-tau) and to bone homeostasis where it antagonizes MERTK/PROS1-driven contractility in osteoblasts.","evidence":"PGRN knock-in mice, phosphoproteomics, inhibitors, knockdown with spine/cognitive rescue (idx26); osteoblast-specific conditional KO with VAV2/RHOA/ROCK analysis (idx27)","pmids":["29382817","36509738"],"confidence":"High","gaps":["PLCγ/PKCα coupling to TYRO3 kinase output not structurally defined","Reconciliation of opposing TYRO3 bone effects across studies needed"]},{"year":2019,"claim":"Defined protein S as a tumour-derived TYRO3-preferential ligand and elaborated TYRO3 survival roles in podocytes, hepatocellular carcinoma feed-forward loops, and epithelial inflammation control.","evidence":"Phosphorylation/apoptosis assays with ProS1 traps (idx29); podocyte KO/transgenic/zebrafish AKT studies (idx31); IL-6/STAT3 HCC screen and xenografts (idx30); gingival epithelial siRNA/SOCS-STAT studies (idx40)","pmids":["31766614","30429374","31831556","30729671"],"confidence":"Medium","gaps":["Ligand preference results from single-lab phosphorylation assays","TNF-α/NF-κB and STAT3 regulatory loops not validated across systems"]},{"year":2020,"claim":"Expanded the ligand repertoire with galectin-3 as a non-canonical TYRO3 agonist driving survival and migration.","evidence":"TYRO3 phosphorylation and ERK/Akt activation by Gal-3 versus Gas6/ProS1, plus apoptosis and migration assays","pmids":["32664510"],"confidence":"Medium","gaps":["Direct Gal-3-TYRO3 binding not demonstrated","Single lab, single publication"]},{"year":2021,"claim":"Positioned TYRO3 as a driver of immunotherapy resistance and metastasis via ferroptosis inhibition, macrophage repolarization, and EV-PS-driven RhoA/YAP signaling, with NK trogocytosis as a novel transfer route.","evidence":"Syngeneic tumor ferroptosis/macrophage analyses (idx33); csEV-PS RhoA/YAP studies with inhibitor (idx35); flow-based trogocytosis and sorted NK functional assays (idx34)","pmids":["33855973","33910929","34326137"],"confidence":"Medium","gaps":["Mechanism linking TYRO3 to ferroptosis suppression not molecularly defined","Trogocytosis functional gain mechanism unresolved"]},{"year":2023,"claim":"Uncovered a non-canonical nuclear function: MMP-2-cleaved TYRO3 phosphorylates BRD3 to reprogram anti-apoptotic/EMT gene expression in colorectal cancer metastasis, independent of ligand binding.","evidence":"Nuclear substrate proteomics, phospho-BRD3 ChIP-seq, kinase-dead mutant, MMP-2/BRD3 inhibitors, organoid and orthotopic models","pmids":["37043564"],"confidence":"High","gaps":["Trigger for nuclear translocation/cleavage in vivo not defined","Generality beyond colorectal cancer untested"]},{"year":null,"claim":"How TYRO3's distinct ligands, homo/heterodimerization, and cleavage states are integrated to select among its many survival, immune, developmental, and nuclear-transcriptional outputs in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of ligand-specific receptor activation","Determinants of cytoplasmic versus nuclear TYRO3 signaling unknown","Endogenous receptor stoichiometry with Axl/Mer in physiological tissues undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,15,25,36]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,18,24]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[5]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[24,35]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,21,28]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[37,3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[36]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,7,22]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,13,31,33]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,9,19,20]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[28,39]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,23,36]}],"complexes":[],"partners":["GAS6","PROS1","AXL","MERTK","PIK3R1","FYN","BRD3","LGALS3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q06418","full_name":"Tyrosine-protein kinase receptor TYRO3","aliases":["Tyrosine-protein kinase BYK","Tyrosine-protein kinase DTK","Tyrosine-protein kinase RSE","Tyrosine-protein kinase SKY","Tyrosine-protein kinase TIF"],"length_aa":890,"mass_kda":96.9,"function":"Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including TULP1 or GAS6. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of TYRO3 on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with PIK3R1 and thereby enhances PI3-kinase activity. Activates the AKT survival pathway, including nuclear translocation of NF-kappa-B and up-regulation of transcription of NF-kappa-B-regulated genes. TYRO3 signaling plays a role in various processes such as neuron protection from excitotoxic injury, platelet aggregation and cytoskeleton reorganization. Also plays an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3 (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","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q06418/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TYRO3","classification":"Not Classified","n_dependent_lines":90,"n_total_lines":1208,"dependency_fraction":0.07450331125827815},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TYRO3","total_profiled":1310},"omim":[{"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"},{"mim_id":"600441","title":"GROWTH ARREST-SPECIFIC 6; GAS6","url":"https://www.omim.org/entry/600441"},{"mim_id":"600341","title":"TYRO3 PROTEIN TYROSINE KINASE; TYRO3","url":"https://www.omim.org/entry/600341"},{"mim_id":"151520","title":"LEUKOCYTE TYROSINE KINASE; LTK","url":"https://www.omim.org/entry/151520"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":37.9},{"tissue":"ovary","ntpm":44.4}],"url":"https://www.proteinatlas.org/search/TYRO3"},"hgnc":{"alias_symbol":["Dtk","Brt","Tif","Sky","Etk-2","Rek"],"prev_symbol":["RSE"]},"alphafold":{"accession":"Q06418","domains":[{"cath_id":"2.60.40.10","chopping":"45-137","consensus_level":"high","plddt":80.1665,"start":45,"end":137},{"cath_id":"2.60.40.10","chopping":"141-222","consensus_level":"medium","plddt":91.1345,"start":141,"end":222},{"cath_id":"2.60.40.10","chopping":"230-317","consensus_level":"medium","plddt":90.7492,"start":230,"end":317},{"cath_id":"2.60.40.10","chopping":"342-412","consensus_level":"high","plddt":82.95,"start":342,"end":412},{"cath_id":"3.30.200.20","chopping":"499-605","consensus_level":"high","plddt":81.9368,"start":499,"end":605},{"cath_id":"1.10.510.10","chopping":"611-798","consensus_level":"high","plddt":84.2993,"start":611,"end":798}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06418","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q06418-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q06418-F1-predicted_aligned_error_v6.png","plddt_mean":74.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TYRO3","jax_strain_url":"https://www.jax.org/strain/search?query=TYRO3"},"sequence":{"accession":"Q06418","fasta_url":"https://rest.uniprot.org/uniprotkb/Q06418.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q06418/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06418"}},"corpus_meta":[{"pmid":"10227296","id":"PMC_10227296","title":"Tyro-3 family receptors are essential regulators of mammalian spermatogenesis.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10227296","citation_count":426,"is_preprint":false},{"pmid":"10657629","id":"PMC_10657629","title":"Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10657629","citation_count":399,"is_preprint":false},{"pmid":"15004009","id":"PMC_15004009","title":"mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability.","date":"2004","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/15004009","citation_count":385,"is_preprint":false},{"pmid":"31088471","id":"PMC_31088471","title":"Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment.","date":"2019","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31088471","citation_count":365,"is_preprint":false},{"pmid":"17442946","id":"PMC_17442946","title":"Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17442946","citation_count":337,"is_preprint":false},{"pmid":"33855973","id":"PMC_33855973","title":"TYRO3 induces anti-PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/33855973","citation_count":285,"is_preprint":false},{"pmid":"17005688","id":"PMC_17005688","title":"Tyro3 family-mediated cell entry of Ebola and Marburg viruses.","date":"2006","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/17005688","citation_count":237,"is_preprint":false},{"pmid":"1107802","id":"PMC_1107802","title":"Prophage induction and cell division in E. coli. III. Mutations sfiA and sfiB restore division in tif and lon strains and permit the expression of mutator properties of tif.","date":"1975","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/1107802","citation_count":227,"is_preprint":false},{"pmid":"25074926","id":"PMC_25074926","title":"Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25074926","citation_count":198,"is_preprint":false},{"pmid":"341152","id":"PMC_341152","title":"Identification of the recA (tif) gene product of Escherichia coli.","date":"1977","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/341152","citation_count":184,"is_preprint":false},{"pmid":"11197690","id":"PMC_11197690","title":"IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes.","date":"2000","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/11197690","citation_count":175,"is_preprint":false},{"pmid":"11463850","id":"PMC_11463850","title":"Tracking the role of a star in the sky of the new millennium.","date":"2001","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/11463850","citation_count":148,"is_preprint":false},{"pmid":"21047970","id":"PMC_21047970","title":"The Tyro3 receptor kinase Axl enhances macropinocytosis of Zaire ebolavirus.","date":"2010","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21047970","citation_count":132,"is_preprint":false},{"pmid":"8108112","id":"PMC_8108112","title":"Cloning of the cDNA for a novel receptor tyrosine kinase, Sky, predominantly expressed in brain.","date":"1994","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8108112","citation_count":126,"is_preprint":false},{"pmid":"16759865","id":"PMC_16759865","title":"Regulation of Streptomyces development: reach for the sky!","date":"2006","source":"Trends in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16759865","citation_count":119,"is_preprint":false},{"pmid":"16751775","id":"PMC_16751775","title":"Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases.","date":"2006","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16751775","citation_count":113,"is_preprint":false},{"pmid":"10954847","id":"PMC_10954847","title":"Expression of the receptor protein-tyrosine kinases Tyro-3, Axl, and mer in the developing rat central nervous system.","date":"2000","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10954847","citation_count":103,"is_preprint":false},{"pmid":"7559388","id":"PMC_7559388","title":"Stimulation of sky receptor tyrosine kinase by the product of growth arrest-specific gene 6.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7559388","citation_count":100,"is_preprint":false},{"pmid":"9878891","id":"PMC_9878891","title":"Gas6, a ligand for the receptor protein-tyrosine kinase Tyro-3, is widely expressed in the central nervous system.","date":"1999","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9878891","citation_count":98,"is_preprint":false},{"pmid":"20348395","id":"PMC_20348395","title":"Protein S controls hypoxic/ischemic blood-brain barrier disruption through the TAM receptor Tyro3 and sphingosine 1-phosphate receptor.","date":"2010","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20348395","citation_count":95,"is_preprint":false},{"pmid":"15733062","id":"PMC_15733062","title":"Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses.","date":"2005","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/15733062","citation_count":93,"is_preprint":false},{"pmid":"25422373","id":"PMC_25422373","title":"Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration.","date":"2014","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25422373","citation_count":81,"is_preprint":false},{"pmid":"18086911","id":"PMC_18086911","title":"Drosophila TIF-IA is required for ribosome synthesis and cell growth and is regulated by the TOR pathway.","date":"2007","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18086911","citation_count":81,"is_preprint":false},{"pmid":"21343401","id":"PMC_21343401","title":"Activation of TYRO3/AXL tyrosine kinase receptors in thyroid cancer.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21343401","citation_count":79,"is_preprint":false},{"pmid":"25544427","id":"PMC_25544427","title":"Inhibition of IL-6/STAT3 axis and targeting Axl and Tyro3 receptor tyrosine kinases by apigenin circumvent taxol resistance in ovarian cancer cells.","date":"2014","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25544427","citation_count":79,"is_preprint":false},{"pmid":"27034374","id":"PMC_27034374","title":"The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity.","date":"2016","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27034374","citation_count":75,"is_preprint":false},{"pmid":"8108111","id":"PMC_8108111","title":"brt, a mouse gene encoding a novel receptor-type protein-tyrosine kinase, is preferentially expressed in the brain.","date":"1994","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8108111","citation_count":73,"is_preprint":false},{"pmid":"19805117","id":"PMC_19805117","title":"A genomic screen identifies TYRO3 as a MITF regulator in melanoma.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19805117","citation_count":73,"is_preprint":false},{"pmid":"29176978","id":"PMC_29176978","title":"Requirement of Gamma-Carboxyglutamic Acid Modification and Phosphatidylserine Binding for the Activation of Tyro3, Axl, and Mertk Receptors by Growth Arrest-Specific 6.","date":"2017","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29176978","citation_count":73,"is_preprint":false},{"pmid":"30501104","id":"PMC_30501104","title":"The Emerging Role of TYRO3 as a Therapeutic Target in Cancer.","date":"2018","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/30501104","citation_count":70,"is_preprint":false},{"pmid":"23203851","id":"PMC_23203851","title":"Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis.","date":"2013","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/23203851","citation_count":67,"is_preprint":false},{"pmid":"18787040","id":"PMC_18787040","title":"Axl and Tyro3 modulate female reproduction by influencing gonadotropin-releasing hormone neuron survival and migration.","date":"2008","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/18787040","citation_count":66,"is_preprint":false},{"pmid":"24297901","id":"PMC_24297901","title":"Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24297901","citation_count":66,"is_preprint":false},{"pmid":"30690089","id":"PMC_30690089","title":"Unravelling the cellular and molecular pathogenesis of bovine babesiosis: is the sky the limit?","date":"2019","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/30690089","citation_count":65,"is_preprint":false},{"pmid":"8108143","id":"PMC_8108143","title":"Molecular cloning of a novel receptor tyrosine kinase, tif, highly expressed in human ovary and testis.","date":"1994","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8108143","citation_count":64,"is_preprint":false},{"pmid":"14623883","id":"PMC_14623883","title":"Ligand recognition and homophilic interactions in Tyro3: structural insights into the Axl/Tyro3 receptor tyrosine kinase family.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14623883","citation_count":63,"is_preprint":false},{"pmid":"27132510","id":"PMC_27132510","title":"Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27132510","citation_count":61,"is_preprint":false},{"pmid":"26656104","id":"PMC_26656104","title":"Tyro3 Modulates Mertk-Associated Retinal Degeneration.","date":"2015","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26656104","citation_count":58,"is_preprint":false},{"pmid":"17980494","id":"PMC_17980494","title":"Localization and signaling of the receptor protein tyrosine kinase Tyro3 in cortical and hippocampal neurons.","date":"2007","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17980494","citation_count":56,"is_preprint":false},{"pmid":"21084607","id":"PMC_21084607","title":"Protein S protects neurons from excitotoxic injury by activating the TAM receptor Tyro3-phosphatidylinositol 3-kinase-Akt pathway through its sex hormone-binding globulin-like region.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21084607","citation_count":52,"is_preprint":false},{"pmid":"7031642","id":"PMC_7031642","title":"tif-1 mutation alters polynucleotide recognition by the recA protein of Escherichia coli.","date":"1981","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7031642","citation_count":47,"is_preprint":false},{"pmid":"10627473","id":"PMC_10627473","title":"Transforming activity of receptor tyrosine kinase tyro3 is mediated, at least in part, by the PI3 kinase-signaling pathway.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10627473","citation_count":46,"is_preprint":false},{"pmid":"22606290","id":"PMC_22606290","title":"Cross-phosphorylation, signaling and proliferative functions of the Tyro3 and Axl receptors in Rat2 cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22606290","citation_count":44,"is_preprint":false},{"pmid":"14518030","id":"PMC_14518030","title":"Spectral karyotype (SKY) analysis of human prostate carcinoma cell lines.","date":"2003","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/14518030","citation_count":42,"is_preprint":false},{"pmid":"23570341","id":"PMC_23570341","title":"Evaluation of Tyro3 expression, Gas6-mediated Akt phosphorylation, and the impact of anti-Tyro3 antibodies in melanoma cell lines.","date":"2013","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23570341","citation_count":41,"is_preprint":false},{"pmid":"9210477","id":"PMC_9210477","title":"Stimulation of Sky tyrosine phosphorylation by bovine protein S--domains involved in the receptor-ligand interaction.","date":"1997","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9210477","citation_count":40,"is_preprint":false},{"pmid":"8545119","id":"PMC_8545119","title":"Overexpression of the Sky receptor tyrosine kinase at the cell surface or in the cytoplasm results in ligand-independent activation.","date":"1995","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8545119","citation_count":40,"is_preprint":false},{"pmid":"24846720","id":"PMC_24846720","title":"Tyro3, Axl, and Mertk receptor signaling in inflammatory bowel disease and colitis-associated cancer.","date":"2014","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24846720","citation_count":37,"is_preprint":false},{"pmid":"21948110","id":"PMC_21948110","title":"Chromosome analysis using spectral karyotyping (SKY).","date":"2012","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/21948110","citation_count":37,"is_preprint":false},{"pmid":"25975389","id":"PMC_25975389","title":"Metformin targets Axl and Tyro3 receptor tyrosine kinases to inhibit cell proliferation and overcome chemoresistance in ovarian cancer cells.","date":"2015","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25975389","citation_count":37,"is_preprint":false},{"pmid":"22701746","id":"PMC_22701746","title":"Involvement of receptor tyrosine kinase Tyro3 in amyloidogenic APP processing and β-amyloid deposition in Alzheimer's disease models.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22701746","citation_count":36,"is_preprint":false},{"pmid":"29024938","id":"PMC_29024938","title":"Expression and role of TYRO3 and AXL as potential therapeutical targets in leiomyosarcoma.","date":"2017","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29024938","citation_count":35,"is_preprint":false},{"pmid":"27500188","id":"PMC_27500188","title":"Telomere Dysfunction Induced Foci (TIF) Analysis.","date":"2015","source":"Bio-protocol","url":"https://pubmed.ncbi.nlm.nih.gov/27500188","citation_count":33,"is_preprint":false},{"pmid":"8641360","id":"PMC_8641360","title":"The Dtk receptor tyrosine kinase, which binds protein S, is expressed during hematopoiesis.","date":"1996","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/8641360","citation_count":32,"is_preprint":false},{"pmid":"28145605","id":"PMC_28145605","title":"The TAM receptor Tyro3 regulates myelination in the central nervous system.","date":"2017","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/28145605","citation_count":32,"is_preprint":false},{"pmid":"23632195","id":"PMC_23632195","title":"Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone damage in arthritis.","date":"2013","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23632195","citation_count":31,"is_preprint":false},{"pmid":"8910558","id":"PMC_8910558","title":"Rek, a gene expressed in retina and brain, encodes a receptor tyrosine kinase of the Axl/Tyro3 family.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8910558","citation_count":31,"is_preprint":false},{"pmid":"36509738","id":"PMC_36509738","title":"Regulation of bone homeostasis by MERTK and TYRO3.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36509738","citation_count":30,"is_preprint":false},{"pmid":"7857657","id":"PMC_7857657","title":"Isolation of a receptor tyrosine kinase (DTK) from embryonic stem cells: structure, genetic mapping and analysis of expression.","date":"1994","source":"Growth factors (Chur, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/7857657","citation_count":30,"is_preprint":false},{"pmid":"27486820","id":"PMC_27486820","title":"TAM receptors Tyro3 and Mer as novel targets in colorectal cancer.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27486820","citation_count":30,"is_preprint":false},{"pmid":"26224309","id":"PMC_26224309","title":"Involvement of the Tyro3 receptor and its intracellular partner Fyn signaling in Schwann cell myelination.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/26224309","citation_count":29,"is_preprint":false},{"pmid":"32051695","id":"PMC_32051695","title":"New Insights into the Role of Tyro3, Axl, and Mer Receptors in Rheumatoid Arthritis.","date":"2020","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/32051695","citation_count":29,"is_preprint":false},{"pmid":"26573872","id":"PMC_26573872","title":"Overexpression of Tyro3 and its implications on hepatocellular carcinoma progression.","date":"2015","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26573872","citation_count":29,"is_preprint":false},{"pmid":"31766614","id":"PMC_31766614","title":"Tumour-Secreted Protein S (ProS1) Activates a Tyro3-Erk Signalling Axis and Protects Cancer Cells from Apoptosis.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31766614","citation_count":29,"is_preprint":false},{"pmid":"21291561","id":"PMC_21291561","title":"Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signaling pathway.","date":"2011","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/21291561","citation_count":29,"is_preprint":false},{"pmid":"34326137","id":"PMC_34326137","title":"Hijacking TYRO3 from Tumor Cells via Trogocytosis Enhances NK-cell Effector Functions and Proliferation.","date":"2021","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/34326137","citation_count":28,"is_preprint":false},{"pmid":"24982338","id":"PMC_24982338","title":"TYRO3 as a potential therapeutic target in breast cancer.","date":"2014","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24982338","citation_count":27,"is_preprint":false},{"pmid":"29382817","id":"PMC_29382817","title":"Targeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29382817","citation_count":27,"is_preprint":false},{"pmid":"30765874","id":"PMC_30765874","title":"TYRO3 as a molecular target for growth inhibition and apoptosis induction in bladder cancer.","date":"2019","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30765874","citation_count":26,"is_preprint":false},{"pmid":"32908453","id":"PMC_32908453","title":"circRAE1 promotes colorectal cancer cell migration and invasion by modulating miR-338-3p/TYRO3 axis.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32908453","citation_count":26,"is_preprint":false},{"pmid":"7723626","id":"PMC_7723626","title":"Isolation and expression analysis of tyro3, a murine growth factor receptor tyrosine kinase preferentially expressed in adult brain.","date":"1995","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/7723626","citation_count":26,"is_preprint":false},{"pmid":"10391562","id":"PMC_10391562","title":"Synthesis and secretion of the anticoagulant protein S and coexpression of the Tyro3 receptor in human lung carcinoma cells.","date":"1999","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10391562","citation_count":26,"is_preprint":false},{"pmid":"30429374","id":"PMC_30429374","title":"Tyro3 is a podocyte protective factor in glomerular disease.","date":"2018","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/30429374","citation_count":25,"is_preprint":false},{"pmid":"30335822","id":"PMC_30335822","title":"Tyro3/Axl/Mertk-deficient mice develop bone marrow edema which is an early pathological marker in rheumatoid arthritis.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30335822","citation_count":25,"is_preprint":false},{"pmid":"34074493","id":"PMC_34074493","title":"Tyro3, Axl, Mertk receptor-mediated efferocytosis and immune regulation in the tumor environment.","date":"2021","source":"International review of cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34074493","citation_count":24,"is_preprint":false},{"pmid":"8262388","id":"PMC_8262388","title":"The human TYRO3 gene and pseudogene are located in chromosome 15q14-q25.","date":"1993","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8262388","citation_count":24,"is_preprint":false},{"pmid":"25815442","id":"PMC_25815442","title":"Overexpression of Tyro3 receptor tyrosine kinase leads to the acquisition of taxol resistance in ovarian cancer cells.","date":"2015","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/25815442","citation_count":24,"is_preprint":false},{"pmid":"29873780","id":"PMC_29873780","title":"Identification of a novel TIF-IA-NF-κB nucleolar stress response pathway.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29873780","citation_count":23,"is_preprint":false},{"pmid":"27641688","id":"PMC_27641688","title":"TIF-IA: An oncogenic target of pre-ribosomal RNA synthesis.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/27641688","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":"30226533","id":"PMC_30226533","title":"MicroRNA-7 inhibits colorectal cancer cell proliferation, migration and invasion via TYRO3 and phosphoinositide 3-kinase/protein B kinase/mammalian target of rapamycin pathway suppression.","date":"2018","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30226533","citation_count":22,"is_preprint":false},{"pmid":"30714403","id":"PMC_30714403","title":"TYRO3: A potential therapeutic target in cancer.","date":"2019","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/30714403","citation_count":21,"is_preprint":false},{"pmid":"37043564","id":"PMC_37043564","title":"Targeting BRD3 eradicates nuclear TYRO3-induced colorectal cancer metastasis.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37043564","citation_count":20,"is_preprint":false},{"pmid":"30729671","id":"PMC_30729671","title":"The Pros1/Tyro3 axis protects against periodontitis by modulating STAT/SOCS signalling.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30729671","citation_count":20,"is_preprint":false},{"pmid":"21461816","id":"PMC_21461816","title":"CO-FISH, COD-FISH, ReD-FISH, SKY-FISH.","date":"2011","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/21461816","citation_count":20,"is_preprint":false},{"pmid":"11528112","id":"PMC_11528112","title":"The combination of SKY and specific loci detection with FISH or immunostaining.","date":"2001","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11528112","citation_count":20,"is_preprint":false},{"pmid":"32664510","id":"PMC_32664510","title":"Galectin-3 Stimulates Tyro3 Receptor Tyrosine Kinase and Erk Signalling, Cell Survival and Migration in Human Cancer Cells.","date":"2020","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/32664510","citation_count":20,"is_preprint":false},{"pmid":"30208252","id":"PMC_30208252","title":"The TAM receptor TYRO3 is a critical regulator of myelin thickness in the central nervous system.","date":"2018","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/30208252","citation_count":20,"is_preprint":false},{"pmid":"35407533","id":"PMC_35407533","title":"Clinical Characteristics of Anti-TIF-1γ Antibody-Positive Dermatomyositis Associated with Malignancy.","date":"2022","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35407533","citation_count":19,"is_preprint":false},{"pmid":"21539887","id":"PMC_21539887","title":"Hypothalamic but not pituitary or ovarian defects underlie the reproductive abnormalities in Axl/Tyro3 null mice.","date":"2011","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21539887","citation_count":19,"is_preprint":false},{"pmid":"16365397","id":"PMC_16365397","title":"Heterogeneous nuclear ribonucleoprotein P2 is an autoantibody target in mice deficient for Mer, Axl, and Tyro3 receptor tyrosine kinases.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16365397","citation_count":19,"is_preprint":false},{"pmid":"33910929","id":"PMC_33910929","title":"Circulating Small Extracellular Vesicles Activate TYRO3 to Drive Cancer Metastasis and Chemoresistance.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33910929","citation_count":18,"is_preprint":false},{"pmid":"19027714","id":"PMC_19027714","title":"NGF-induced Tyro3 and Axl function as survival factors for differentiating PC12 cells.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19027714","citation_count":18,"is_preprint":false},{"pmid":"7784069","id":"PMC_7784069","title":"Identification of alternative exons, including a novel exon, in the tyrosine kinase receptor gene Etk2/tyro3 that explain differences in 5' cDNA sequences.","date":"1995","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/7784069","citation_count":18,"is_preprint":false},{"pmid":"29274473","id":"PMC_29274473","title":"Tyro3-mediated phosphorylation of ACTN4 at tyrosines is FAK-dependent and decreases susceptibility to cleavage by m-Calpain.","date":"2017","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29274473","citation_count":17,"is_preprint":false},{"pmid":"30249810","id":"PMC_30249810","title":"Augmentation of Human Monocyte Responses to Lipopolysaccharide by the Protein S and Mer/Tyro3 Receptor Tyrosine Kinase Axis.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/30249810","citation_count":17,"is_preprint":false},{"pmid":"6445897","id":"PMC_6445897","title":"Dissociation of tsl-tif-induced filamentation and recA protein synthesis in Escherichia coli K-12.","date":"1980","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/6445897","citation_count":17,"is_preprint":false},{"pmid":"31346082","id":"PMC_31346082","title":"Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31346082","citation_count":17,"is_preprint":false},{"pmid":"31831556","id":"PMC_31831556","title":"Functional Genomics Identifies Hepatitis-Induced STAT3-TYRO3-STAT3 Signaling as a Potential Therapeutic Target of Hepatoma.","date":"2019","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/31831556","citation_count":16,"is_preprint":false},{"pmid":"37537628","id":"PMC_37537628","title":"Receptor tyrosine kinases Tyro3, Axl, and Mertk differentially contribute to antibody-induced arthritis.","date":"2023","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/37537628","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49846,"output_tokens":10586,"usd":0.154164,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21294,"output_tokens":7184,"usd":0.143035,"stage2_stop_reason":"end_turn"},"total_usd":0.297199,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Gas6 (growth arrest-specific gene 6 product) is a ligand for the Sky/TYRO3 receptor tyrosine kinase. Gas6, but not protein S, specifically binds to the soluble extracellular domain of Sky (Sky-Fc) and stimulates tyrosine phosphorylation of Sky in CHO cells with half-maximal activation at ~1 nM.\",\n      \"method\": \"Ligand-binding assay with soluble Sky-Fc fusion protein, tyrosine phosphorylation assay in transfected CHO cells, competition inhibition with Sky-Fc\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro binding and kinase activation assay with multiple orthogonal methods (pulldown, phosphorylation, competition); independently replicated by other labs\",\n      \"pmids\": [\"7559388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Bovine protein S activates human Sky/TYRO3 receptor tyrosine kinase, and the SHBG-like (sex hormone-binding globulin) C-terminal region of protein S is essential for receptor interaction, while N-terminal Gla domain contributes to binding affinity. Human protein S does not activate human Sky.\",\n      \"method\": \"Chimeric protein S domain-swap constructs, Sky phosphorylation assay, C4b-binding protein competition inhibition\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain mutagenesis/chimera approach with kinase phosphorylation readout, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9210477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Triple knockout of Tyro3, Axl, and Mer in mice causes progressive death of differentiating germ cells and complete absence of mature sperm, due to failure of Sertoli cell trophic support. Tyro3, Axl, and Mer are expressed by Sertoli cells; their ligands Gas6 and protein S are produced by Leydig cells and later by both Leydig and Sertoli cells.\",\n      \"method\": \"Triple receptor knockout mouse model (loss-of-function genetics), histological analysis of seminiferous tubules, expression analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — triple-knockout genetic epistasis with defined cellular phenotype, independently recognized as foundational study\",\n      \"pmids\": [\"10227296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The p85 subunit of PI3-kinase interacts with the cytoplasmic domain of TYRO3, is recruited and phosphorylated upon TYRO3 activation, and TYRO3-associated PI3K exhibits enhanced kinase activity. Downstream Akt phosphorylation is increased upon TYRO3 activation, and TYRO3-mediated cellular transformation is blocked by the PI3K inhibitor wortmannin.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, Western blot for Akt phosphorylation, wortmannin inhibition in soft agar colony assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast 2-hybrid + GST pulldown + Co-IP + functional inhibitor assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"10627473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of the two N-terminal Ig domains of human TYRO3 at 1.95 Å resolution reveals a ligand-binding site at the Ig domain interface, unusually rich in cis-prolines, shared with Axl. The receptor fragment undergoes ligand-independent homodimerization both in crystal and in solution, suggesting a role in cell adhesion.\",\n      \"method\": \"X-ray crystallography (1.95 Å), solution dimerization analysis, biochemical ligand-binding specificity profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biochemical validation, single lab with structure + binding data\",\n      \"pmids\": [\"14623883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Tyro3 (Dtk), Axl, and Mer family members each function as cell entry factors for Ebola and Marburg viruses. Ectopic expression of these receptors in otherwise virus-resistant lymphoid cells enhanced pseudotype and live filovirus infection; blocking antibodies, soluble ectodomains, and Gas6 ligand each reduced infection.\",\n      \"method\": \"Ectopic expression in lymphoid cells, pseudotype virus infection assay, live EBOV infection, antibody and soluble ectodomain blocking experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function expression + multiple blocking reagents (antibody, soluble domain, ligand) in multiple assays\",\n      \"pmids\": [\"17005688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Tyro3, Axl, and Mer are essential for NK cell functional maturation. All three receptors are expressed in maturing NK cells; their ligands (Gas6/protein S) are produced by bone marrow stromal cells. Recombinant ligands drove NK cell differentiation in vitro, and triple-receptor-deficient mice lacked mature NK cells.\",\n      \"method\": \"Representational difference analysis, knockout mouse (single and combined), in vitro NK differentiation assay with recombinant ligands, expression analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function + in vitro rescue with defined ligands, multi-method\",\n      \"pmids\": [\"16751775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In dendritic cells, apoptotic cell phagocytosis (efferocytosis) relies primarily on Axl and Tyro3, in contrast to macrophages where Mertk predominates. In macrophages, Mertk tyrosine phosphorylation in response to apoptotic cells is markedly reduced in Axl/Tyro3 double-knockout mice, suggesting these receptors can heterodimerize functionally.\",\n      \"method\": \"Single- and double-receptor knockout mice, apoptotic cell phagocytosis assay in primary macrophages and dendritic cells, Mertk phosphorylation Western blot\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined phagocytosis phenotype across multiple cell types + biochemical phosphorylation readout\",\n      \"pmids\": [\"17442946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TYRO3 localizes to dendrites, soma (punctate), and axons/growth cones of hippocampal and cortical neurons. Gas6 stimulation of TYRO3 in cortical neurons activates both MAPK (ERK) and PI3K signaling pathways.\",\n      \"method\": \"Immunofluorescence localization in primary neurons, Gas6-induced phosphorylation assay, pathway inhibitor studies (MAPK and PI3K inhibitors)\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct immunofluorescence localization + functional signaling assay in primary neurons, single lab\",\n      \"pmids\": [\"17980494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Axl and Tyro3 mediate Gas6-stimulated GnRH neuron survival and migration. Axl/Tyro3 double-knockout mice show a 24–34% loss of GnRH neurons in the hypothalamus, increased caspase-3 cleavage in the forebrain, delayed sexual maturation, and irregular estrous cycles.\",\n      \"method\": \"siRNA silencing in NLT GnRH cells, Axl/Tyro3 double-knockout mouse analysis, GnRH neuron counting/immunostaining, caspase-3 apoptosis assay\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — silencing + knockout mouse with cellular and in vivo phenotypic readout, single lab with multiple methods\",\n      \"pmids\": [\"18787040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TYRO3 is an upstream regulator of MITF-M expression in melanoma cells, acting in a SOX10-dependent manner. Identified by genome-wide gain-of-function cDNA screen; TYRO3 overexpression bypasses BRAF(V600E)-induced senescence and transforms non-tumorigenic cells.\",\n      \"method\": \"Genome-wide gain-of-function cDNA screen, TYRO3 knockdown, SOX10 dependence assay, cellular transformation assay\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen + KD + OE with mechanistic pathway (SOX10) identified, single lab\",\n      \"pmids\": [\"19805117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Protein S (PS) protects the blood-brain barrier from hypoxic/ischemic disruption via Tyro3-mediated signaling. Tyro3 is required for PS vasculoprotection: siRNA silencing of Tyro3, Tyro3-blocking antibodies, and Tyro3-deficient mouse endothelial cells all abolish PS protection. Tyro3 ligation by PS activates sphingosine 1-phosphate receptor 1 (S1P1), leading to Rac1-dependent BBB protection.\",\n      \"method\": \"RNA interference, receptor-blocking antibodies, Tyro3/Axl/Mer knockout mouse brain endothelial cells, Tyro3 phosphorylation assay, 2-photon in vivo imaging, S1P1 antagonist\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (RNAi, antibody, KO cells, in vivo KO mice, pharmacological inhibitor) establishing signaling axis\",\n      \"pmids\": [\"20348395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Protein S (PS) protects neurons from NMDA excitotoxicity by activating the Tyro3-PI3K-Akt pathway via its C-terminal sex hormone-binding globulin-like (SHBG) domain. PS specifically requires Tyro3 (not Axl or Mer) to phosphorylate Akt, and downstream phosphorylation of Bad and Mdm2 increases Bcl-2/Bcl-XL and reduces p53/Bax. A kinase-deficient Akt mutant blocks PS-mediated protection.\",\n      \"method\": \"Tyro3/Axl/Mer knockout neurons, adenoviral kinase-dead Akt construct, PS structural analogs, in vivo NMDA excitotoxicity model in KO mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple KO lines + dominant-negative construct + structural domain analysis + in vivo model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21084607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Protein S protects neurons from tPA/NMDA injury via Tyro3-dependent Akt activation and Akt-mediated phosphorylation of FKHRL1 (Forkhead transcription factor), which suppresses Fas-ligand production and caspase-8 activation in the extrinsic apoptotic cascade. Axl and Mer do not mediate this effect.\",\n      \"method\": \"Tyro3/Axl/Mer knockout neurons, adenoviral kinase-dead Akt and FKHRL1 triple mutant constructs, caspase-8 activity assay, FasL detection\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — receptor-specific KO neurons + dominant-negative constructs + defined downstream signaling cascade, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21291561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hypothalamic GnRH neuron loss (not pituitary or ovarian defects) underlies the reproductive abnormalities in Axl/Tyro3 null mice. Axl/Tyro3 null mice have impaired steroid-induced LH surge but normal pituitary LH response to exogenous GnRH and normal ovarian histology.\",\n      \"method\": \"Axl/Tyro3 double-knockout mouse, ovariectomy + steroid priming, exogenous GnRH challenge, ovarian histology, folliculogenesis markers\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with tissue-specific phenotypic dissection, single lab, multiple physiological readouts\",\n      \"pmids\": [\"21539887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Overexpression of Tyro3 in Rat2 cells promotes cell proliferation through the MAPK/ERK pathway but not PI3K; this is distinct from Axl which uses PI3K. Tyro3 overexpression enhances Gas6-mediated Axl phosphorylation in a kinase-dependent manner, and Axl overexpression induces kinase-dead Tyro3 phosphorylation (cross-phosphorylation). Co-immunoprecipitation confirms physical association of Axl and Tyro3.\",\n      \"method\": \"Overexpression of WT and kinase-dead Tyro3 in Rat2 cells, MAPK/PI3K pathway inhibitors, co-immunoprecipitation, cross-phosphorylation Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP + kinase-dead controls + pathway inhibitors, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22606290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Gas6-stimulated TYRO3 in melanoma cells induces Akt phosphorylation but not ERK phosphorylation. Calcium is critical for correct Gas6 folding and its binding to TYRO3. Anti-TYRO3 monoclonal antibodies that partially block ligand binding (recognizing Ig domains) are the most effective at blocking downstream signaling.\",\n      \"method\": \"Soluble TYRO3 extracellular domain and Gas6 protein production for affinity measurement, shRNA knockdown, Gas6-induced phosphorylation in cell lines, calcium chelation experiment, monoclonal antibody characterization\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity measurements + cell-based phosphorylation assays + KD + antibody blocking, single lab\",\n      \"pmids\": [\"23570341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tyro3 is required for GAS6-induced synovial fibroblast proliferation and osteoclast differentiation. Tyro3-deficient mice have higher bone mass than WT, and in arthritis show less synovial hyperplasia, fewer osteoclasts, and reduced bone damage.\",\n      \"method\": \"Tyro3 knockout mice, collagen-induced arthritis model, in vitro osteoclastogenesis with human cells, GAS6 stimulation, histomorphometry\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse + in vivo arthritis model + human cell functional assay, single lab, multiple readouts\",\n      \"pmids\": [\"23632195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TYRO3, AXL, and MER show distinct patterns of activation by Gas6 and Protein S: each receptor has a unique ligand-activation profile, differentially affected by apoptotic cells, PS-containing vesicles, and enveloped virus. γ-carboxylation of ligands is essential for full TAM activation; soluble Ig-like TAM domains act as specific ligand antagonists.\",\n      \"method\": \"Reporter cell lines expressing chimeric TAM receptors, ligand activation assays with PS vesicles, apoptotic cells, warfarin (anti-γ-carboxylation), soluble TAM ectodomain competition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstituted reporter system + multiple ligand conditions + mutagenesis/warfarin, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25074926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tyro3 is required for Gas6-induced CNS myelination. In the absence of Tyro3 on oligodendrocytes, the pro-myelinating effect of Gas6 is lost, developmental myelination is delayed, and myelin is thinner. This effect may be mediated by activation of Erk1.\",\n      \"method\": \"Tyro3 knockout mice, Gas6 stimulation in vitro myelination assay, oligodendrocyte precursor cell analysis, Erk1 phosphorylation assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse + in vitro rescue assay + pathway identification (Erk1), single lab, multiple methods\",\n      \"pmids\": [\"28145605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tyro3 receptor interacts with the non-receptor cytoplasmic tyrosine kinase Fyn via its intracellular domain (identified by affinity chromatography). Fyn activity is downregulated in Tyro3-knockout mice. Loss of Tyro3 or Fyn impairs Schwann cell myelination and reduces myelin thickness in the peripheral nervous system.\",\n      \"method\": \"Tyro3 and Fyn knockout mice, affinity chromatography to identify Tyro3 binding partners, DRG neuronal culture myelination assay, kinase activity measurement\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity chromatography identifying Fyn as binding partner + KO mouse phenotype + DRG culture assay, single lab\",\n      \"pmids\": [\"26224309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TYRO3 protein is expressed in retinal pigment epithelium (RPE) and co-localizes with nascent photoreceptor outer segment (POS) phagosomes. Expression of Tyro3 in cultured cells stimulates phagocytic ingestion of POS. Loss of Tyro3 function accelerates photoreceptor degeneration in Mertk knockout mice.\",\n      \"method\": \"Tyro3 knockout mice crossed with Mertk knockout, RPE phagocytosis assay in cell culture, Tyro3 immunolocalization, retinal histology\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double-KO modifier analysis + cell-based phagocytosis assay + co-localization, single lab\",\n      \"pmids\": [\"26656104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TYRO3 genetic ablation in mice or functional neutralization of its human ortholog in dendritic cells results in enhanced type 2 immunity. The TYRO3 agonist PROS1 is induced in T cells by IL-4, and T cell-specific Pros1 knockout phenocopies loss of Tyro3, establishing a PROS1-mediated adaptive-to-innate feedback circuit through TYRO3 that limits type 2 responses.\",\n      \"method\": \"Tyro3 knockout mice, PROS1 T cell-specific knockout (Pros1-flox/T cell-Cre), DC functional neutralization, in vivo parasite/allergen challenge models\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO + conditional T cell-specific KO phenocopy + functional DC neutralization, multiple orthogonal approaches\",\n      \"pmids\": [\"27034374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TYRO3 induces epithelial-mesenchymal transition (EMT) in colon cancer by regulating expression of SNAI1. Gain- and loss-of-function experiments show TYRO3 controls SNAI1 expression as the master EMT regulator; anti-TYRO3 human antibody treatment abolishes TYRO3-induced EMT.\",\n      \"method\": \"TYRO3 overexpression, siRNA knockdown, murine colon cancer model, SNAI1 expression analysis, anti-TYRO3 antibody treatment, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain/loss-of-function + antibody + in vivo model with defined downstream pathway (SNAI1), single lab\",\n      \"pmids\": [\"27132510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Gas6 activation of TYRO3 requires both γ-carboxylation (Gla domain) and phosphatidylserine (PS) binding; non-γ-carboxylated Gas6 and Gla/EGF-domain deletion mutants retain TAM binding but act as blocking decoys. The Gla and EGF-like domains function cooperatively for TAM activation. PS-positive apoptotic cells, stressed cells, and exosomes all serve as cell-derived Gas6-presenting platforms to activate TAMs.\",\n      \"method\": \"TAM/IFNγR1 reporter cell lines, warfarin treatment (blocks γ-carboxylation), domain deletion mutagenesis, PS vesicle/apoptotic cell/exosome assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted reporter system + mutagenesis + multiple PS sources, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29176978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TYRO3-mediated phosphorylation of ACTN4 at tyrosines 11 and 13 requires FAK activation at Y397 and the EGF receptor cascade (but not EGFR ligand binding). This phosphorylation renders ACTN4 resistant to m-calpain cleavage between Y13-G14 and promotes invasive progression in melanoma cells.\",\n      \"method\": \"TYRO3 overexpression in fibroblasts, PCR-based site-directed mutagenesis of ACTN4, siRNA to TYRO3, FAK inhibition, m-calpain cleavage assay, actin-binding assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis mapping phosphosites + calpain cleavage assay + inhibitor studies, single lab\",\n      \"pmids\": [\"29274473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In PGRN-deficient frontotemporal lobar degeneration (FTLD-TDP) model, reduced PGRN leads to disinhibition of Gas6 binding to Tyro3, which activates PKCα via PLCγ, inducing tau phosphorylation at Ser203, mislocalization of tau to dendritic spines, and spine loss. Knockdown of molecules in the Gas6-Tyro3-PKCα-tau axis rescues spine and cognitive deficits.\",\n      \"method\": \"PGRN-KI knock-in mouse, phosphoproteomic analysis, PKC inhibitor, B-Raf inhibitor, siRNA knockdown of Gas6/Tyro3/PLCγ/PKCα, dendritic spine imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphoproteomics + pharmacological inhibitors + genetic knockdown + in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"29382817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TYRO3 in osteoblasts antagonizes MERTK/PROS1-induced inhibition of osteoblast differentiation. MERTK signaling via PROS1 activates the VAV2-RHOA-ROCK axis to increase cell contractility; TYRO3 counteracts this effect in osteoblasts. Osteoblast-targeted knockout of TYRO3 reduces bone mass.\",\n      \"method\": \"Osteoblast-specific conditional TYRO3 and MERTK knockout mice, signaling pathway analysis (VAV2/RHOA/ROCK), pharmacological MERTK inhibitor, bone mass measurement by micro-CT\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO + defined downstream pathway + pharmacological validation, single lab, multiple methods\",\n      \"pmids\": [\"36509738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Axl and Tyro3 (but not Mertk) play important roles in platelet activation and thrombus formation. In Axl- and Tyro3-deficient platelets, GPVI agonist-induced Syk and PLCγ2 tyrosine phosphorylation is decreased; platelet aggregation, spreading, JON/A binding, and P-selectin expression are inhibited. This occurs in a Gas6-independent but TAM extracellular domain-dependent manner.\",\n      \"method\": \"Single TAM-receptor knockout mouse platelets, GPVI agonist stimulation, Syk/PLCγ2 phosphorylation assay, platelet aggregation/spreading assays, Gas6 neutralizing antibody, neutralizing anti-Axl/Tyro3 antibodies, laser-induced thrombosis model in vivo\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single KO platelets + multiple functional assays + in vivo thrombosis + antibody/domain blocking, multiple orthogonal methods\",\n      \"pmids\": [\"30541554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Protein S (ProS1) is a functional tumour-derived ligand for Tyro3 that preferentially activates Tyro3 (and downstream Erk) over Gas6 in SCC-25 and MGH-U3 cancer cells. In cells expressing Tyro3 alone (MGH-U3), ProS1 additionally activates Akt. ProS1 activation of Tyro3 protects cancer cells from apoptosis.\",\n      \"method\": \"Western blot for Tyro3 and downstream kinase (Erk, Akt) phosphorylation upon recombinant ProS1/Gas6, conditioned medium with ProS1 trap and warfarin specificity controls, apoptosis assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — phosphorylation assays with specificity controls + functional apoptosis assay, single lab\",\n      \"pmids\": [\"31766614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In hepatocellular carcinoma, hepatitis-driven IL-6/STAT3 signaling transcriptionally activates TYRO3 expression, and hepatitis-associated apoptotic cells facilitate GAS6 presentation to further activate TYRO3. Activated TYRO3 then elicits intracellular SRC and STAT3 signaling, forming a 'TYRO3-STAT3-TYRO3' feed-forward loop.\",\n      \"method\": \"Loss-of-function screening (siRNA), TYRO3 silencing/inhibition, IL-6/STAT3 signaling analysis, GAS6 apoptotic cell presentation assay, xenograft mouse model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional screen + KD + signaling pathway dissection + in vivo xenograft, single lab\",\n      \"pmids\": [\"31831556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tyro3 signaling in podocytes confers antiapoptotic effects through activation of AKT. Tyro3 expression is suppressed by the TNF-α/NF-κB pathway; genetic ablation of Tyro3 worsens glomerular injury in multiple nephropathy models, while podocyte-specific TYRO3 overexpression is protective.\",\n      \"method\": \"Tyro3 knockout mice in DKD/ADRN/HIVAN models, podocyte-specific TYRO3 transgenic overexpression, morpholino knockdown in zebrafish, AKT phosphorylation assay, TNF-α/NF-κB pathway analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse + transgenic overexpression + zebrafish knockdown + signaling assay, replicated across multiple disease models\",\n      \"pmids\": [\"30429374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Galectin-3 (Gal-3) is a novel non-canonical agonist for TYRO3 receptor tyrosine kinase. Exogenous Gal-3 stimulates TYRO3 phosphorylation to the same extent as ProS1, activates Erk and Akt signaling, promotes cell survival against staurosporine-induced apoptosis, and stimulates cancer cell migration.\",\n      \"method\": \"TYRO3 phosphorylation Western blot upon Gal-3 vs. Gas6/ProS1, Erk/Akt activation assay, apoptosis assay, migration assay with Axl blocker\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct phosphorylation assay + functional assays, single lab, single publication\",\n      \"pmids\": [\"32664510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TYRO3 inhibits tumor cell ferroptosis triggered by anti-PD-1/PD-L1 therapy and facilitates a pro-tumor microenvironment by reducing the M1/M2 macrophage ratio, causing resistance to immune checkpoint blockade. Inhibition of TYRO3 promotes ferroptosis and sensitizes resistant tumors to anti-PD-1 therapy.\",\n      \"method\": \"Syngeneic mouse tumor model, TYRO3 overexpression/inhibition, ferroptosis assays, macrophage polarization analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — syngeneic in vivo model + mechanistic ferroptosis assays + macrophage polarization analysis, single lab\",\n      \"pmids\": [\"33855973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Activated NK cells acquire TYRO3 from tumor cells via trogocytosis (cell-contact-dependent membrane transfer) in vitro and in vivo. NK cells that acquire TYRO3 (TYRO3+ NK cells) exhibit significantly enhanced cytotoxicity and IFNγ production compared to TYRO3- NK cells.\",\n      \"method\": \"Flow cytometry to detect TYRO3 transfer, in vitro co-culture and in vivo trogocytosis assays, functional cytotoxicity and cytokine assays with TYRO3+ vs TYRO3- NK cell sorting\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct in vitro/in vivo transfer measurement + sorted cell functional assay, single lab\",\n      \"pmids\": [\"34326137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TYRO3 activation by circulating small extracellular vesicles (csEVs) through vesicle phosphatidylserine promotes cancer cell migration and metastasis via RhoA and epithelial-mesenchymal transition, and induces YAP activation leading to proliferation and chemoresistance.\",\n      \"method\": \"TYRO3 knockdown, csEV-TYRO3 interaction assays (phosphatidylserine blocking), RhoA/YAP activation Western blot, migration assay, xenograft tumor model with TYRO3 inhibitor KRCT-6j\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection (RhoA/YAP) + in vivo xenograft + selective inhibitor, single lab\",\n      \"pmids\": [\"33910929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear TYRO3 promotes colorectal cancer metastasis through a mechanism requiring its kinase activity and MMP-2-mediated cleavage but independent of ligand binding. Nuclear TYRO3 phosphorylates BRD3 (bromodomain-containing protein 3, an acetyl-lysine reader), and phospho-BRD3 regulates genes involved in anti-apoptosis and EMT as revealed by ChIP-seq.\",\n      \"method\": \"Proteomic analysis of TYRO3 nuclear substrates, ChIP-seq for phospho-BRD3 regulated genes, MMP-2 inhibitor, BRD3 inhibitor, kinase-dead TYRO3 mutant, organoid culture, orthotopic mouse model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — proteomics identifying substrate + mutagenesis (kinase-dead) + ChIP-seq + selective inhibitors + in vivo model, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37043564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TYRO3/Sky overexpressed at the cell surface or in the cytoplasm undergoes ligand-independent activation (dimerization and autophosphorylation). A cytoplasmic isoform (Sky Isoform I / Brt) resides naturally in the cytoplasm and retains kinase and transforming activity.\",\n      \"method\": \"Overexpression constructs in RatB1a fibroblasts, transformation assay (focus formation), tyrosine phosphorylation Western blot, subcellular localization analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — overexpression + functional transformation assay + localization, single lab\",\n      \"pmids\": [\"8545119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Rek (chick ortholog of TYRO3/Axl family), when overexpressed in NIH3T3 fibroblasts, undergoes autophosphorylation and induces morphologically transformed foci, indicating oncogenic potential when overexpressed.\",\n      \"method\": \"COS cell transfection for expression, immune complex kinase autophosphorylation assay, NIH3T3 focus formation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression system + focus formation assay for chick ortholog, single lab\",\n      \"pmids\": [\"8910558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Sky/TYRO3 and Mer (but not Axl) on human platelets mediate Gas6-induced platelet aggregation and degranulation; blocking antibodies to Sky or Mer inhibit platelet aggregation by >80%. Sky-blocking antibody prevents thrombus formation in a mouse thrombosis model.\",\n      \"method\": \"Flow cytometry (receptor detection on platelets), anti-Gas6 and anti-receptor blocking antibodies, platelet aggregation assay, mouse thrombosis model\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — receptor-blocking antibodies + functional platelet assay + in vivo model, single lab\",\n      \"pmids\": [\"15733062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The Pros1/Tyro3 axis in gingival epithelial cells suppresses periodontitis-associated inflammatory cytokine production (TNF-α, IL-6, IL-1β, MMP9/2, RANKL) via the SOCS1/3 and STAT1/3 signaling pathway.\",\n      \"method\": \"siRNA knockdown of Tyro3, exogenous Pros1 treatment of LPS-stimulated human gingival epithelial cells, Western blot/ELISA/gelatin zymography, rat periodontitis model with Pros1 administration\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD + in vitro signaling assay + in vivo model, single lab\",\n      \"pmids\": [\"30729671\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TYRO3 is a receptor tyrosine kinase activated primarily by Gas6 (via γ-carboxylated Gla domain + phosphatidylserine bridging) and protein S (via its SHBG domain), which triggers downstream PI3K-Akt, MAPK/ERK, and Src/STAT3 signaling cascades; its extracellular Ig domains can mediate ligand-independent homodimerization and heterodimerization with Axl for cross-phosphorylation; in specific cellular contexts it translocates to the nucleus where MMP-2-dependent cleavage enables kinase-dependent phosphorylation of epigenetic reader BRD3 to drive metastatic gene programs; and physiologically TYRO3 acts as a key regulator of apoptotic cell clearance (efferocytosis via phosphatidylserine recognition), innate immune dampening, myelination (via Fyn), spermatogenesis (Sertoli cell support), GnRH neuron survival/migration, retinal pigment epithelium phagocytosis, platelet activation, and blood-brain barrier integrity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TYRO3 (Sky) is a TAM-family receptor tyrosine kinase that couples recognition of phosphatidylserine-displaying surfaces to survival, immune-regulatory, and developmental signaling [#0, #18]. It is activated by the vitamin-K-dependent ligands Gas6 and protein S, with full Gas6 activation requiring both Gla-domain \\u03b3-carboxylation and phosphatidylserine bridging via apoptotic cells, stressed cells, and exosomes, while non-carboxylated or Gla/EGF-deleted ligands act as blocking decoys [#0, #18, #24]; protein S engages TYRO3 through its C-terminal SHBG-like domain [#1, #12], and galectin-3 acts as a non-canonical agonist [#32]. Crystallography of its two N-terminal Ig domains defines a ligand-binding interface shared with Axl and shows ligand-independent homodimerization, and TYRO3 physically associates with Axl for cross-phosphorylation [#4, #15]. Ligand engagement recruits the p85 subunit of PI3K to drive Akt activation [#3] and engages MAPK/ERK [#8, #15], with downstream Akt phosphorylating Bad, Mdm2, and FKHRL1 to suppress both intrinsic and Fas-ligand/caspase-8 extrinsic apoptosis in neurons [#12, #13]; it also binds and sustains the cytoplasmic kinase Fyn [#20]. Physiologically TYRO3 supports Sertoli-cell-dependent spermatogenesis [#2], NK-cell maturation [#6], efferocytosis in dendritic cells [#7], GnRH neuron survival and migration [#9], CNS and peripheral myelination via ERK1 and Fyn [#19, #20], retinal pigment epithelium phagocytosis [#21], platelet activation and thrombosis [#28], podocyte survival [#31], blood-brain barrier protection through an S1P1/Rac1 axis [#11], and dampening of type-2 and inflammatory immunity via a PROS1 feedback circuit [#22]. In cancer it promotes EMT through SNAI1 and RhoA/YAP, protects from ferroptosis to confer checkpoint-blockade resistance, and, after MMP-2-mediated cleavage, acts in the nucleus to phosphorylate the acetyl-lysine reader BRD3 and drive pro-metastatic gene programs [#23, #33, #35, #36]. TYRO3, Axl, and Mer additionally serve as entry factors for Ebola and Marburg filoviruses [#5].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing the ligand and kinase output of an orphan receptor: Gas6 was identified as the activating ligand of Sky/TYRO3, defining it as a ligand-responsive tyrosine kinase.\",\n      \"evidence\": \"Soluble Sky-Fc binding and tyrosine phosphorylation in transfected CHO cells with competition controls\",\n      \"pmids\": [\"7559388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve protein S as an activating ligand\", \"No downstream signaling pathway mapped\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed TYRO3 has intrinsic oncogenic/transforming potential, including a naturally cytoplasmic isoform, when overexpressed.\",\n      \"evidence\": \"Overexpression and focus-formation transformation assays in RatB1a fibroblasts with localization analysis\",\n      \"pmids\": [\"8545119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transformation shown only on overexpression, physiological relevance unclear\", \"Cytoplasmic isoform function in normal tissue not defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined protein S as a second TYRO3 ligand and mapped the SHBG domain as the key receptor-engaging module, broadening the ligand repertoire.\",\n      \"evidence\": \"Protein S domain-swap chimeras with Sky phosphorylation readout\",\n      \"pmids\": [\"9210477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human protein S did not activate human Sky, leaving species/context dependence unresolved\", \"Structural basis of SHBG-receptor contact not determined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Placed TYRO3 in a developmental context: combined TAM loss abolishes Sertoli-cell trophic support and spermatogenesis.\",\n      \"evidence\": \"Tyro3/Axl/Mer triple-knockout mice with seminiferous tubule histology and ligand expression mapping\",\n      \"pmids\": [\"10227296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TYRO3-specific contribution not separated from Axl/Mer\", \"Signaling cascade in Sertoli cells not defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified the proximal survival/transformation signaling module: TYRO3 recruits and activates PI3K p85 to drive Akt.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, Co-IP, Akt Western blot, and wortmannin block of soft-agar colony formation\",\n      \"pmids\": [\"10627473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphosite mediating p85 recruitment not mapped\", \"Cell-type generality not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the structural basis for ligand binding and revealed ligand-independent homodimerization, implicating an adhesion-like role.\",\n      \"evidence\": \"1.95 \\u00c5 crystal structure of the two N-terminal Ig domains plus solution dimerization analysis\",\n      \"pmids\": [\"14623883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure with Gas6 or protein S\", \"Functional consequence of homodimerization in cells not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended TAM receptor function to host-pathogen biology and innate immune development.\",\n      \"evidence\": \"Ectopic TAM expression with filovirus pseudotype/live infection and blocking reagents (idx5); RDA, knockouts, and in vitro NK differentiation (idx6)\",\n      \"pmids\": [\"17005688\", \"16751775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TYRO3-specific versus shared TAM roles in viral entry not dissected\", \"NK maturation signaling pathway downstream of TYRO3 not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined cell-type-specialized efferocytosis: TYRO3/Axl dominate apoptotic-cell clearance in dendritic cells and support Mer phosphorylation, indicating functional heterodimerization.\",\n      \"evidence\": \"Single/double TAM knockout mice with phagocytosis assays and Mertk phosphorylation blots\",\n      \"pmids\": [\"17442946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical TYRO3-Mer/Axl interaction not directly shown here\", \"Receptor recruitment to phagosome mechanism unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Localized TYRO3 to neurons and linked it to neuroendocrine development through GnRH neuron survival and migration.\",\n      \"evidence\": \"siRNA in NLT cells, Axl/Tyro3 double-knockout mouse neuron counts, caspase-3 assays, neuronal immunofluorescence and signaling (idx8, idx9)\",\n      \"pmids\": [\"17980494\", \"18787040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Axl and TYRO3 contributions not fully separated\", \"Ligand source in vivo for GnRH neurons not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established receptor-specific protein S neuroprotection and vascular protection, defining downstream Akt-Bad/Mdm2 and S1P1/Rac1 axes.\",\n      \"evidence\": \"TAM-specific knockout neurons/endothelium, kinase-dead Akt, S1P1 antagonist, in vivo NMDA and BBB models (idx11, idx12)\",\n      \"pmids\": [\"20348395\", \"21084607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling of TYRO3 to S1P1 mechanistically unresolved\", \"Human protein S relevance given earlier non-activation data unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the survival cascade to extrinsic apoptosis and clarified that GnRH neuron loss, not pituitary/ovarian defects, drives the reproductive phenotype.\",\n      \"evidence\": \"TAM-specific knockout neurons with kinase-dead Akt/FKHRL1 mutants and caspase-8 assays (idx13); ovariectomy/GnRH-challenge dissection in double-KO mice (idx14)\",\n      \"pmids\": [\"21291561\", \"21539887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FKHRL1/FasL axis tested only in neurons\", \"TYRO3-specific in vivo reproductive role not isolated from Axl\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Distinguished TYRO3 signaling from Axl (ERK- vs PI3K-biased) and demonstrated physical Axl-TYRO3 association and cross-phosphorylation.\",\n      \"evidence\": \"WT/kinase-dead overexpression in Rat2 cells, pathway inhibitors, Co-IP, cross-phosphorylation blots\",\n      \"pmids\": [\"22606290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression system may not reflect endogenous stoichiometry\", \"Heterodimer interface not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected TYRO3 to melanoma transformation via MITF-M/SOX10 and refined ligand-binding requirements and antibody-blockable signaling.\",\n      \"evidence\": \"Genome-wide gain-of-function cDNA screen, knockdown, SOX10 dependence (idx10); affinity/calcium and monoclonal antibody studies (idx16); arthritis KO and osteoclastogenesis (idx17)\",\n      \"pmids\": [\"19805117\", \"23570341\", \"23632195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional mechanism to MITF-M not resolved\", \"Bone phenotypes mechanistically distinct from later osteoblast work need reconciliation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Quantified distinct ligand-activation profiles across TAM receptors and established \\u03b3-carboxylation and PS as gating requirements with soluble ectodomains as antagonists.\",\n      \"evidence\": \"Chimeric TAM reporter cell lines with PS vesicles, apoptotic cells, warfarin, and ectodomain competition\",\n      \"pmids\": [\"25074926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous-context ligand preference not addressed\", \"Structural basis of profile differences not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined TYRO3's role in myelination through ERK1 and a direct Fyn interaction in CNS and PNS glia.\",\n      \"evidence\": \"Tyro3 KO mice, in vitro myelination/ERK1 assays (idx19); affinity chromatography identifying Fyn, Tyro3/Fyn KO DRG myelination (idx20)\",\n      \"pmids\": [\"28145605\", \"26224309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Fyn binding links to ERK1 activation not integrated\", \"Reciprocal validation of Fyn interaction limited\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated TYRO3-dependent RPE phagocytosis and that TYRO3 loss accelerates Mertk-deficient photoreceptor degeneration, establishing functional redundancy in retinal clearance.\",\n      \"evidence\": \"Tyro3/Mertk double-knockout mice, RPE phagocytosis assay, immunolocalization, retinal histology\",\n      \"pmids\": [\"26656104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling downstream of TYRO3 in RPE not defined\", \"TYRO3 ligand presenting POS not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an adaptive-to-innate immune feedback circuit in which T-cell PROS1 acts through TYRO3 to restrain type-2 immunity, and a SNAI1-driven EMT role in colon cancer.\",\n      \"evidence\": \"Tyro3 KO and T-cell-specific Pros1 KO with allergen/parasite challenge (idx22); gain/loss-of-function and anti-TYRO3 antibody in colon cancer models (idx23)\",\n      \"pmids\": [\"27034374\", \"27132510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular immunosuppressive signaling from TYRO3 in DCs not fully mapped\", \"SNAI1 regulation mechanism (transcriptional vs post-translational) unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the molecular requirements of Gas6 activation (cooperative Gla/EGF + PS) and identified a cytoskeletal substrate axis (ACTN4) promoting invasion.\",\n      \"evidence\": \"TAM reporter cells with warfarin/domain deletions/PS sources (idx24); ACTN4 phosphosite mapping and calpain cleavage assays (idx25)\",\n      \"pmids\": [\"29176978\", \"29274473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ACTN4 is a direct TYRO3 substrate not definitively shown\", \"FAK/EGFR-cascade ordering relative to TYRO3 incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked TYRO3 to neurodegeneration (Gas6-TYRO3-PKC\\u03b1-tau) and to bone homeostasis where it antagonizes MERTK/PROS1-driven contractility in osteoblasts.\",\n      \"evidence\": \"PGRN knock-in mice, phosphoproteomics, inhibitors, knockdown with spine/cognitive rescue (idx26); osteoblast-specific conditional KO with VAV2/RHOA/ROCK analysis (idx27)\",\n      \"pmids\": [\"29382817\", \"36509738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PLC\\u03b3/PKC\\u03b1 coupling to TYRO3 kinase output not structurally defined\", \"Reconciliation of opposing TYRO3 bone effects across studies needed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined protein S as a tumour-derived TYRO3-preferential ligand and elaborated TYRO3 survival roles in podocytes, hepatocellular carcinoma feed-forward loops, and epithelial inflammation control.\",\n      \"evidence\": \"Phosphorylation/apoptosis assays with ProS1 traps (idx29); podocyte KO/transgenic/zebrafish AKT studies (idx31); IL-6/STAT3 HCC screen and xenografts (idx30); gingival epithelial siRNA/SOCS-STAT studies (idx40)\",\n      \"pmids\": [\"31766614\", \"30429374\", \"31831556\", \"30729671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand preference results from single-lab phosphorylation assays\", \"TNF-\\u03b1/NF-\\u03baB and STAT3 regulatory loops not validated across systems\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the ligand repertoire with galectin-3 as a non-canonical TYRO3 agonist driving survival and migration.\",\n      \"evidence\": \"TYRO3 phosphorylation and ERK/Akt activation by Gal-3 versus Gas6/ProS1, plus apoptosis and migration assays\",\n      \"pmids\": [\"32664510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Gal-3-TYRO3 binding not demonstrated\", \"Single lab, single publication\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioned TYRO3 as a driver of immunotherapy resistance and metastasis via ferroptosis inhibition, macrophage repolarization, and EV-PS-driven RhoA/YAP signaling, with NK trogocytosis as a novel transfer route.\",\n      \"evidence\": \"Syngeneic tumor ferroptosis/macrophage analyses (idx33); csEV-PS RhoA/YAP studies with inhibitor (idx35); flow-based trogocytosis and sorted NK functional assays (idx34)\",\n      \"pmids\": [\"33855973\", \"33910929\", \"34326137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking TYRO3 to ferroptosis suppression not molecularly defined\", \"Trogocytosis functional gain mechanism unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a non-canonical nuclear function: MMP-2-cleaved TYRO3 phosphorylates BRD3 to reprogram anti-apoptotic/EMT gene expression in colorectal cancer metastasis, independent of ligand binding.\",\n      \"evidence\": \"Nuclear substrate proteomics, phospho-BRD3 ChIP-seq, kinase-dead mutant, MMP-2/BRD3 inhibitors, organoid and orthotopic models\",\n      \"pmids\": [\"37043564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for nuclear translocation/cleavage in vivo not defined\", \"Generality beyond colorectal cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TYRO3's distinct ligands, homo/heterodimerization, and cleavage states are integrated to select among its many survival, immune, developmental, and nuclear-transcriptional outputs in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of ligand-specific receptor activation\", \"Determinants of cytoplasmic versus nuclear TYRO3 signaling unknown\", \"Endogenous receptor stoichiometry with Axl/Mer in physiological tissues undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 15, 25, 36]},\n      {\"term_id\": \"GO:0004714\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 18, 24]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [24, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 21, 28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [37, 3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 7, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 13, 31, 33]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 9, 19, 20]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [28, 39]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 23, 36]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GAS6\", \"PROS1\", \"AXL\", \"MERTK\", \"PIK3R1\", \"FYN\", \"BRD3\", \"LGALS3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}