| 1995 |
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. |
Ligand-binding assay with soluble Sky-Fc fusion protein, tyrosine phosphorylation assay in transfected CHO cells, competition inhibition with Sky-Fc |
The Journal of biological chemistry |
High |
7559388
|
| 1997 |
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. |
Chimeric protein S domain-swap constructs, Sky phosphorylation assay, C4b-binding protein competition inhibition |
European journal of biochemistry |
High |
9210477
|
| 1999 |
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. |
Triple receptor knockout mouse model (loss-of-function genetics), histological analysis of seminiferous tubules, expression analysis |
Nature |
High |
10227296
|
| 2000 |
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. |
Yeast two-hybrid, GST pull-down, co-immunoprecipitation, Western blot for Akt phosphorylation, wortmannin inhibition in soft agar colony assay |
Blood |
High |
10627473
|
| 2003 |
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. |
X-ray crystallography (1.95 Å), solution dimerization analysis, biochemical ligand-binding specificity profiling |
The Journal of biological chemistry |
High |
14623883
|
| 2006 |
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. |
Ectopic expression in lymphoid cells, pseudotype virus infection assay, live EBOV infection, antibody and soluble ectodomain blocking experiments |
Journal of virology |
High |
17005688
|
| 2006 |
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. |
Representational difference analysis, knockout mouse (single and combined), in vitro NK differentiation assay with recombinant ligands, expression analysis |
Nature immunology |
High |
16751775
|
| 2007 |
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. |
Single- and double-receptor knockout mice, apoptotic cell phagocytosis assay in primary macrophages and dendritic cells, Mertk phosphorylation Western blot |
Journal of immunology |
High |
17442946
|
| 2007 |
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. |
Immunofluorescence localization in primary neurons, Gas6-induced phosphorylation assay, pathway inhibitor studies (MAPK and PI3K inhibitors) |
Neuroscience |
Medium |
17980494
|
| 2008 |
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. |
siRNA silencing in NLT GnRH cells, Axl/Tyro3 double-knockout mouse analysis, GnRH neuron counting/immunostaining, caspase-3 apoptosis assay |
Molecular endocrinology |
High |
18787040
|
| 2009 |
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. |
Genome-wide gain-of-function cDNA screen, TYRO3 knockdown, SOX10 dependence assay, cellular transformation assay |
PNAS |
Medium |
19805117
|
| 2010 |
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. |
RNA interference, receptor-blocking antibodies, Tyro3/Axl/Mer knockout mouse brain endothelial cells, Tyro3 phosphorylation assay, 2-photon in vivo imaging, S1P1 antagonist |
Blood |
High |
20348395
|
| 2010 |
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. |
Tyro3/Axl/Mer knockout neurons, adenoviral kinase-dead Akt construct, PS structural analogs, in vivo NMDA excitotoxicity model in KO mice |
The Journal of neuroscience |
High |
21084607
|
| 2011 |
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. |
Tyro3/Axl/Mer knockout neurons, adenoviral kinase-dead Akt and FKHRL1 triple mutant constructs, caspase-8 activity assay, FasL detection |
Molecular neurodegeneration |
High |
21291561
|
| 2011 |
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. |
Axl/Tyro3 double-knockout mouse, ovariectomy + steroid priming, exogenous GnRH challenge, ovarian histology, folliculogenesis markers |
Molecular and cellular endocrinology |
High |
21539887
|
| 2012 |
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. |
Overexpression of WT and kinase-dead Tyro3 in Rat2 cells, MAPK/PI3K pathway inhibitors, co-immunoprecipitation, cross-phosphorylation Western blot |
PloS one |
Medium |
22606290
|
| 2013 |
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. |
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 |
Biochemistry |
Medium |
23570341
|
| 2013 |
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. |
Tyro3 knockout mice, collagen-induced arthritis model, in vitro osteoclastogenesis with human cells, GAS6 stimulation, histomorphometry |
Annals of the rheumatic diseases |
High |
23632195
|
| 2014 |
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. |
Reporter cell lines expressing chimeric TAM receptors, ligand activation assays with PS vesicles, apoptotic cells, warfarin (anti-γ-carboxylation), soluble TAM ectodomain competition |
The Journal of biological chemistry |
High |
25074926
|
| 2015 |
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. |
Tyro3 knockout mice, Gas6 stimulation in vitro myelination assay, oligodendrocyte precursor cell analysis, Erk1 phosphorylation assay |
Glia |
High |
28145605
|
| 2015 |
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. |
Tyro3 and Fyn knockout mice, affinity chromatography to identify Tyro3 binding partners, DRG neuronal culture myelination assay, kinase activity measurement |
Molecular biology of the cell |
High |
26224309
|
| 2015 |
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. |
Tyro3 knockout mice crossed with Mertk knockout, RPE phagocytosis assay in cell culture, Tyro3 immunolocalization, retinal histology |
PLoS genetics |
High |
26656104
|
| 2016 |
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. |
Tyro3 knockout mice, PROS1 T cell-specific knockout (Pros1-flox/T cell-Cre), DC functional neutralization, in vivo parasite/allergen challenge models |
Science |
High |
27034374
|
| 2016 |
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. |
TYRO3 overexpression, siRNA knockdown, murine colon cancer model, SNAI1 expression analysis, anti-TYRO3 antibody treatment, xenograft model |
Oncogene |
Medium |
27132510
|
| 2017 |
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. |
TAM/IFNγR1 reporter cell lines, warfarin treatment (blocks γ-carboxylation), domain deletion mutagenesis, PS vesicle/apoptotic cell/exosome assays |
Frontiers in immunology |
High |
29176978
|
| 2017 |
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. |
TYRO3 overexpression in fibroblasts, PCR-based site-directed mutagenesis of ACTN4, siRNA to TYRO3, FAK inhibition, m-calpain cleavage assay, actin-binding assay |
The international journal of biochemistry & cell biology |
Medium |
29274473
|
| 2018 |
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. |
PGRN-KI knock-in mouse, phosphoproteomic analysis, PKC inhibitor, B-Raf inhibitor, siRNA knockdown of Gas6/Tyro3/PLCγ/PKCα, dendritic spine imaging |
Nature communications |
High |
29382817
|
| 2018 |
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. |
Osteoblast-specific conditional TYRO3 and MERTK knockout mice, signaling pathway analysis (VAV2/RHOA/ROCK), pharmacological MERTK inhibitor, bone mass measurement by micro-CT |
Nature communications |
High |
36509738
|
| 2018 |
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. |
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 |
Cell communication and signaling |
High |
30541554
|
| 2019 |
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. |
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 |
Cancers |
Medium |
31766614
|
| 2019 |
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. |
Loss-of-function screening (siRNA), TYRO3 silencing/inhibition, IL-6/STAT3 signaling analysis, GAS6 apoptotic cell presentation assay, xenograft mouse model |
Clinical cancer research |
Medium |
31831556
|
| 2019 |
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. |
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 |
JCI insight |
High |
30429374
|
| 2020 |
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. |
TYRO3 phosphorylation Western blot upon Gal-3 vs. Gas6/ProS1, Erk/Akt activation assay, apoptosis assay, migration assay with Axl blocker |
Biomolecules |
Medium |
32664510
|
| 2021 |
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. |
Syngeneic mouse tumor model, TYRO3 overexpression/inhibition, ferroptosis assays, macrophage polarization analysis |
The Journal of clinical investigation |
Medium |
33855973
|
| 2021 |
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. |
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 |
Cancer immunology research |
Medium |
34326137
|
| 2021 |
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. |
TYRO3 knockdown, csEV-TYRO3 interaction assays (phosphatidylserine blocking), RhoA/YAP activation Western blot, migration assay, xenograft tumor model with TYRO3 inhibitor KRCT-6j |
Cancer research |
Medium |
33910929
|
| 2023 |
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. |
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 |
Science advances |
High |
37043564
|
| 1995 |
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. |
Overexpression constructs in RatB1a fibroblasts, transformation assay (focus formation), tyrosine phosphorylation Western blot, subcellular localization analysis |
Oncogene |
Medium |
8545119
|
| 1996 |
Rek (chick ortholog of TYRO3/Axl family), when overexpressed in NIH3T3 fibroblasts, undergoes autophosphorylation and induces morphologically transformed foci, indicating oncogenic potential when overexpressed. |
COS cell transfection for expression, immune complex kinase autophosphorylation assay, NIH3T3 focus formation assay |
The Journal of biological chemistry |
Low |
8910558
|
| 2005 |
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. |
Flow cytometry (receptor detection on platelets), anti-Gas6 and anti-receptor blocking antibodies, platelet aggregation assay, mouse thrombosis model |
Journal of thrombosis and haemostasis |
Medium |
15733062
|
| 2019 |
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. |
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 of cellular and molecular medicine |
Medium |
30729671
|