Affinage

GAS6

Growth arrest-specific protein 6 · UniProt Q14393

Length
678 aa
Mass
74.9 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GAS6 is a secreted, vitamin K-dependent ligand for the TAM receptor tyrosine kinases (AXL, TYRO3, MERTK) that functions as a context-dependent amplifier of cell survival, proliferation, efferocytosis, platelet activation, and anti-inflammatory signaling. Its Gla domain requires γ-carboxylation for phosphatidylserine binding and receptor activation, and the ligand engages AXL through a structurally defined 2:2 complex in which two distinct binding contacts are both required for productive signaling (PMID:16362042, PMID:16359517). Downstream of TAM receptors, GAS6 activates PI3K/AKT, ERK, STAT3, RAC1, and NF-κB cascades to inhibit apoptosis, stabilize β-catenin, drive macropinocytosis and cell migration, promote efferocytosis of apoptotic cells and photoreceptor outer segments, and suppress TLR-driven pro-inflammatory cytokine production (PMID:15380678, PMID:11546821, PMID:34244439, PMID:20103767, PMID:31363052). GAS6 amplifies platelet aggregation through all three TAM receptors and is essential for thrombus stabilization in vivo—Gas6-deficient mice are protected from thrombosis without spontaneous bleeding—while in circulation all GAS6 is sequestered in a complex with soluble AXL (PMID:11175853, PMID:15733062, PMID:20088931).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    GAS6 was shown to mediate heterotypic cell–cell adhesion by binding membranes through domains separate from its AXL-binding motifs, establishing that it can bridge cells independently of receptor kinase activity.

    Evidence Cell aggregation assay in 32D myeloid cells expressing wild-type or kinase-dead AXL, with domain-mapping of membrane vs. receptor-binding regions

    PMID:9287338

    Open questions at the time
    • Identity of the non-AXL membrane-binding partner was not determined
    • Relevance of kinase-independent adhesion in vivo was not tested
  2. 2001 High

    Gas6-knockout mice revealed that GAS6 is a platelet-response amplifier essential for thrombus formation but dispensable for primary hemostasis, answering whether GAS6 has a non-redundant role in vivo.

    Evidence Gas6-/- mice challenged in multiple thrombosis models (venous, arterial, collagen/epinephrine thromboembolism) and tail-clip bleeding assay

    PMID:11175853

    Open questions at the time
    • Which TAM receptor(s) on platelets mediate the effect was not yet resolved
    • Mechanism of amplification at the signaling level was unknown
  3. 2001 High

    GAS6/AXL was shown to activate PI3K/AKT/GSK3/β-catenin and STAT3 as mitogenic signaling cascades, defining the intracellular pathways downstream of AXL engagement.

    Evidence Pharmacological dissection (wortmannin, dominant-negative STAT3) in mammary cells and mesangial cells, with TCF reporter and nuclear STAT3 translocation; validated in rat glomerulonephritis with warfarin and Axl-Fc

    PMID:11154277 PMID:11546821

    Open questions at the time
    • Whether STAT3 and β-catenin pathways operate in the same or distinct cell types in vivo was unclear
    • Direct AXL–STAT3 interaction versus intermediate kinases was not resolved
  4. 2004 High

    The requirement for γ-carboxylation and AXL kinase activity/PI3K-binding for anti-apoptotic and mitogenic functions was established, defining the minimal biochemical requirements for GAS6 bioactivity.

    Evidence Warfarin-decarboxylated GAS6 compared with carboxylated GAS6 for AXL phosphorylation, ERK activation, proliferation, and apoptosis protection; kinase-dead and ΔPI3K AXL mutants in vascular smooth muscle and cardiac fibroblasts

    PMID:15184064 PMID:15380678 PMID:16359517

    Open questions at the time
    • Whether partial carboxylation retains some activity was not tested
    • Structural basis for how Gla-domain carboxylation enables PS-dependent receptor engagement was not resolved
  5. 2005 High

    The crystal structure of the GAS6/AXL complex revealed a 2:2 stoichiometry with two distinct binding interfaces both required for signaling, answering how ligand-receptor engagement achieves receptor dimerization.

    Evidence 3.3 Å X-ray crystallography of human GAS6/AXL ectodomain complex, validated by structure-based mutagenesis and receptor activation assays

    PMID:16362042

    Open questions at the time
    • Full-length receptor dimerization in a membrane context was not visualized
    • How the Gla domain orients on PS-containing membranes in the context of the full complex remained unknown
  6. 2005 High

    All three TAM receptors were shown to be present on platelets and individually required for GAS6-mediated platelet activation, resolving receptor redundancy in thrombosis.

    Evidence Receptor-specific blocking antibodies and single TAM-receptor KO mice in platelet aggregation and thrombosis models; PI3K/AKT/β3-integrin signaling analysis

    PMID:15733062 PMID:16564713

    Open questions at the time
    • Relative contribution of each receptor at physiological GAS6 concentrations was not quantified
    • Whether receptor heterodimerization occurs on platelets was not tested
  7. 2005 Medium

    GAS6 was identified as a bridging ligand for MerTK-dependent phagocytosis of photoreceptor outer segments by retinal pigment epithelium, expanding GAS6's role to efferocytosis.

    Evidence Recombinant GAS6 and protein S in RPE phagocytosis assays with Mer-blocking approaches; convergence with αvβ5 integrin on L-type Ca²⁺ channels

    PMID:15949798 PMID:18395422

    Open questions at the time
    • Relative contribution of GAS6 versus protein S in RPE in vivo was not determined
    • Single-lab findings without independent replication
  8. 2008 High

    GAS6 was shown to function as an autocrine/paracrine amplifier of erythropoietin signaling via AKT in erythroblasts, establishing a role beyond hemostasis and immunity.

    Evidence Gas6-/- mice with impaired erythropoietic recovery from acute anemia, rescued by recombinant GAS6; AKT phosphorylation analysis in erythroid progenitors

    PMID:18188450

    Open questions at the time
    • Which TAM receptor mediates GAS6 signaling in erythroblasts was not identified
    • Mechanism of EpoR–TAM cross-talk was not resolved
  9. 2010 High

    All circulating GAS6 was found sequestered in complex with soluble AXL, identifying sAXL as the physiological buffer that regulates GAS6 bioavailability.

    Evidence Serum gel filtration, specific ELISA, and immunoprecipitation showing exclusive GAS6-sAXL complex (no sMer or sTyro3 complexes)

    PMID:20088931

    Open questions at the time
    • What triggers GAS6 release from sAXL at sites of action was not determined
    • Whether sAXL/GAS6 ratio changes in disease states was not systematically assessed
  10. 2010 High

    GAS6 was shown to suppress TLR-driven inflammation in macrophages specifically via MerTK/AKT/GSK3β-mediated NF-κB inhibition, delineating receptor-specific anti-inflammatory signaling.

    Evidence Receptor expression profiling and Mer-specific activation in differentiated U937 macrophages with AKT/GSK3β/NF-κB pathway dissection

    PMID:20103767

    Open questions at the time
    • Whether SOCS induction is part of this Mer-specific pathway was not addressed in this study
    • Physiological Mer vs. AXL selectivity in tissue-resident macrophages was not tested
  11. 2017 High

    GAS6-AXL double knockout mice showed that this pathway suppresses neuroinflammation and promotes remyelination after demyelination, extending the anti-inflammatory role to the CNS.

    Evidence Gas6-/-Axl-/- DKO mice in cuprizone model with TEM, immunofluorescence, cytokine/SOCS expression, and motor behavior; complemented by Tyro3-dependent oligodendrogenesis and IL-10-mediated myelination studies

    PMID:27630207 PMID:28925029 PMID:32722558

    Open questions at the time
    • Cell-type-specific contributions (microglia vs. oligodendrocyte precursors) were not resolved by conditional KO
    • Whether GAS6 directly signals to oligodendrocyte precursors or acts indirectly through glia-derived cytokines is not fully settled
  12. 2019 High

    STAT6 was identified as the transcriptional driver of GAS6 expression in anti-inflammatory macrophages, and GAS6 was shown to be required for efferocytosis-dependent resolution of acute lung injury.

    Evidence BMDM polarization, STAT6 activation analysis, Gas6 depletion by siRNA/KO, adoptive macrophage transfer in murine ALI model

    PMID:31363052

    Open questions at the time
    • Whether other transcription factors contribute to GAS6 induction in different tissue macrophages was not explored
    • The efferocytosis receptor (AXL vs. MerTK) downstream of macrophage-derived GAS6 was not specified
  13. 2021 High

    GAS6/AXL signaling was shown to drive actin remodeling, membrane ruffling, macropinocytosis, and 3D invasion through PI3K/RAC1, defining the cytoskeletal effector pathway.

    Evidence AXL interactome by mass spectrometry, live imaging, macropinocytosis and spheroid invasion assays with kinase-dead AXL, PI3K/RAC1 inhibitors

    PMID:34244439

    Open questions at the time
    • Identity of the GEF linking AXL to RAC1 was not determined
    • Whether macropinocytosis contributes to nutrient scavenging in GAS6-dependent tumors was not tested
  14. 2021 High

    Corticosterone was found to suppress GAS6 in dermal papilla cells, establishing an adrenal→corticosterone→GAS6 axis that controls hair follicle stem cell quiescence versus activation.

    Evidence Adrenalectomy and chronic stress mouse models, Gas6 gene rescue experiments in dermal papilla, HFSC activation by live imaging and histology

    PMID:33790465

    Open questions at the time
    • Which TAM receptor on HFSCs transduces GAS6 signaling was not identified
    • Whether other dermal papilla secreted factors act in parallel with GAS6 was not fully resolved
  15. 2022 High

    Chemotherapy-recruited neutrophils were identified as a source of GAS6 in the metastatic liver that reactivates pancreatic cancer cell proliferation via AXL, revealing a therapy-induced paracrine loop.

    Evidence Mouse PDAC liver metastasis models, CXCL1/2 blockade, Gas6/AXL inhibition, patient-derived liver explant treatment with recombinant GAS6

    PMID:35022267

    Open questions at the time
    • Whether this neutrophil-GAS6-AXL axis operates in other metastatic organs was not tested
    • Mechanism by which chemotherapy induces GAS6 expression in neutrophils was not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for GAS6 Gla domain engagement with PS/PE membranes in the context of the full 2:2 receptor complex; the mechanisms that regulate GAS6 release from the circulating sAXL complex at injury sites; and the cell-type-specific contributions of individual TAM receptors in GAS6-dependent processes such as myelination and tumor dormancy.
  • No full-length GAS6/TAM receptor structure on a membrane surface exists
  • Mechanism of GAS6 liberation from sAXL at sites of activation is unknown
  • Conditional/cell-type-specific TAM receptor knockouts have not been systematically applied across GAS6-dependent phenotypes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 7 GO:0008289 lipid binding 2 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-109582 Hemostasis 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 4
Partners
AXLCBLMERTKPIK3CARAC1SRCTYRO3
Complex memberships
GAS6/sAXL circulating complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Crystal structure at 3.3 Å of the human Gas6/Axl complex reveals a 2:2 stoichiometric assembly in which the first laminin G-like domain of Gas6 crosslinks two Ig-like domains of the Axl ectodomain. Two distinct Gas6/Axl binding contacts are both required for productive transmembrane signaling, as shown by structure-based mutagenesis and receptor activation assays. X-ray crystallography (3.3 Å), structure-based mutagenesis, protein binding assays, receptor activation experiments The EMBO journal High 16362042
2001 Gas6-deficient mice are protected from venous and arterial thrombosis and from fatal collagen/epinephrine-induced thromboembolism without spontaneous bleeding. Gas6 amplifies platelet aggregation and secretion in response to known agonists, identifying it as a platelet-response amplifier essential for thrombus formation. Gas6 knockout mouse model, platelet aggregation assays in vitro, thrombosis challenge in vivo, tail-clip bleeding assay Nature medicine High 11175853
2005 All three Gas6 receptors (Axl, Sky/Tyro3, and Mer) are present on human and mouse platelets. Blocking antibodies against Gas6, Sky, or Mer inhibit platelet aggregation and degranulation by >80%, whereas a stimulatory anti-Axl antibody enhances activation, establishing that Gas6 potentiates platelet activation through all three TAM receptors. Flow cytometry of platelet receptors, antibody blocking of Gas6 and individual TAM receptors, aggregation and degranulation assays, mouse thrombosis model Journal of thrombosis and haemostasis High 15733062
2006 Loss of any single Gas6 receptor (Tyro3, Axl, or Mer) protects mice against thromboembolism without spontaneous bleeding. Gas6 reinforces outside-in αIIbβ3 signaling by activating PI3K and Akt, and stimulates tyrosine phosphorylation of the β3 integrin subunit, identifying the Gas6-receptor/αIIbβ3 cross-talk as the mechanism of thrombus stabilization. Single TAM-receptor knockout mice, thrombosis challenge, platelet aggregation (second wave), clot retraction assay, PI3K/Akt signaling analysis, β3 phosphorylation assay Blood cells, molecules & diseases High 16564713
2004 Gas6-mediated anti-apoptotic protection of vascular smooth muscle cells requires both Gas6 binding to Axl and Axl kinase activity. The protective effect is abolished by a kinase-inactive Axl mutant (K567R) or by an Axl deletion mutant lacking the PI3K-binding site (AxlΔPI3K), establishing Gas6→Axl→PI3K→Akt as the anti-apoptotic signaling pathway. Serum-starvation apoptosis assay, transfection of dominant-negative and deletion mutants, soluble Axl extracellular domain competition, LY294002 PI3K inhibitor, TUNEL/annexin V quantification Journal of molecular and cellular cardiology High 15380678
2005 γ-Carboxylation of Gas6's Gla domain is required for its biological activity: decarboxylated Gas6 (produced under warfarin treatment) fails to bind phosphatidylserine-containing membranes, does not activate Axl, does not stimulate PI3K, and loses its anti-apoptotic effect in endothelial cells and NIH3T3 fibroblasts. Phospholipid-binding assays, warfarin-treated recombinant Gas6, Axl phosphorylation immunoblot, PI3K activation assay, serum-starvation apoptosis assay Journal of thrombosis and haemostasis High 16359517
2004 Vitamin K-dependent γ-carboxylation is required for Gas6 mitogenic activity. Warfarin-treated Gas6, lacking carboxylation, neither activates Axl tyrosine phosphorylation nor stimulates ERK phosphorylation or proliferation of cardiac fibroblasts, whereas carboxylated Gas6 does. Gas6-knockout cardiac fibroblast cultures, recombinant Gas6 ± warfarin treatment, DNA synthesis assay, Axl/ERK phosphorylation immunoblot, neutralizing antibody and soluble Axl-Fc competition Biochemical and biophysical research communications High 15184064
2010 In human blood, all circulating Gas6 is bound to soluble Axl (sAxl), forming a Gas6/sAxl complex detectable by ELISA and confirmed by immunoprecipitation. No complexes with soluble Mer or Tyro3 were found, indicating sAxl is the physiological circulating binder that sequesters Gas6 and prevents TAM receptor activation. Gel filtration fractionation of serum, ELISA for Gas6/sAxl/sAxl-Gas6 complexes, immunoprecipitation Journal of thrombosis and haemostasis High 20088931
2001 Gas6 induces mesangial cell proliferation through Axl and activates STAT3 with nuclear translocation; dominant-negative STAT3 abolishes Gas6-induced proliferation. In a rat glomerulonephritis model, blocking Gas6/Axl with warfarin or soluble Axl-Fc prevents STAT3 phosphorylation in mesangial cells, establishing Gas6→Axl→STAT3 as the mitogenic pathway in vivo. Mesangial cell culture, dominant-negative STAT3 transfection, STAT3 phosphorylation/nuclear translocation, warfarin and Axl-Fc treatment in anti-Thy1.1 glomerulonephritis rat model The Journal of biological chemistry High 11546821
2001 Gas6/Axl signaling drives mesangial cell proliferation in vivo. In experimental anti-Thy1.1 glomerulonephritis, Gas6 and Axl expression increase in glomeruli in parallel with proliferation. Warfarin or soluble Axl-Fc inhibits both proliferation and PDGF-B induction, demonstrating that the Gas6/Axl pathway is required for disease progression. Rat anti-Thy1.1 glomerulonephritis model, warfarin treatment, Axl-Fc administration, immunohistochemistry, PDGF-B mRNA/protein measurement The American journal of pathology High 11290560
1997 Gas6 mediates cell–cell adhesion through a heterotypic mechanism: Gas6 binds to the plasma membrane of 32D cells (not expressing Axl) via distinct membrane-interacting domains separate from the Axl-binding motifs, allowing cell-bound Gas6 to engage Axl on adjacent cells and drive aggregation. Aggregation does not require Axl kinase activity. 32D myeloid cell line expressing Axl, cell aggregation assay, blocking with soluble Axl extracellular domain, kinase-dead Axl mutant, domain-mapping of membrane and Axl-binding regions The Journal of biological chemistry High 9287338
2010 Gas6 inhibits TNF-α and IL-6 secretion from LPS-stimulated macrophages via Mer (not Axl or Tyro3), activating Akt, phosphorylating GSK3β, and thereby preventing NF-κB nuclear translocation. U937 cell differentiation, receptor expression profiling by immunoblot, Gas6 stimulation, Mer-specific activation, Akt/GSK3β/NF-κB pathway analysis Journal of leukocyte biology High 20103767
2019 STAT6 activation downstream of IL-4 or TSG6 induces Gas6 expression in macrophages undergoing anti-inflammatory transition. Gas6-depleted macrophages fail to efferocytose apoptotic neutrophils and do not resolve LPS-induced acute lung injury in vivo, establishing STAT6→Gas6 as the transcriptional driver of efferocytosis-dependent inflammation resolution. Bone marrow-derived macrophage polarization, STAT6 activation analysis, Gas6 depletion (siRNA/KO), adoptive macrophage transfer in murine ALI model, efferocytosis assay Proceedings of the National Academy of Sciences High 31363052
2021 Corticosterone suppresses Gas6 expression in dermal papilla cells; loss of systemic corticosterone accelerates hair follicle stem cell (HFSC) cycling, while restoring Gas6 expression rescues HFSCs from stress-induced quiescence, establishing an adrenal gland → corticosterone → dermal papilla → Gas6 suppression → HFSC quiescence axis. Adrenalectomy mouse model, chronic stress model, Gas6 gene rescue experiments, HFSC activation quantification by live imaging and histology Nature High 33790465
2014 An engineered high-affinity Axl 'decoy receptor' binds Gas6 with femtomolar affinity (80-fold improvement over wild-type), sequestering Gas6 and specifically blocking Axl signaling. Four mutations stabilize a conformational change in Gas6 at the Gas6-Axl binding interface, demonstrating the structural basis for improved Gas6 capture. Rational and combinatorial protein engineering, binding assays, cell-based signaling assays, in vivo metastasis models, crystal structure-guided mutagenesis Nature chemical biology High 25242553
2008 Gas6 released by erythroblasts in response to Epo enhances Epo receptor signaling by activating Akt. Gas6-null erythroid progenitors are hyporesponsive to Epo survival signals and fail to restore hematocrit after acute anemia, establishing a Gas6→Akt positive-feedback loop in erythropoiesis. Gas6-knockout mouse model, acute and chronic anemia models, recombinant Gas6 treatment, Akt phosphorylation analysis, colony assays The Journal of clinical investigation High 18188450
2001 Gas6 induces β-catenin stabilization via PI3K/Akt-mediated GSK3 inhibition and activates TCF/Lef transcriptional responses in mammary C57MG cells, establishing Gas6→Axl→PI3K→S6K/Ras→Akt→GSK3 inhibition→β-catenin/TCF as a mitogenic signaling cascade. Density-inhibited cell culture, wortmannin inhibition, PI3K/S6K/Ras pathway analysis, Akt and GSK3 activity assays, β-catenin fractionation, TCF reporter assay Molecular and cellular biology High 11154277
2005 Gas6 binding to Axl induces Axl ubiquitination via the ubiquitin ligase c-Cbl and subsequent lysosomal degradation (blocked by endocytosis/lysosomal inhibitors but not proteasome inhibitors). Hydrogen peroxide activates Axl phosphorylation but not ubiquitination, thereby preventing Axl downregulation. Endocytosis and lysosomal inhibitor treatment, proteasome inhibitor treatment, Axl ubiquitination immunoprecipitation, c-Cbl co-immunoprecipitation, H2O2 stimulation Biochemical and biophysical research communications Medium 15958209
2005 Both Gas6 and protein S stimulate phagocytosis of photoreceptor outer segments by rat retinal pigment epithelium through a Mer-dependent mechanism, demonstrating that Gas6 bridges phosphatidylserine-exposing outer segments to MerTK on RPE to drive efferocytosis. Cultured rat RPE OS phagocytosis assay with recombinant Gas6 and protein S, Mer-dependent mechanism established by receptor-blocking approach Experimental eye research Medium 15949798
2008 Endogenous Gas6 expressed by RPE promotes phagocytosis of outer-segment fragments via MerTK stimulation. L-type Ca2+ channels act downstream of both MerTK and αvβ5 integrin, indicating convergence of the Gas6/MerTK and integrin pathways on Ca2+ channel activation for phagocytosis. Antibody blockade of Gas6 and MerTK, nifedipine (L-type Ca2+ channel blocker), RGD peptides, herbimycin A, RPE phagocytosis assay Cellular signalling Medium 18395422
2021 GAS6-induced AXL activation triggers peripheral membrane ruffling and circular dorsal ruffles, promotes macropinocytosis mediating GAS6-AXL complex internalization, drives focal adhesion turnover and cell elongation, and promotes 3D spheroid invasion. These effects require AXL kinase activity and downstream PI3K and RAC1 activation but not TYRO3. AXL interactome (MS), live imaging of actin ruffles, macropinocytosis assay, spheroid invasion assay, kinase-dead AXL mutant, PI3K/RAC1 inhibitors, TYRO3 comparison Proceedings of the National Academy of Sciences High 34244439
2016 The Gas6-Axl protein interaction mediates endothelial phagocytosis of platelet-derived microparticles (PMPs). siRNA knockdown of individual TAM receptors identifies Axl (not Mer or Tyro3) as the key endothelial receptor, and Gas6 (not protein S) as the primary bridging ligand for PMP uptake. siRNA knockdown of Axl/Mer/Tyro3, TAM-blocking antibodies, biotin/PKH67-labeled PMP uptake by flow cytometry, Western blot, confocal and electron microscopy in HAEC and HUVEC The Journal of biological chemistry High 27006397
2008 The Axl/Gas6 pathway is required for IL-15-mediated human NK cell development from CD34+ progenitors. Blocking Axl-Gas6 interaction (soluble Axl-Fc or warfarin) reduces STAT5 phosphorylation and NK cell differentiation, and impairs T-BET expression in mature NK cells, placing Gas6/Axl upstream of both the IL-15/STAT5 and c-Kit signaling axes during NK development. Human CD34+ HPC culture with IL-15, soluble Axl-Fc competition, warfarin treatment, flow cytometry, STAT5/c-Kit phosphorylation analysis, IFN-γ and T-BET expression assays Blood Medium 18840707
2009 IFN-α induces Axl expression during human dendritic cell differentiation. Gas6/Axl signaling drives DC chemotaxis and rescues DCs from apoptosis. LPS-induced Axl downregulation involves proteolytic shedding by MMP/ADAM family proteases (reversed by GM6001 and TAPI-1), identifying Axl ectodomain shedding as a regulatory mechanism. Human DC differentiation assay, IFN-α induction, LPS maturation, GM6001/TAPI-1 protease inhibitors, Axl surface/soluble form ELISA, DC chemotaxis assay, apoptosis assay Journal of immunology Medium 19657094
2015 Gas6 upregulates prostaglandin E synthase (Ptges) expression in endothelial cells through ERK1/2 phosphorylation, leading to increased PGE2 secretion. Cancer-induced venous thrombus enlargement is absent in Gas6-/- mice, and EP3 receptor antagonism reverses cancer-induced thrombosis in vivo, placing Gas6→ERK→Ptges→PGE2→EP3 as a coagulopathy pathway. Gas6-/- mouse thrombosis model, whole-genome microarray of WT vs. Gas6-/- endothelial cells, qPCR/immunofluorescence for Ptges, ERK1/2 phosphorylation, PGE2 ELISA, EP3 receptor antagonism in vivo Blood High 26585956
2006 Gas6 is expressed in macrophages and hepatic stellate cells (HSC) after CCl4-induced liver injury. Gas6 exerts an anti-apoptotic effect on HSC and HSC/myofibroblasts mediated through the Axl/PI3K/Akt pathway, established by γ-carboxylated Gas6 expression during HSC activation. Rat CCl4 liver injury model, immunohistochemistry for Gas6/Axl in ED1+ macrophages and desmin+ HSC, in vitro HSC culture, PI3K/Akt pathway analysis, Gas6 carboxylation assessment Hepatology Medium 16799993
2011 Gas6 deficiency attenuates steatohepatitis and liver fibrosis by limiting macrophage recruitment, reducing inflammatory cytokine expression (IL-1β, TNF-α, MCP-1), and suppressing TGF-β and collagen 1 mRNA, with impaired myofibroblast activation. This establishes Gas6 as a promoter of the macrophage-mediated inflammatory cascade driving fibrosis. Gas6-/- mice on CDE diet and chronic CCl4, F4/80 macrophage staining, cytokine/fibrosis gene expression (qPCR), collagen/TGF-β measurement, hepatic progenitor cell analysis American journal of physiology — Gastrointestinal and liver physiology Medium 21350191
2013 Gas6/Axl signaling in schwannoma cells recruits Src, FAK, and NF-κB; NF-κB mediates Gas6/Axl-dependent upregulation of survivin, cyclin D1, and FAK, driving schwannoma cell survival, matrix adhesion, and proliferation. Primary human schwannoma cell culture, Gas6/Axl stimulation, Src/FAK/NF-κB pathway analysis, survivin/cyclin D1 immunoblot, proliferation and adhesion assays Oncogene Medium 23318455
2017 Loss of Gas6 and Axl (DKO mice) results in prolonged neuroinflammation, impaired remyelination, extensive axonal damage, and motor deficits after cuprizone demyelination, with increased proinflammatory cytokines and altered SOCS expression. This establishes Gas6-Axl signaling as a suppressor of CNS proinflammatory cytokine production during demyelination/remyelination. Gas6-/- Axl-/- double-knockout mice, cuprizone demyelination model, transmission electron microscopy, immunofluorescence (SMI32, APP, MBP), cytokine mRNA, SOCS expression, motor behavior testing Glia High 28925029
2016 Gas6 promotes oligodendrogenesis and myelination in adult CNS via Tyro3 receptor phosphorylation, and activates STAT3 signaling while downregulating MMP9 in optic nerves. In cerebellar slice demyelination, Gas6 co-treatment significantly attenuates lysolecithin-induced demyelination. Mouse optic nerve and cerebellar slice cultures, Tyro3 phosphorylation assay, MBP immunostaining, STAT3 activation, MMP9 gene expression, lysolecithin demyelination model ASN neuro Medium 27630207
2020 Gas6 inhibits LPS-induced TNF-α production in microglia via both Axl and Mer, and suppresses LPS-induced morphological changes (area, perimeter, roundness). Under basal conditions, Axl-/- microglia show lower TNF-α expression, while Mer expression on LPS-stimulated cells is reduced in Axl-/- background, indicating cross-regulation between the two TAM receptors. Primary WT, Mer-/- and Axl-/- microglia cultures, LPS stimulation, Gas6 pre-treatment, RT-qPCR, ELISA for TNF-α, ImageJ morphometric analysis Frontiers in cellular neuroscience Medium 33192322
2020 Gas6 upregulates anti-inflammatory IL-10 and TGF-β in optic nerve and glial cultures via both Axl and Tyro3 (effect absent in either single KO). IL-10 mediates the pro-myelinating effect of Gas6 on MBP expression, as shown by neutralizing anti-IL-10 antibody blockade. Single TAM-receptor KO mouse glial cultures, Gas6 treatment, IL-10/TGF-β qPCR, MBP expression in optic nerve, anti-IL-10 neutralizing antibody Cells Medium 32722558
2020 Phosphatidylethanolamine (PE) synergizes with phosphatidylserine (PS) to enhance GAS6 binding to PS-containing surfaces, dramatically increasing AXL-mediated efferocytosis and enveloped virus entry. Liposomes containing both PE and PS bind GAS6 and are engulfed by AXL-expressing cells far more efficiently than PS-only liposomes. Liposome binding assays with recombinant GAS6, AXL-expressing cell efferocytosis assay, Zika/Ebola/Chikungunya/EEEV pseudovirus infection inhibition assays Journal of virology Medium 33115868
2022 Gas6 promotes microglial efferocytosis of apoptotic neurons after subarachnoid hemorrhage via Axl/Rac1 signaling. The beneficial effects of recombinant Gas6 (reduced inflammation, BBB protection, improved neurological deficits) are abolished by Axl or Rac1 inhibition/siRNA knockdown. Mouse SAH model, intraventricular rGas6/rPros1 injection, Axl and Rac1 siRNA knockdown or pharmacological inhibition, efferocytosis assay in vivo and in vitro, cytokine measurement, BBB assay Translational stroke research Medium 36324028
2019 S100A10 is a critical downstream mediator of GAS6/AXL-induced angiogenesis in renal cell carcinoma. GAS6/AXL signaling activates S100A10 expression through SRC, which promotes plasmin production, endothelial cell invasion, and angiogenesis. Genetic and therapeutic AXL inhibition reduces tumor vessel density. Genetic AXL KO/inhibition in xenograft models, S100A10 siRNA, SRC inhibition, plasmin generation assay, endothelial invasion assay, tumor vascular density measurement Cancer research Medium 31585940
2006 GAS6 is a direct estrogen target gene in mammary epithelial cells. An estrogen response element (ERE) in the GAS6 promoter binds ERα as shown by EMSA and ChIP upon estrogen stimulation. Microarray, RNase protection assay, ERE identification by sequence analysis, EMSA, chromatin immunoprecipitation (ChIP) Biochemical and biophysical research communications Medium 17174935
2022 Chemotherapy-induced neutrophils infiltrating the metastatic liver express Gas6, which activates AXL on pancreatic cancer cells to drive their regrowth. Disruption of neutrophil infiltration (via CXCL1/2 blockade) or Gas6/AXL inhibition in combination with chemotherapy inhibits metastatic growth; recombinant Gas6 alone is sufficient to promote tumor cell proliferation in patient-derived liver explants. Flow/mass cytometry, mouse PDAC liver metastasis models, CXCL1/2 blockade, Gas6/AXL inhibition, ex vivo patient-derived liver explants, recombinant Gas6 treatment Gut High 35022267
2024 MSC-EV-derived GAS6 activates MerTK/ERK/COX2 signaling in macrophages to enhance efferocytosis efficiency, reducing hepatic ischemia-reperfusion injury. Knockdown of GAS6 in MSC-EVs or MerTK inhibition (UNC2025) abolishes these protective effects. Murine HIRI model, MSC-EV administration, proteomic profiling of EVs, GAS6 lentiviral KD, UNC2025 MerTK inhibitor, macrophage efferocytosis assay, liver injury markers Cell death discovery Medium 39256347
2024 Gas6/AXL signaling inhibits ferroptosis in hepatocytes during ischemia-reperfusion injury through activation of the PI3K/AKT pathway. AXL inhibition (R428) exacerbates lipid peroxidation and iron accumulation, while recombinant Gas6 (AXL activator) reduces these ferroptotic markers in vivo and in vitro. Mouse liver warm I/R model, primary hepatocyte hypoxia/reoxygenation, recombinant Gas6 and R428 treatment, LY294002 PI3K inhibitor, lipid peroxidation, iron accumulation, and AXL phosphorylation assays Transplantation Medium 38725107
2013 In the bone marrow microenvironment, the balance between Axl and Tyro3 expression on prostate cancer cells acts as a molecular switch: predominance of Axl maintains dormancy, whereas predominance of Tyro3 permits rapid growth, establishing differential TAM receptor engagement by Gas6 as a regulator of metastatic dormancy vs. proliferation. In vivo prostate cancer bone metastasis models, receptor expression analysis, comparison of dormant vs. proliferative phenotypes PloS one Low 23637920
2009 Gas6 inhibits IGF-I-mediated proliferation of growth-plate chondrocytes by attenuating ERK1/2 activation, while promoting chondrocyte differentiation in ATDC5 cells through distinct gene expression patterns (collagen X, collagen 2, aggrecan, lysyl oxidase). Primary bovine chondrocyte proliferation assay, ERK1/2 phosphorylation measurement, ATDC5 differentiation assay, microarray-guided receptor identification Molecular endocrinology Medium 19897599

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nature medicine 351 11175853
2005 Structural basis for Gas6-Axl signalling. The EMBO journal 238 16362042
2005 Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor. Journal of cellular physiology 172 15605394
2010 TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages. Journal of leukocyte biology 163 20103767
2018 Targeting Gas6/TAM in cancer cells and tumor microenvironment. Molecular cancer 146 29386018
2016 Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3β/β-catenin Signaling. Theranostics 131 27279912
2021 Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence. Nature 126 33790465
2014 An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis. Nature chemical biology 123 25242553
1997 GAS6 mediates adhesion of cells expressing the receptor tyrosine kinase Axl. The Journal of biological chemistry 118 9287338
2019 STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation. Proceedings of the National Academy of Sciences of the United States of America 113 31363052
2020 Gas6/Axl Signaling Pathway in the Tumor Immune Microenvironment. Cancers 112 32660000
2004 Gas6 inhibits apoptosis in vascular smooth muscle: role of Axl kinase and Akt. Journal of molecular and cellular cardiology 111 15380678
2004 Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts. Biochemical and biophysical research communications 107 15184064
2005 Both protein S and Gas6 stimulate outer segment phagocytosis by cultured rat retinal pigment epithelial cells. Experimental eye research 106 15949798
2013 GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PloS one 104 23637920
2017 Molecular insights of Gas6/TAM in cancer development and therapy. Cell death & disease 93 28333143
2016 Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies. The Journal of clinical investigation 93 27893463
2005 Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses. Journal of thrombosis and haemostasis : JTH 93 15733062
2001 Gas6 regulates mesangial cell proliferation through Axl in experimental glomerulonephritis. The American journal of pathology 90 11290560
2012 Hypoxia stabilizes GAS6/Axl signaling in metastatic prostate cancer. Molecular cancer research : MCR 88 22516347
2010 Gas6 is complexed to the soluble tyrosine kinase receptor Axl in human blood. Journal of thrombosis and haemostasis : JTH 85 20088931
2005 The role of gamma-carboxylation in the anti-apoptotic function of gas6. Journal of thrombosis and haemostasis : JTH 83 16359517
2013 Axl/Gas6/NFκB signalling in schwannoma pathological proliferation, adhesion and survival. Oncogene 82 23318455
2008 Role of Gas6 in erythropoiesis and anemia in mice. The Journal of clinical investigation 82 18188450
2001 Gas6 induces mesangial cell proliferation via latent transcription factor STAT3. The Journal of biological chemistry 82 11546821
2002 Gas6 rescues cortical neurons from amyloid beta protein-induced apoptosis. Neuropharmacology 81 12527478
2022 Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. Gut 79 35022267
2008 Growth arrest-specific gene 6 (GAS6). An outline of its role in haemostasis and inflammation. Thrombosis and haemostasis 79 18841281
2009 Survival and migration of human dendritic cells are regulated by an IFN-alpha-inducible Axl/Gas6 pathway. Journal of immunology (Baltimore, Md. : 1950) 77 19657094
2021 The GAS6-AXL signaling pathway triggers actin remodeling that drives membrane ruffling, macropinocytosis, and cancer-cell invasion. Proceedings of the National Academy of Sciences of the United States of America 76 34244439
1999 The Gas6/Axl system: a novel regulator of vascular cell function. Trends in cardiovascular medicine 76 11094334
2010 TAM receptor ligands in lupus: protein S but not Gas6 levels reflect disease activity in systemic lupus erythematosus. Arthritis research & therapy 74 20637106
2012 Growth arrest-specific gene 6 (gas6) and vascular hemostasis. Advances in nutrition (Bethesda, Md.) 71 22516727
2001 Gas6 induces growth, beta-catenin stabilization, and T-cell factor transcriptional activation in contact-inhibited C57 mammary cells. Molecular and cellular biology 67 11154277
2022 Anti-inflammatory clearance of amyloid-β by a chimeric Gas6 fusion protein. Nature medicine 66 35927581
2019 Gas6/TAM System: A Key Modulator of the Interplay between Inflammation and Fibrosis. International journal of molecular sciences 63 31614787
2015 Polarization of tumor-associated macrophages and Gas6/Axl signaling in oral squamous cell carcinoma. Oral oncology 62 25910588
2021 Therapeutic Targeting of the Gas6/Axl Signaling Pathway in Cancer. International journal of molecular sciences 61 34576116
2006 Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells. Hepatology (Baltimore, Md.) 61 16799993
2011 Gas6 deficiency prevents liver inflammation, steatohepatitis, and fibrosis in mice. American journal of physiology. Gastrointestinal and liver physiology 59 21350191
2008 Vitamin K-dependent actions of Gas6. Vitamins and hormones 59 18374195
2017 Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure. Glia 58 28925029
2008 The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development. Blood 58 18840707
1999 Axl-gas6 interaction counteracts E1A-mediated cell growth suppression and proapoptotic activity. Molecular and cellular biology 56 10567533
2019 S100A10 Is a Critical Mediator of GAS6/AXL-Induced Angiogenesis in Renal Cell Carcinoma. Cancer research 53 31585940
2019 A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target. Cellular and molecular gastroenterology and hepatology 53 31689560
2016 Recombinant Gas6 augments Axl and facilitates immune restoration in an intracerebral hemorrhage mouse model. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 52 27389179
2020 Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth. Nature communications 51 32499572
2005 Effects of Gas6 and hydrogen peroxide in Axl ubiquitination and downregulation. Biochemical and biophysical research communications 51 15958209
2018 LncRNA GAS6-AS2 promotes bladder cancer proliferation and metastasis via GAS6-AS2/miR-298/CDK9 axis. Journal of cellular and molecular medicine 48 30394665
2004 Role of Gas6/Axl signaling in lens epithelial cell proliferation and survival. Experimental eye research 48 14667825
2017 Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity. Scientific reports 47 28272423
2004 Human vitamin K-dependent GAS6: gene structure, allelic variation, and association with stroke. Human mutation 47 15108283
2016 The Gas6-Axl Protein Interaction Mediates Endothelial Uptake of Platelet Microparticles. The Journal of biological chemistry 46 27006397
2016 The Gas6/TAM System and Multiple Sclerosis. International journal of molecular sciences 45 27801848
2020 Blockade of Stromal Gas6 Alters Cancer Cell Plasticity, Activates NK Cells, and Inhibits Pancreatic Cancer Metastasis. Frontiers in immunology 44 32174917
2018 GAS6/TAM Pathway Signaling in Hemostasis and Thrombosis. Frontiers in medicine 42 29868590
2022 Gas6 Promotes Microglia Efferocytosis and Suppresses Inflammation Through Activating Axl/Rac1 Signaling in Subarachnoid Hemorrhage Mice. Translational stroke research 41 36324028
2016 Gas6 Promotes Oligodendrogenesis and Myelination in the Adult Central Nervous System and After Lysolecithin-Induced Demyelination. ASN neuro 39 27630207
2008 Endogenous Gas6 and Ca2+ -channel activation modulate phagocytosis by retinal pigment epithelium. Cellular signalling 37 18395422
2020 Therapeutic aspects of the Axl/Gas6 molecular system. Drug discovery today 36 33002607
2017 Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells. Molecular cancer research : MCR 35 28923840
2023 Gas6/AXL pathway: immunological landscape and therapeutic potential. Frontiers in oncology 33 37265798
2021 Tumor perivascular cell-derived extracellular vesicles promote angiogenesis via the Gas6/Axl pathway. Cancer letters 33 34678434
2009 SCF, BDNF, and Gas6 are regulators of growth plate chondrocyte proliferation and differentiation. Molecular endocrinology (Baltimore, Md.) 33 19897599
2020 Phosphatidylethanolamine and Phosphatidylserine Synergize To Enhance GAS6/AXL-Mediated Virus Infection and Efferocytosis. Journal of virology 32 33115868
2019 Gas6 Attenuates Sepsis-Induced Tight Junction Injury and Vascular Endothelial Hyperpermeability via the Axl/NF-κB Signaling Pathway. Frontiers in pharmacology 31 31263416
2020 Testosterone ameliorates vascular aging via the Gas6/Axl signaling pathway. Aging 30 32717722
2016 Endogenous GAS6 and Mer receptor signaling regulate prostate cancer stem cells in bone marrow. Oncotarget 30 27028863
2022 LncRNA GAS6-AS1 facilitates tumorigenesis and metastasis of colorectal cancer by regulating TRIM14 through miR-370-3p/miR-1296-5p and FUS. Journal of translational medicine 29 35962353
2020 The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation. EMBO reports 29 32909687
2010 Association study between polymorphims in GAS6-TAM genes and carotid atherosclerosis. Thrombosis and haemostasis 29 20664904
2020 Gas6 Induces Myelination through Anti-Inflammatory IL-10 and TGF-β Upregulation in White Matter and Glia. Cells 28 32722558
2020 Gas6 Inhibits Toll-Like Receptor-Mediated Inflammatory Pathways in Mouse Microglia via Axl and Mer. Frontiers in cellular neuroscience 28 33192322
2006 Role of the growth arrest-specific gene 6 (gas6) product in thrombus stabilization. Blood cells, molecules & diseases 28 16564713
2006 GAS6 is an estrogen-inducible gene in mammary epithelial cells. Biochemical and biophysical research communications 26 17174935
2024 Extracellular vesicles containing GAS6 protect the liver from ischemia-reperfusion injury by enhancing macrophage efferocytosis via MerTK-ERK-COX2 signaling. Cell death discovery 25 39256347
2021 Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia. Journal of experimental & clinical cancer research : CR 25 34753494
2017 Luteolin inhibits angiogenesis by blocking Gas6/Axl signaling pathway. International journal of oncology 25 28627676
2023 GAS6 attenuates sepsis-induced cardiac dysfunction through NLRP3 inflammasome-dependent mechanism. Free radical biology & medicine 24 37979891
2004 The role of the vitamin K-dependent growth factor Gas6 in glomerular pathophysiology. Current opinion in nephrology and hypertension 24 15199298
2019 Genetic loss of Gas6/Mer pathway attenuates silica-induced lung inflammation and fibrosis in mice. Toxicology letters 23 31284023
2015 The Involvement of GAS6 Signaling in the Development of Obesity and Associated Inflammation. International journal of endocrinology 22 25954309
2015 Prostaglandin E synthase is upregulated by Gas6 during cancer-induced venous thrombosis. Blood 22 26585956
2020 Crosstalk between Akt and NF-κB pathway mediates inhibitory effect of gas6 on monocytes-endothelial cells interactions stimulated by P. gingivalis-LPS. Journal of cellular and molecular medicine 21 32462812
2020 Increased plasma levels of Gas6 and its soluble tyrosine kinase receptors Mer and Axl are associated with immunological activity and severity of lupus nephritis. Clinical and experimental rheumatology 20 32573415
2020 GAS6 signaling tempers Th17 development in patients with multiple sclerosis and helminth infection. PLoS pathogens 19 33347509
2019 Macrophage phenotypes and Gas6/Axl signaling in apical lesions. Journal of dental sciences 19 31528256
2018 Protein S and Gas6 induce efferocytosis of HIV-1-infected cells. Virology 18 29304470
2023 Gas6/TAM Axis Involvement in Modulating Inflammation and Fibrosis in COVID-19 Patients. International journal of molecular sciences 17 36674471
2022 Baseline Plasma Gas6 Protein Elevation Predicts Adverse Outcomes in Hospitalized COVID-19 Patients. Disease markers 17 35531477
2020 USF1-mediated upregulation of lncRNA GAS6-AS2 facilitates osteosarcoma progression through miR-934/BCAT1 axis. Aging 17 32269179
2019 Upregulated LINC00565 Accelerates Ovarian Cancer Progression By Targeting GAS6. OncoTargets and therapy 17 31819497
2024 Administration of Gas6 attenuates lung fibrosis via inhibition of the epithelial-mesenchymal transition and fibroblast activation. Cell biology and toxicology 16 38578518
2024 Gas6/AXL Alleviates Hepatic Ischemia/Reperfusion Injury by Inhibiting Ferroptosis via the PI3K/AKT Pathway. Transplantation 16 38725107
2022 GAS6/Axl is associated with AMPK activation and attenuates H2O2-induced oxidative stress. Apoptosis : an international journal on programmed cell death 16 36580193
2019 Plasma sMer, sAxl and GAS6 levels correlate with disease activity and severity in lupus nephritis. European journal of clinical investigation 16 30588607
2023 PRAME Is a Novel Target of Tumor-Intrinsic Gas6/Axl Activation and Promotes Cancer Cell Invasion in Hepatocellular Carcinoma. Cancers 15 37173882
2022 Psoralidin protects against cerebral hypoxia/reoxygenation injury: Role of GAS6/Axl signaling. Phytotherapy research : PTR 15 35583809
2017 Implication of a novel Gla-containing protein, Gas6 in the pathogenesis of insulin resistance, impaired glucose homeostasis, and inflammation: A review. Diabetes research and clinical practice 15 28453960