Growth arrest-specific protein 6 (Gas6) encodes a secreted, vitamin K-dependent extracellular ligand for TAM receptor tyrosine kinases AXL, TYRO3, and MER/MERTK. Carboxylated GAS6 binds phosphatidylserine-bearing membranes through its Gla domain and TAM receptor ectodomains through its C-terminal laminin G-like domains, promoting receptor activation, PI3K/AKT and ERK signaling, apoptotic-cell clearance, cell survival, and context-specific immune, vascular, platelet, and hematopoietic responses.
Definition: Binding phosphatidylserine-containing membranes and a TAM-family receptor tyrosine kinase to bridge the membrane surface to the receptor-bearing cell and promote TAM receptor activation.
Justification: GAS6 is currently split across receptor ligand activity, phosphatidylserine binding, and broad adaptor activity. A single MF term would more precisely capture the vitamin K-dependent bridging mechanism used by GAS6 and related TAM ligands during efferocytosis and activated-membrane signaling.
Parent term: receptor ligand activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT: negative regulation of apoptotic process is a recurrent GAS6/TAM signaling output in several cell types, including fibroblasts and oligodendrocytes. Reason: Gas6 protects cells from serum deprivation, TNF-alpha, and growth factor withdrawal through AXL/TAM signaling. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:0005615 extracellular space | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT: extracellular space is the correct functional location for the mature secreted GAS6 ligand. Reason: GAS6 has a signal peptide, is annotated by UniProt as secreted, and acts extracellularly on cell-surface TAM receptors. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0007166 cell surface receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT: GAS6 is directly involved in cell-surface receptor signaling through TAM receptor tyrosine kinases. Reason: Ligand binding to AXL/TYRO3/MERTK initiates receptor activation and downstream signaling at the cell surface. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT: positive regulation of PI3K/protein kinase B signaling is a well-supported GAS6/TAM output in oligodendrocytes, erythroblasts, and platelets. Reason: Multiple mouse-relevant experiments show Gas6/TAM signaling activates PI3K-Akt survival or platelet signaling pathways. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. PMID:15650770 Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0048018 receptor ligand activity | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT: receptor ligand activity is the clearest existing MF term for GAS6. Mouse GAS6 is a secreted vitamin K-dependent ligand for TAM receptor tyrosine kinases, especially AXL, and ligand binding activates receptor phosphorylation and downstream signaling. Reason: This term captures the core molecular role of GAS6 better than generic receptor-binding terms. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: calcium binding is supported by the Gla and calcium-binding EGF-like domains and is important for the carboxylated extracellular ligand, but it is an enabling structural property rather than the main biological function. Reason: Retain as an ancillary molecular property of GAS6, not as the curated core function. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: ACCEPT: extracellular region is a broader but correct location for secreted GAS6. Reason: The mature protein is secreted and functions outside the cell. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0016477 cell migration | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: cell migration is a known downstream outcome of GAS6/TAM signaling but is broad and cell-context dependent. Reason: Retain as a non-core downstream process. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:18787040 Silencing studies evaluated the role of Tyro3 and Axl in NLT GnRH neuronal cells and suggest that both play a role in Gas6 stimulation of GnRH neuronal survival and migration. |
| GO:0030154 cell differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: cell differentiation reflects context-specific immune or hematopoietic consequences of GAS6/TAM signaling rather than a primary GAS6 function. Reason: Retain as a broad non-core process. Supporting Evidence: PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0031669 cellular response to nutrient levels | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: cellular response to nutrient levels describes a context that can affect GAS6 expression or vitamin K-dependent modification, not the function executed by the GAS6 protein. Reason: Do not treat upstream expression or modification context as a core Gas6 biological process. Supporting Evidence: PMID:8336730 This finding thus defines a new member of vitamin K-dependent proteins that is expressed in many human and mouse tissues and may be involved in the regulation of a protease cascade relevant in growth regulation. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MODIFY | Summary: MODIFY: metal ion binding is too generic. GAS6 has specific calcium-binding Gla and EGF-like domains that support its vitamin K-dependent extracellular ligand function. Reason: Replace the generic metal-binding annotation with calcium ion binding. Proposed replacements: calcium ion binding Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. |
| GO:0050878 regulation of body fluid levels | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: regulation of body fluid levels is too broad and physiologically remote for the evidence reviewed. Reason: The direct function is secreted TAM ligand signaling, not general body-fluid regulation. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. |
| GO:0001786 phosphatidylserine binding | IEA GO_REF:0000107 | ACCEPT | Summary: ACCEPT: phosphatidylserine binding is a core biochemical property of vitamin K-carboxylated GAS6, allowing it to bridge PtdSer-exposed apoptotic or activated membranes to TAM receptors. Reason: The Gla-domain PtdSer interaction is central to GAS6-dependent TAM activation and efferocytosis. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0001961 positive regulation of cytokine-mediated signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: GAS6/TAM signaling can tune cytokine-mediated pathways, including Epo-associated erythroid survival and immune signaling, but this is context-dependent. Reason: The annotation is plausible as a downstream regulatory effect rather than the core function. Supporting Evidence: PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0003104 positive regulation of glomerular filtration | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: glomerular filtration is a high-level renal physiological phenotype and is too indirect for mouse Gas6 as a core GO process. Reason: The curated mechanism is extracellular TAM ligand signaling; renal filtration effects should be supported with narrower contextual evidence before retention as a core-like process. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000107 | MODIFY | Summary: MODIFY: signaling receptor binding is true but too generic for GAS6. The more informative annotation is receptor ligand activity for TAM receptor tyrosine kinases. Reason: Receptor ligand activity captures both binding and receptor activation. Proposed replacements: receptor ligand activity Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0005615 extracellular space | IEA GO_REF:0000120 | ACCEPT | Summary: ACCEPT: extracellular space is the correct functional location for the mature secreted GAS6 ligand. Reason: GAS6 has a signal peptide, is annotated by UniProt as secreted, and acts extracellularly on cell-surface TAM receptors. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | REMOVE | Summary: REMOVE: cytoplasm is not the functional location of mature GAS6. The reviewed protein is secreted and acts extracellularly on cell-surface TAM receptors. Reason: Any cytoplasmic signal would reflect biosynthesis or transfer noise rather than the active mature protein location. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0006909 phagocytosis | IEA GO_REF:0000107 | MODIFY | Summary: MODIFY: generic phagocytosis is too broad. GAS6 most specifically promotes apoptotic-cell clearance/efferocytosis via TAM receptors. Reason: Replace broad phagocytosis with apoptotic cell clearance for this ligand mechanism. Proposed replacements: apoptotic cell clearance Supporting Evidence: PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0007165 signal transduction | IEA GO_REF:0000120 | MODIFY | Summary: MODIFY: signal transduction is too broad. GAS6 specifically acts in cell-surface receptor signaling through TAM receptor tyrosine kinases. Reason: Replace with a more specific receptor-signaling process already supported for GAS6. Proposed replacements: cell surface receptor signaling pathway Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: ACCEPT: GAS6 is directly involved in cell-surface receptor signaling through TAM receptor tyrosine kinases. Reason: Ligand binding to AXL/TYRO3/MERTK initiates receptor activation and downstream signaling at the cell surface. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: positive regulation of gene expression is an indirect downstream consequence of receptor signaling and is too broad for Gas6 curation. Reason: Use signaling pathway terms rather than generic gene-expression outcomes for GAS6. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0010804 negative regulation of tumor necrosis factor-mediated signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: negative regulation of TNF-mediated signaling is consistent with GAS6/TAM anti-inflammatory and survival signaling, but it is a context-specific output. Reason: Retain as non-core because the primary molecular role is TAM receptor activation. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0019064 fusion of virus membrane with host plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: enveloped viruses can exploit GAS6/TAM phosphatidylserine bridging for apoptotic mimicry, but this host-factor role is not an evolved core function of mouse Gas6. Reason: Retain as a pathogen-context annotation, explicitly non-core. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0019079 viral genome replication | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: viral genome replication is an indirect pathogen-context consequence of GAS6/TAM-mediated viral entry or signaling and is not a core host function. Reason: Retain only as a non-core host-factor annotation. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0030674 protein-macromolecule adaptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: ACCEPT: GAS6 functions as an extracellular bridging/adaptor ligand by engaging phosphatidylserine-containing membranes through its Gla domain and TAM receptor ectodomains through its C-terminal LG domains. The term is imperfectly broad but captures this bridging role better than generic protein binding. Reason: The annotation represents a core bridging function, although a more specific PtdSer-dependent TAM receptor bridging MF would be preferable. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. |
| GO:0030971 receptor tyrosine kinase binding | IEA GO_REF:0000107 | ACCEPT | Summary: ACCEPT: receptor tyrosine kinase binding is directly supported because GAS6 binds and activates the TAM receptor tyrosine kinases AXL, TYRO3, and MER/MERTK. Reason: This specific binding term is mechanistically correct for the GAS6 receptor-ligand interaction. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0031100 animal organ regeneration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: organ regeneration is noted in UniProt/Falcon summaries for GAS6/TAM signaling, but it is a physiological outcome rather than a direct core function. Reason: Retain as a non-core tissue-repair outcome. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0032008 positive regulation of TOR signaling | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: TOR signaling can lie downstream of PI3K/AKT, but this is a secondary pathway branch rather than the primary GAS6 function. Reason: Retain as non-core downstream signaling. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032689 negative regulation of type II interferon production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: suppression of interferon-gamma/type II interferon production is consistent with reported GAS6/TAM immunoregulatory programs but is a downstream immune-context effect. Reason: Retain as non-core immunoregulation rather than primary GAS6 function. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032692 negative regulation of interleukin-1 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: reduced interleukin-1 production is consistent with TAM-mediated anti-inflammatory feedback but is not the primary molecular function of GAS6. Reason: Retain as non-core immunoregulatory output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032715 negative regulation of interleukin-6 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: reduced interleukin-6 production is consistent with GAS6/TAM anti-inflammatory signaling but is context-specific. Reason: Retain as non-core immunoregulatory output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032720 negative regulation of tumor necrosis factor production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: reduced tumor necrosis factor production is consistent with GAS6/TAM anti-inflammatory feedback but is not the core ligand function. Reason: Retain as non-core immunoregulatory output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032825 positive regulation of natural killer cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: natural killer cell differentiation is noted as a GAS6/TAM-associated immune outcome, but it is downstream and cell-context specific. Reason: Retain as non-core because the core role is extracellular TAM receptor activation. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0035457 cellular response to interferon-alpha | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: cellular response to interferon-alpha is a plausible immune-context annotation for TAM signaling crosstalk, but it is not a defining function of GAS6. Reason: Retain as non-core immune signaling context. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0035754 B cell chemotaxis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: B cell chemotaxis may reflect immune-cell responses to GAS6/TAM signaling, but it is a downstream context rather than the core molecular role. Reason: Retain as non-core pending more specific direct mouse evidence. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0043027 cysteine-type endopeptidase inhibitor activity involved in apoptotic process | IEA GO_REF:0000107 | MODIFY | Summary: MODIFY: GAS6 does not directly inhibit cysteine-type endopeptidases/caspases. It reduces apoptosis through TAM receptor signaling and downstream survival pathways. Reason: Replace the incorrect molecular-function term with the supported biological-process term for anti-apoptotic signaling. Proposed replacements: negative regulation of apoptotic process Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000107 | ACCEPT | Summary: ACCEPT: negative regulation of apoptotic process is a recurrent GAS6/TAM signaling output in several cell types, including fibroblasts and oligodendrocytes. Reason: Gas6 protects cells from serum deprivation, TNF-alpha, and growth factor withdrawal through AXL/TAM signaling. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:0043277 apoptotic cell clearance | IEA GO_REF:0000120 | ACCEPT | Summary: ACCEPT: apoptotic cell clearance is a core cellular role of GAS6/TAM signaling. GAS6 promotes recognition and phagocytosis of apoptotic cells by TAM-expressing phagocytes. Reason: The Sertoli-cell study and broader TAM literature support GAS6 as an efferocytosis ligand. Supporting Evidence: PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0045892 negative regulation of DNA-templated transcription | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: negative regulation of DNA-templated transcription is an indirect downstream signaling consequence and not a direct function of GAS6. Reason: This term overstates downstream transcriptional effects as a Gas6 process. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0046718 symbiont entry into host cell | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: symbiont/virus entry annotations reflect pathogen exploitation of GAS6/TAM phosphatidylserine bridging rather than physiological GAS6 function. Reason: Retain as non-core pathogen-context annotation. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0046813 receptor-mediated virion attachment to host cell | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: receptor-mediated virion attachment can occur through GAS6/TAM apoptotic mimicry, but it is a pathogen-context use of the normal PtdSer/TAM bridging mechanism. Reason: Retain as non-core pathogen-context annotation. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0046827 positive regulation of protein export from nucleus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: positive regulation of protein export from nucleus is too indirect and not part of the established GAS6/TAM ligand mechanism. Reason: No reviewed mouse evidence makes nuclear export a direct or central Gas6 function. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0048018 receptor ligand activity | IEA GO_REF:0000120 | ACCEPT | Summary: ACCEPT: receptor ligand activity is the clearest existing MF term for GAS6. Mouse GAS6 is a secreted vitamin K-dependent ligand for TAM receptor tyrosine kinases, especially AXL, and ligand binding activates receptor phosphorylation and downstream signaling. Reason: This term captures the core molecular role of GAS6 better than generic receptor-binding terms. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0050766 positive regulation of phagocytosis | IEA GO_REF:0000107 | ACCEPT | Summary: ACCEPT: positive regulation of phagocytosis is supported by Gas6-enhanced phagocytic uptake of apoptotic cells, especially in TAM receptor contexts. Reason: This is a core cellular consequence of the GAS6 phosphatidylserine/TAM bridging mechanism. Supporting Evidence: PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IEA GO_REF:0000120 | ACCEPT | Summary: ACCEPT: positive regulation of PI3K/protein kinase B signaling is a well-supported GAS6/TAM output in oligodendrocytes, erythroblasts, and platelets. Reason: Multiple mouse-relevant experiments show Gas6/TAM signaling activates PI3K-Akt survival or platelet signaling pathways. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. PMID:15650770 Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0070168 negative regulation of biomineral tissue development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: negative regulation of biomineral tissue development may reflect GAS6/AXL effects on survival/calcification contexts, but it is peripheral to the core ligand mechanism. Reason: Retain as non-core because the direct role is TAM receptor signaling. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0070588 calcium ion transmembrane transport | IEA GO_REF:0000107 | REMOVE | Summary: REMOVE: GAS6 binds calcium as a vitamin K-dependent Gla/EGF-domain protein but is not a calcium transporter and does not mediate calcium transmembrane transport. Reason: The term confuses calcium binding with transport activity. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. |
| GO:0071307 cellular response to vitamin K | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: vitamin K is required for GAS6 gamma-carboxylation, but GAS6 is a vitamin K-dependent protein rather than a mediator of cellular response to vitamin K. Reason: Post-translational dependence should not be represented as a protein-level response process. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. |
| GO:0071333 cellular response to glucose stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: cellular response to glucose stimulus is too far upstream or contextual for the reviewed Gas6 evidence. Reason: The direct Gas6 role is extracellular TAM receptor signaling, not glucose-response execution. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0071466 cellular response to xenobiotic stimulus | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: xenobiotic-response annotations likely reflect warfarin sensitivity of GAS6 carboxylation rather than a function performed by GAS6. Reason: Warfarin affects GAS6 maturation; GAS6 itself should not be curated as mediating a xenobiotic response without direct evidence. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. |
| GO:0072659 protein localization to plasma membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: protein localization to plasma membrane is a downstream or inferred cellular effect and is not a precise annotation for secreted GAS6. Reason: The appropriate direct annotation is extracellular TAM receptor ligand/signaling activity. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. |
| GO:0085029 extracellular matrix assembly | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: extracellular matrix assembly is likely an indirect fibroblast/secretome-context association and not a direct Gas6 function. Reason: Retain the extracellular-location evidence but do not curate ECM assembly as a core or direct process. Supporting Evidence: PMID:24006456 Mouse cardiac fibroblasts were transfected with pre-/anti-miR of miR-29b and miR-30c, and their conditioned medium was analyzed by mass spectrometry. |
| GO:0097028 dendritic cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: dendritic-cell differentiation is plausible within GAS6/TAM immune regulation, but it is a downstream immune-context annotation. Reason: Retain as non-core. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0097241 hematopoietic stem cell migration to bone marrow | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: hematopoietic stem cell migration to bone marrow is a specific hematopoietic context and not the main molecular function of GAS6. Reason: Retain as non-core pending direct mouse-specific support. Supporting Evidence: PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. |
| GO:1900142 negative regulation of oligodendrocyte apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: protection of oligodendrocytes from apoptosis is experimentally supported but is a specific cellular context of the broader GAS6/TAM survival pathway. Reason: Retain as non-core cell-type-specific survival output. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. |
| GO:2000270 negative regulation of fibroblast apoptotic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Gas6 supports fibroblast survival under starvation, but the cell-type-specific anti-apoptotic term is a downstream outcome. Reason: Retain as non-core survival output. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:2000352 negative regulation of endothelial cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: endothelial-cell survival is consistent with UniProt-described GAS6/AXL function, but this cell-type-specific survival outcome is non-core. Reason: Retain as non-core survival output. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:2000510 positive regulation of dendritic cell chemotaxis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: dendritic-cell chemotaxis is a context-specific immune-cell response and not the defining role of GAS6. Reason: Retain as non-core immune-cell outcome. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:2000533 negative regulation of renal albumin absorption | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: renal albumin absorption is a very specific renal outcome transferred from orthologous/automated evidence and is not established as a direct mouse Gas6 function here. Reason: This appears downstream and context-specific relative to the conserved TAM ligand role. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:2000669 negative regulation of dendritic cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: dendritic-cell survival regulation is plausible for GAS6/TAM immune signaling but is a cell-context-specific outcome. Reason: Retain as non-core immune-cell survival output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0001934 positive regulation of protein phosphorylation | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: positive regulation of protein phosphorylation is broadly correct for GAS6/TAM signaling but less specific than positive regulation of protein kinase activity and PI3K/AKT signaling. Reason: Retain as a broad downstream signaling consequence, not as a primary core annotation. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0001934 positive regulation of protein phosphorylation | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: positive regulation of protein phosphorylation is broadly correct for GAS6/TAM signaling but less specific than positive regulation of protein kinase activity and PI3K/AKT signaling. Reason: Retain as a broad downstream signaling consequence, not as a primary core annotation. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0006468 protein phosphorylation | ISO GO_REF:0000119 | MODIFY | Summary: MODIFY: protein phosphorylation incorrectly suggests GAS6 participates in the phosphorylation process itself. GAS6 is the extracellular ligand that activates receptor and downstream protein kinases. Reason: Replace with positive regulation of protein kinase activity, which accurately describes ligand-mediated kinase activation. Proposed replacements: positive regulation of protein kinase activity Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032148 activation of protein kinase B activity | ISO GO_REF:0000096 | ACCEPT | Summary: ACCEPT: activation of protein kinase B activity is supported as a direct downstream effect of GAS6/Axl signaling. Reason: The term captures the AKT activation branch of GAS6/TAM signaling. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. PMID:15650770 Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. |
| GO:0045860 positive regulation of protein kinase activity | ISO GO_REF:0000119 | ACCEPT | Summary: ACCEPT: GAS6 positively regulates protein kinase activity by activating TAM receptor tyrosine kinases and downstream kinases such as AKT and ERK. Reason: This regulatory BP accurately describes ligand-driven activation without implying that GAS6 itself is a kinase. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0001786 phosphatidylserine binding | ISO GO_REF:0000119 | ACCEPT | Summary: ACCEPT: phosphatidylserine binding is a core biochemical property of vitamin K-carboxylated GAS6, allowing it to bridge PtdSer-exposed apoptotic or activated membranes to TAM receptors. Reason: The Gla-domain PtdSer interaction is central to GAS6-dependent TAM activation and efferocytosis. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0001961 positive regulation of cytokine-mediated signaling pathway | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: GAS6/TAM signaling can tune cytokine-mediated pathways, including Epo-associated erythroid survival and immune signaling, but this is context-dependent. Reason: The annotation is plausible as a downstream regulatory effect rather than the core function. Supporting Evidence: PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0003104 positive regulation of glomerular filtration | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: glomerular filtration is a high-level renal physiological phenotype and is too indirect for mouse Gas6 as a core GO process. Reason: The curated mechanism is extracellular TAM ligand signaling; renal filtration effects should be supported with narrower contextual evidence before retention as a core-like process. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0005102 signaling receptor binding | ISO GO_REF:0000119 | MODIFY | Summary: MODIFY: signaling receptor binding is true but too generic for GAS6. The more informative annotation is receptor ligand activity for TAM receptor tyrosine kinases. Reason: Receptor ligand activity captures both binding and receptor activation. Proposed replacements: receptor ligand activity Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0005615 extracellular space | ISO GO_REF:0000096 | ACCEPT | Summary: ACCEPT: extracellular space is the correct functional location for the mature secreted GAS6 ligand. Reason: GAS6 has a signal peptide, is annotated by UniProt as secreted, and acts extracellularly on cell-surface TAM receptors. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0005615 extracellular space | ISO GO_REF:0000119 | ACCEPT | Summary: ACCEPT: extracellular space is the correct functional location for the mature secreted GAS6 ligand. Reason: GAS6 has a signal peptide, is annotated by UniProt as secreted, and acts extracellularly on cell-surface TAM receptors. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0005737 cytoplasm | ISO GO_REF:0000119 | REMOVE | Summary: REMOVE: cytoplasm is not the functional location of mature GAS6. The reviewed protein is secreted and acts extracellularly on cell-surface TAM receptors. Reason: Any cytoplasmic signal would reflect biosynthesis or transfer noise rather than the active mature protein location. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0006909 phagocytosis | ISO GO_REF:0000119 | MODIFY | Summary: MODIFY: generic phagocytosis is too broad. GAS6 most specifically promotes apoptotic-cell clearance/efferocytosis via TAM receptors. Reason: Replace broad phagocytosis with apoptotic cell clearance for this ligand mechanism. Proposed replacements: apoptotic cell clearance Supporting Evidence: PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0007165 signal transduction | ISO GO_REF:0000096 | MODIFY | Summary: MODIFY: signal transduction is too broad. GAS6 specifically acts in cell-surface receptor signaling through TAM receptor tyrosine kinases. Reason: Replace with a more specific receptor-signaling process already supported for GAS6. Proposed replacements: cell surface receptor signaling pathway Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. |
| GO:0007165 signal transduction | ISO GO_REF:0000119 | MODIFY | Summary: MODIFY: signal transduction is too broad. GAS6 specifically acts in cell-surface receptor signaling through TAM receptor tyrosine kinases. Reason: Replace with a more specific receptor-signaling process already supported for GAS6. Proposed replacements: cell surface receptor signaling pathway Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. |
| GO:0007166 cell surface receptor signaling pathway | ISO GO_REF:0000119 | ACCEPT | Summary: ACCEPT: GAS6 is directly involved in cell-surface receptor signaling through TAM receptor tyrosine kinases. Reason: Ligand binding to AXL/TYRO3/MERTK initiates receptor activation and downstream signaling at the cell surface. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0010628 positive regulation of gene expression | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: positive regulation of gene expression is an indirect downstream consequence of receptor signaling and is too broad for Gas6 curation. Reason: Use signaling pathway terms rather than generic gene-expression outcomes for GAS6. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0010804 negative regulation of tumor necrosis factor-mediated signaling pathway | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: negative regulation of TNF-mediated signaling is consistent with GAS6/TAM anti-inflammatory and survival signaling, but it is a context-specific output. Reason: Retain as non-core because the primary molecular role is TAM receptor activation. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0019064 fusion of virus membrane with host plasma membrane | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: enveloped viruses can exploit GAS6/TAM phosphatidylserine bridging for apoptotic mimicry, but this host-factor role is not an evolved core function of mouse Gas6. Reason: Retain as a pathogen-context annotation, explicitly non-core. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0019079 viral genome replication | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: viral genome replication is an indirect pathogen-context consequence of GAS6/TAM-mediated viral entry or signaling and is not a core host function. Reason: Retain only as a non-core host-factor annotation. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0030674 protein-macromolecule adaptor activity | ISO GO_REF:0000119 | ACCEPT | Summary: ACCEPT: GAS6 functions as an extracellular bridging/adaptor ligand by engaging phosphatidylserine-containing membranes through its Gla domain and TAM receptor ectodomains through its C-terminal LG domains. The term is imperfectly broad but captures this bridging role better than generic protein binding. Reason: The annotation represents a core bridging function, although a more specific PtdSer-dependent TAM receptor bridging MF would be preferable. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. |
| GO:0030971 receptor tyrosine kinase binding | ISO GO_REF:0000119 | ACCEPT | Summary: ACCEPT: receptor tyrosine kinase binding is directly supported because GAS6 binds and activates the TAM receptor tyrosine kinases AXL, TYRO3, and MER/MERTK. Reason: This specific binding term is mechanistically correct for the GAS6 receptor-ligand interaction. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0032008 positive regulation of TOR signaling | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: TOR signaling can lie downstream of PI3K/AKT, but this is a secondary pathway branch rather than the primary GAS6 function. Reason: Retain as non-core downstream signaling. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032689 negative regulation of type II interferon production | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: suppression of interferon-gamma/type II interferon production is consistent with reported GAS6/TAM immunoregulatory programs but is a downstream immune-context effect. Reason: Retain as non-core immunoregulation rather than primary GAS6 function. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032692 negative regulation of interleukin-1 production | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: reduced interleukin-1 production is consistent with TAM-mediated anti-inflammatory feedback but is not the primary molecular function of GAS6. Reason: Retain as non-core immunoregulatory output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032715 negative regulation of interleukin-6 production | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: reduced interleukin-6 production is consistent with GAS6/TAM anti-inflammatory signaling but is context-specific. Reason: Retain as non-core immunoregulatory output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032720 negative regulation of tumor necrosis factor production | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: reduced tumor necrosis factor production is consistent with GAS6/TAM anti-inflammatory feedback but is not the core ligand function. Reason: Retain as non-core immunoregulatory output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032825 positive regulation of natural killer cell differentiation | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: natural killer cell differentiation is noted as a GAS6/TAM-associated immune outcome, but it is downstream and cell-context specific. Reason: Retain as non-core because the core role is extracellular TAM receptor activation. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0035457 cellular response to interferon-alpha | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: cellular response to interferon-alpha is a plausible immune-context annotation for TAM signaling crosstalk, but it is not a defining function of GAS6. Reason: Retain as non-core immune signaling context. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0035754 B cell chemotaxis | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: B cell chemotaxis may reflect immune-cell responses to GAS6/TAM signaling, but it is a downstream context rather than the core molecular role. Reason: Retain as non-core pending more specific direct mouse evidence. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0043027 cysteine-type endopeptidase inhibitor activity involved in apoptotic process | ISO GO_REF:0000119 | MODIFY | Summary: MODIFY: GAS6 does not directly inhibit cysteine-type endopeptidases/caspases. It reduces apoptosis through TAM receptor signaling and downstream survival pathways. Reason: Replace the incorrect molecular-function term with the supported biological-process term for anti-apoptotic signaling. Proposed replacements: negative regulation of apoptotic process Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. |
| GO:0043066 negative regulation of apoptotic process | ISO GO_REF:0000119 | ACCEPT | Summary: ACCEPT: negative regulation of apoptotic process is a recurrent GAS6/TAM signaling output in several cell types, including fibroblasts and oligodendrocytes. Reason: Gas6 protects cells from serum deprivation, TNF-alpha, and growth factor withdrawal through AXL/TAM signaling. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:0043277 apoptotic cell clearance | ISO GO_REF:0000119 | ACCEPT | Summary: ACCEPT: apoptotic cell clearance is a core cellular role of GAS6/TAM signaling. GAS6 promotes recognition and phagocytosis of apoptotic cells by TAM-expressing phagocytes. Reason: The Sertoli-cell study and broader TAM literature support GAS6 as an efferocytosis ligand. Supporting Evidence: PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0045892 negative regulation of DNA-templated transcription | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: negative regulation of DNA-templated transcription is an indirect downstream signaling consequence and not a direct function of GAS6. Reason: This term overstates downstream transcriptional effects as a Gas6 process. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0046718 symbiont entry into host cell | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: symbiont/virus entry annotations reflect pathogen exploitation of GAS6/TAM phosphatidylserine bridging rather than physiological GAS6 function. Reason: Retain as non-core pathogen-context annotation. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0046813 receptor-mediated virion attachment to host cell | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: receptor-mediated virion attachment can occur through GAS6/TAM apoptotic mimicry, but it is a pathogen-context use of the normal PtdSer/TAM bridging mechanism. Reason: Retain as non-core pathogen-context annotation. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0046827 positive regulation of protein export from nucleus | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: positive regulation of protein export from nucleus is too indirect and not part of the established GAS6/TAM ligand mechanism. Reason: No reviewed mouse evidence makes nuclear export a direct or central Gas6 function. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0048018 receptor ligand activity | ISO GO_REF:0000119 | ACCEPT | Summary: ACCEPT: receptor ligand activity is the clearest existing MF term for GAS6. Mouse GAS6 is a secreted vitamin K-dependent ligand for TAM receptor tyrosine kinases, especially AXL, and ligand binding activates receptor phosphorylation and downstream signaling. Reason: This term captures the core molecular role of GAS6 better than generic receptor-binding terms. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0048146 positive regulation of fibroblast proliferation | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Gas6 stimulates cardiac fibroblast proliferation through vitamin K-dependent Axl/ERK signaling, but fibroblast proliferation is a tissue-specific outcome. Reason: Retain as a supported non-core biological effect. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:0050766 positive regulation of phagocytosis | ISO GO_REF:0000119 | ACCEPT | Summary: ACCEPT: positive regulation of phagocytosis is supported by Gas6-enhanced phagocytic uptake of apoptotic cells, especially in TAM receptor contexts. Reason: This is a core cellular consequence of the GAS6 phosphatidylserine/TAM bridging mechanism. Supporting Evidence: PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | ISO GO_REF:0000096 | ACCEPT | Summary: ACCEPT: positive regulation of PI3K/protein kinase B signaling is a well-supported GAS6/TAM output in oligodendrocytes, erythroblasts, and platelets. Reason: Multiple mouse-relevant experiments show Gas6/TAM signaling activates PI3K-Akt survival or platelet signaling pathways. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. PMID:15650770 Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | ISO GO_REF:0000119 | ACCEPT | Summary: ACCEPT: positive regulation of PI3K/protein kinase B signaling is a well-supported GAS6/TAM output in oligodendrocytes, erythroblasts, and platelets. Reason: Multiple mouse-relevant experiments show Gas6/TAM signaling activates PI3K-Akt survival or platelet signaling pathways. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. PMID:15650770 Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0070168 negative regulation of biomineral tissue development | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: negative regulation of biomineral tissue development may reflect GAS6/AXL effects on survival/calcification contexts, but it is peripheral to the core ligand mechanism. Reason: Retain as non-core because the direct role is TAM receptor signaling. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0070588 calcium ion transmembrane transport | ISO GO_REF:0000119 | REMOVE | Summary: REMOVE: GAS6 binds calcium as a vitamin K-dependent Gla/EGF-domain protein but is not a calcium transporter and does not mediate calcium transmembrane transport. Reason: The term confuses calcium binding with transport activity. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. |
| GO:0071307 cellular response to vitamin K | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: vitamin K is required for GAS6 gamma-carboxylation, but GAS6 is a vitamin K-dependent protein rather than a mediator of cellular response to vitamin K. Reason: Post-translational dependence should not be represented as a protein-level response process. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. |
| GO:0071333 cellular response to glucose stimulus | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: cellular response to glucose stimulus is too far upstream or contextual for the reviewed Gas6 evidence. Reason: The direct Gas6 role is extracellular TAM receptor signaling, not glucose-response execution. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0071466 cellular response to xenobiotic stimulus | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: xenobiotic-response annotations likely reflect warfarin sensitivity of GAS6 carboxylation rather than a function performed by GAS6. Reason: Warfarin affects GAS6 maturation; GAS6 itself should not be curated as mediating a xenobiotic response without direct evidence. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. |
| GO:0071466 cellular response to xenobiotic stimulus | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: xenobiotic-response annotations likely reflect warfarin sensitivity of GAS6 carboxylation rather than a function performed by GAS6. Reason: Warfarin affects GAS6 maturation; GAS6 itself should not be curated as mediating a xenobiotic response without direct evidence. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. |
| GO:0072659 protein localization to plasma membrane | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: protein localization to plasma membrane is a downstream or inferred cellular effect and is not a precise annotation for secreted GAS6. Reason: The appropriate direct annotation is extracellular TAM receptor ligand/signaling activity. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. |
| GO:0097241 hematopoietic stem cell migration to bone marrow | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: hematopoietic stem cell migration to bone marrow is a specific hematopoietic context and not the main molecular function of GAS6. Reason: Retain as non-core pending direct mouse-specific support. Supporting Evidence: PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. |
| GO:1900142 negative regulation of oligodendrocyte apoptotic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: protection of oligodendrocytes from apoptosis is experimentally supported but is a specific cellular context of the broader GAS6/TAM survival pathway. Reason: Retain as non-core cell-type-specific survival output. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. |
| GO:2000270 negative regulation of fibroblast apoptotic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Gas6 supports fibroblast survival under starvation, but the cell-type-specific anti-apoptotic term is a downstream outcome. Reason: Retain as non-core survival output. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:2000352 negative regulation of endothelial cell apoptotic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: endothelial-cell survival is consistent with UniProt-described GAS6/AXL function, but this cell-type-specific survival outcome is non-core. Reason: Retain as non-core survival output. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:2000510 positive regulation of dendritic cell chemotaxis | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: dendritic-cell chemotaxis is a context-specific immune-cell response and not the defining role of GAS6. Reason: Retain as non-core immune-cell outcome. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:2000669 negative regulation of dendritic cell apoptotic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: dendritic-cell survival regulation is plausible for GAS6/TAM immune signaling but is a cell-context-specific outcome. Reason: Retain as non-core immune-cell survival output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0048018 receptor ligand activity | ISS GO_REF:0000024 | ACCEPT | Summary: ACCEPT: receptor ligand activity is the clearest existing MF term for GAS6. Mouse GAS6 is a secreted vitamin K-dependent ligand for TAM receptor tyrosine kinases, especially AXL, and ligand binding activates receptor phosphorylation and downstream signaling. Reason: This term captures the core molecular role of GAS6 better than generic receptor-binding terms. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0030674 protein-macromolecule adaptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: ACCEPT: GAS6 functions as an extracellular bridging/adaptor ligand by engaging phosphatidylserine-containing membranes through its Gla domain and TAM receptor ectodomains through its C-terminal LG domains. The term is imperfectly broad but captures this bridging role better than generic protein binding. Reason: The annotation represents a core bridging function, although a more specific PtdSer-dependent TAM receptor bridging MF would be preferable. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. |
| GO:0005615 extracellular space | HDA PMID:24006456 Extracellular matrix secretion by cardiac fibroblasts: role ... | ACCEPT | Summary: ACCEPT: extracellular space is the correct functional location for the mature secreted GAS6 ligand. Reason: GAS6 has a signal peptide, is annotated by UniProt as secreted, and acts extracellularly on cell-surface TAM receptors. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0046827 positive regulation of protein export from nucleus | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: positive regulation of protein export from nucleus is too indirect and not part of the established GAS6/TAM ligand mechanism. Reason: No reviewed mouse evidence makes nuclear export a direct or central Gas6 function. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | REMOVE | Summary: REMOVE: cytoplasm is not the functional location of mature GAS6. The reviewed protein is secreted and acts extracellularly on cell-surface TAM receptors. Reason: Any cytoplasmic signal would reflect biosynthesis or transfer noise rather than the active mature protein location. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0045860 positive regulation of protein kinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ACCEPT: GAS6 positively regulates protein kinase activity by activating TAM receptor tyrosine kinases and downstream kinases such as AKT and ERK. Reason: This regulatory BP accurately describes ligand-driven activation without implying that GAS6 itself is a kinase. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0048146 positive regulation of fibroblast proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Gas6 stimulates cardiac fibroblast proliferation through vitamin K-dependent Axl/ERK signaling, but fibroblast proliferation is a tissue-specific outcome. Reason: Retain as a supported non-core biological effect. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:0032715 negative regulation of interleukin-6 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: reduced interleukin-6 production is consistent with GAS6/TAM anti-inflammatory signaling but is context-specific. Reason: Retain as non-core immunoregulatory output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0019064 fusion of virus membrane with host plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: enveloped viruses can exploit GAS6/TAM phosphatidylserine bridging for apoptotic mimicry, but this host-factor role is not an evolved core function of mouse Gas6. Reason: Retain as a pathogen-context annotation, explicitly non-core. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0046813 receptor-mediated virion attachment to host cell | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: receptor-mediated virion attachment can occur through GAS6/TAM apoptotic mimicry, but it is a pathogen-context use of the normal PtdSer/TAM bridging mechanism. Reason: Retain as non-core pathogen-context annotation. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0001786 phosphatidylserine binding | ISS GO_REF:0000024 | ACCEPT | Summary: ACCEPT: phosphatidylserine binding is a core biochemical property of vitamin K-carboxylated GAS6, allowing it to bridge PtdSer-exposed apoptotic or activated membranes to TAM receptors. Reason: The Gla-domain PtdSer interaction is central to GAS6-dependent TAM activation and efferocytosis. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0001961 positive regulation of cytokine-mediated signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: GAS6/TAM signaling can tune cytokine-mediated pathways, including Epo-associated erythroid survival and immune signaling, but this is context-dependent. Reason: The annotation is plausible as a downstream regulatory effect rather than the core function. Supporting Evidence: PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0006909 phagocytosis | ISS GO_REF:0000024 | MODIFY | Summary: MODIFY: generic phagocytosis is too broad. GAS6 most specifically promotes apoptotic-cell clearance/efferocytosis via TAM receptors. Reason: Replace broad phagocytosis with apoptotic cell clearance for this ligand mechanism. Proposed replacements: apoptotic cell clearance Supporting Evidence: PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0010628 positive regulation of gene expression | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: positive regulation of gene expression is an indirect downstream consequence of receptor signaling and is too broad for Gas6 curation. Reason: Use signaling pathway terms rather than generic gene-expression outcomes for GAS6. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0010804 negative regulation of tumor necrosis factor-mediated signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: negative regulation of TNF-mediated signaling is consistent with GAS6/TAM anti-inflammatory and survival signaling, but it is a context-specific output. Reason: Retain as non-core because the primary molecular role is TAM receptor activation. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0019079 viral genome replication | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: viral genome replication is an indirect pathogen-context consequence of GAS6/TAM-mediated viral entry or signaling and is not a core host function. Reason: Retain only as a non-core host-factor annotation. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0032689 negative regulation of type II interferon production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: suppression of interferon-gamma/type II interferon production is consistent with reported GAS6/TAM immunoregulatory programs but is a downstream immune-context effect. Reason: Retain as non-core immunoregulation rather than primary GAS6 function. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032692 negative regulation of interleukin-1 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: reduced interleukin-1 production is consistent with TAM-mediated anti-inflammatory feedback but is not the primary molecular function of GAS6. Reason: Retain as non-core immunoregulatory output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032720 negative regulation of tumor necrosis factor production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: reduced tumor necrosis factor production is consistent with GAS6/TAM anti-inflammatory feedback but is not the core ligand function. Reason: Retain as non-core immunoregulatory output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032825 positive regulation of natural killer cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: natural killer cell differentiation is noted as a GAS6/TAM-associated immune outcome, but it is downstream and cell-context specific. Reason: Retain as non-core because the core role is extracellular TAM receptor activation. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0035457 cellular response to interferon-alpha | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: cellular response to interferon-alpha is a plausible immune-context annotation for TAM signaling crosstalk, but it is not a defining function of GAS6. Reason: Retain as non-core immune signaling context. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0035754 B cell chemotaxis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: B cell chemotaxis may reflect immune-cell responses to GAS6/TAM signaling, but it is a downstream context rather than the core molecular role. Reason: Retain as non-core pending more specific direct mouse evidence. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0043027 cysteine-type endopeptidase inhibitor activity involved in apoptotic process | ISS GO_REF:0000024 | MODIFY | Summary: MODIFY: GAS6 does not directly inhibit cysteine-type endopeptidases/caspases. It reduces apoptosis through TAM receptor signaling and downstream survival pathways. Reason: Replace the incorrect molecular-function term with the supported biological-process term for anti-apoptotic signaling. Proposed replacements: negative regulation of apoptotic process Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. |
| GO:0045892 negative regulation of DNA-templated transcription | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: negative regulation of DNA-templated transcription is an indirect downstream signaling consequence and not a direct function of GAS6. Reason: This term overstates downstream transcriptional effects as a Gas6 process. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0046718 symbiont entry into host cell | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: symbiont/virus entry annotations reflect pathogen exploitation of GAS6/TAM phosphatidylserine bridging rather than physiological GAS6 function. Reason: Retain as non-core pathogen-context annotation. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0050766 positive regulation of phagocytosis | ISS GO_REF:0000024 | ACCEPT | Summary: ACCEPT: positive regulation of phagocytosis is supported by Gas6-enhanced phagocytic uptake of apoptotic cells, especially in TAM receptor contexts. Reason: This is a core cellular consequence of the GAS6 phosphatidylserine/TAM bridging mechanism. Supporting Evidence: PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0070168 negative regulation of biomineral tissue development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: negative regulation of biomineral tissue development may reflect GAS6/AXL effects on survival/calcification contexts, but it is peripheral to the core ligand mechanism. Reason: Retain as non-core because the direct role is TAM receptor signaling. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0097241 hematopoietic stem cell migration to bone marrow | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: hematopoietic stem cell migration to bone marrow is a specific hematopoietic context and not the main molecular function of GAS6. Reason: Retain as non-core pending direct mouse-specific support. Supporting Evidence: PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. |
| GO:2000669 negative regulation of dendritic cell apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: dendritic-cell survival regulation is plausible for GAS6/TAM immune signaling but is a cell-context-specific outcome. Reason: Retain as non-core immune-cell survival output. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0001934 positive regulation of protein phosphorylation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: positive regulation of protein phosphorylation is broadly correct for GAS6/TAM signaling but less specific than positive regulation of protein kinase activity and PI3K/AKT signaling. Reason: Retain as a broad downstream signaling consequence, not as a primary core annotation. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0003104 positive regulation of glomerular filtration | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: glomerular filtration is a high-level renal physiological phenotype and is too indirect for mouse Gas6 as a core GO process. Reason: The curated mechanism is extracellular TAM ligand signaling; renal filtration effects should be supported with narrower contextual evidence before retention as a core-like process. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0005102 signaling receptor binding | ISS GO_REF:0000024 | MODIFY | Summary: MODIFY: signaling receptor binding is true but too generic for GAS6. The more informative annotation is receptor ligand activity for TAM receptor tyrosine kinases. Reason: Receptor ligand activity captures both binding and receptor activation. Proposed replacements: receptor ligand activity Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0006468 protein phosphorylation | ISS GO_REF:0000024 | MODIFY | Summary: MODIFY: protein phosphorylation incorrectly suggests GAS6 participates in the phosphorylation process itself. GAS6 is the extracellular ligand that activates receptor and downstream protein kinases. Reason: Replace with positive regulation of protein kinase activity, which accurately describes ligand-mediated kinase activation. Proposed replacements: positive regulation of protein kinase activity Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032008 positive regulation of TOR signaling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: TOR signaling can lie downstream of PI3K/AKT, but this is a secondary pathway branch rather than the primary GAS6 function. Reason: Retain as non-core downstream signaling. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0032148 activation of protein kinase B activity | ISS GO_REF:0000024 | ACCEPT | Summary: ACCEPT: activation of protein kinase B activity is supported as a direct downstream effect of GAS6/Axl signaling. Reason: The term captures the AKT activation branch of GAS6/TAM signaling. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. PMID:15650770 Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | ISS GO_REF:0000024 | ACCEPT | Summary: ACCEPT: positive regulation of PI3K/protein kinase B signaling is a well-supported GAS6/TAM output in oligodendrocytes, erythroblasts, and platelets. Reason: Multiple mouse-relevant experiments show Gas6/TAM signaling activates PI3K-Akt survival or platelet signaling pathways. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. PMID:15650770 Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0071307 cellular response to vitamin K | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: vitamin K is required for GAS6 gamma-carboxylation, but GAS6 is a vitamin K-dependent protein rather than a mediator of cellular response to vitamin K. Reason: Post-translational dependence should not be represented as a protein-level response process. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. |
| GO:0071333 cellular response to glucose stimulus | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: cellular response to glucose stimulus is too far upstream or contextual for the reviewed Gas6 evidence. Reason: The direct Gas6 role is extracellular TAM receptor signaling, not glucose-response execution. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0071466 cellular response to xenobiotic stimulus | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: xenobiotic-response annotations likely reflect warfarin sensitivity of GAS6 carboxylation rather than a function performed by GAS6. Reason: Warfarin affects GAS6 maturation; GAS6 itself should not be curated as mediating a xenobiotic response without direct evidence. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. |
| GO:0072659 protein localization to plasma membrane | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: protein localization to plasma membrane is a downstream or inferred cellular effect and is not a precise annotation for secreted GAS6. Reason: The appropriate direct annotation is extracellular TAM receptor ligand/signaling activity. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. |
| GO:0085029 extracellular matrix assembly | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: extracellular matrix assembly is likely an indirect fibroblast/secretome-context association and not a direct Gas6 function. Reason: Retain the extracellular-location evidence but do not curate ECM assembly as a core or direct process. Supporting Evidence: PMID:24006456 Mouse cardiac fibroblasts were transfected with pre-/anti-miR of miR-29b and miR-30c, and their conditioned medium was analyzed by mass spectrometry. |
| GO:2000270 negative regulation of fibroblast apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Gas6 supports fibroblast survival under starvation, but the cell-type-specific anti-apoptotic term is a downstream outcome. Reason: Retain as non-core survival output. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:2000352 negative regulation of endothelial cell apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: endothelial-cell survival is consistent with UniProt-described GAS6/AXL function, but this cell-type-specific survival outcome is non-core. Reason: Retain as non-core survival output. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:2000533 negative regulation of renal albumin absorption | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: renal albumin absorption is a very specific renal outcome transferred from orthologous/automated evidence and is not established as a direct mouse Gas6 function here. Reason: This appears downstream and context-specific relative to the conserved TAM ligand role. Supporting Evidence: file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:16723520 Gas6/Axl signaling activates the phosphatidylinositol 3-kina... | ACCEPT | Summary: ACCEPT: negative regulation of apoptotic process is a recurrent GAS6/TAM signaling output in several cell types, including fibroblasts and oligodendrocytes. Reason: Gas6 protects cells from serum deprivation, TNF-alpha, and growth factor withdrawal through AXL/TAM signaling. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:0001764 neuron migration | IGI PMID:18787040 Axl and Tyro3 modulate female reproduction by influencing go... | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: GnRH neuron migration/survival depends on Axl and Tyro3 and is stimulated by Gas6 in the cited system, but it is a developmental consequence of TAM signaling rather than the main GAS6 function. Reason: Retain as a supported developmental phenotype-level annotation, non-core. Supporting Evidence: PMID:18787040 Silencing studies evaluated the role of Tyro3 and Axl in NLT GnRH neuronal cells and suggest that both play a role in Gas6 stimulation of GnRH neuronal survival and migration. |
| GO:0005615 extracellular space | IDA PMID:18188450 Role of Gas6 in erythropoiesis and anemia in mice. | ACCEPT | Summary: ACCEPT: extracellular space is the correct functional location for the mature secreted GAS6 ligand. Reason: GAS6 has a signal peptide, is annotated by UniProt as secreted, and acts extracellularly on cell-surface TAM receptors. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0031589 cell-substrate adhesion | IMP PMID:18188450 Role of Gas6 in erythropoiesis and anemia in mice. | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: erythroid or stromal adhesion effects may occur in the anemia/Epo context, but they are downstream of Gas6 signaling and not the defining molecular function. Reason: Retain as a context-specific non-core outcome. Supporting Evidence: PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:18188450 Role of Gas6 in erythropoiesis and anemia in mice. | ACCEPT | Summary: ACCEPT: negative regulation of apoptotic process is a recurrent GAS6/TAM signaling output in several cell types, including fibroblasts and oligodendrocytes. Reason: Gas6 protects cells from serum deprivation, TNF-alpha, and growth factor withdrawal through AXL/TAM signaling. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:0043277 apoptotic cell clearance | IDA PMID:18159085 Gas6 and the Tyro 3 receptor tyrosine kinase subfamily regul... | ACCEPT | Summary: ACCEPT: apoptotic cell clearance is a core cellular role of GAS6/TAM signaling. GAS6 promotes recognition and phagocytosis of apoptotic cells by TAM-expressing phagocytes. Reason: The Sertoli-cell study and broader TAM literature support GAS6 as an efferocytosis ligand. Supporting Evidence: PMID:18159085 The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon highlights efferocytosis as a central GAS6/TAM function, with GAS6 bridging apoptotic-cell phosphatidylserine to TAM receptors on phagocytes. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IMP PMID:18188450 Role of Gas6 in erythropoiesis and anemia in mice. | ACCEPT | Summary: ACCEPT: positive regulation of PI3K/protein kinase B signaling is a well-supported GAS6/TAM output in oligodendrocytes, erythroblasts, and platelets. Reason: Multiple mouse-relevant experiments show Gas6/TAM signaling activates PI3K-Akt survival or platelet signaling pathways. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. PMID:15650770 Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0071363 cellular response to growth factor stimulus | IMP PMID:18188450 Role of Gas6 in erythropoiesis and anemia in mice. | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Gas6 participates in cellular responses to growth-factor contexts such as Epo and serum-starvation/growth stimulation, but this term is broad and context-dependent. Reason: Retain as non-core because it describes the biological context, not the primary molecular activity. Supporting Evidence: PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. PMID:8336730 This finding thus defines a new member of vitamin K-dependent proteins that is expressed in many human and mouse tissues and may be involved in the regulation of a protease cascade relevant in growth regulation. |
| GO:0007596 blood coagulation | IMP PMID:15184064 Vitamin K-dependent Gas6 activates ERK kinase and stimulates... | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: Gas6 influences platelet signaling and thrombus stabilization, but blood coagulation is too broad and can imply direct participation in the coagulation cascade. Reason: Gas6-deficient or TAM-blocked mice have impaired thrombus stabilization without the protein acting as a coagulation enzyme or core cascade component. Supporting Evidence: PMID:15650770 Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:15184064 Vitamin K-dependent Gas6 activates ERK kinase and stimulates... | ACCEPT | Summary: ACCEPT: negative regulation of apoptotic process is a recurrent GAS6/TAM signaling output in several cell types, including fibroblasts and oligodendrocytes. Reason: Gas6 protects cells from serum deprivation, TNF-alpha, and growth factor withdrawal through AXL/TAM signaling. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:0048018 receptor ligand activity | ISO GO_REF:0000008 | ACCEPT | Summary: ACCEPT: receptor ligand activity is the clearest existing MF term for GAS6. Mouse GAS6 is a secreted vitamin K-dependent ligand for TAM receptor tyrosine kinases, especially AXL, and ligand binding activates receptor phosphorylation and downstream signaling. Reason: This term captures the core molecular role of GAS6 better than generic receptor-binding terms. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0048146 positive regulation of fibroblast proliferation | ISO GO_REF:0000008 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Gas6 stimulates cardiac fibroblast proliferation through vitamin K-dependent Axl/ERK signaling, but fibroblast proliferation is a tissue-specific outcome. Reason: Retain as a supported non-core biological effect. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IGI PMID:15650770 Role of Gas6 receptors in platelet signaling during thrombus... | ACCEPT | Summary: ACCEPT: positive regulation of PI3K/protein kinase B signaling is a well-supported GAS6/TAM output in oligodendrocytes, erythroblasts, and platelets. Reason: Multiple mouse-relevant experiments show Gas6/TAM signaling activates PI3K-Akt survival or platelet signaling pathways. Supporting Evidence: PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. PMID:15650770 Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | ISO GO_REF:0000008 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: ERK1/ERK2 activation is experimentally supported in cardiac fibroblasts but is one context-specific signaling branch downstream of the TAM receptor-ligand interaction. Reason: Retain as a supported downstream outcome, but do not treat it as the defining GAS6 function. Supporting Evidence: PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon identifies PI3K-AKT, MEK-ERK/MAPK, SRC/GRB2, and SOCS-linked inflammatory feedback as major GAS6/TAM signaling outputs. |
| GO:0007167 enzyme-linked receptor protein signaling pathway | IGI PMID:9395235 Signaling through the ARK tyrosine kinase receptor protects ... | ACCEPT | Summary: ACCEPT: enzyme-linked receptor protein signaling pathway is appropriate because GAS6 activates TAM receptor tyrosine kinases. Reason: The primary signaling receptors for GAS6 are enzyme-linked receptor tyrosine kinases. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:9395235 Signaling through the ARK tyrosine kinase receptor protects ... | ACCEPT | Summary: ACCEPT: negative regulation of apoptotic process is a recurrent GAS6/TAM signaling output in several cell types, including fibroblasts and oligodendrocytes. Reason: Gas6 protects cells from serum deprivation, TNF-alpha, and growth factor withdrawal through AXL/TAM signaling. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:0043066 negative regulation of apoptotic process | IGI PMID:9395235 Signaling through the ARK tyrosine kinase receptor protects ... | ACCEPT | Summary: ACCEPT: negative regulation of apoptotic process is a recurrent GAS6/TAM signaling output in several cell types, including fibroblasts and oligodendrocytes. Reason: Gas6 protects cells from serum deprivation, TNF-alpha, and growth factor withdrawal through AXL/TAM signaling. Supporting Evidence: PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:16723520 We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFalpha-mediated cell death. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. |
| GO:0048018 receptor ligand activity | IDA PMID:9395235 Signaling through the ARK tyrosine kinase receptor protects ... | ACCEPT | Summary: ACCEPT: receptor ligand activity is the clearest existing MF term for GAS6. Mouse GAS6 is a secreted vitamin K-dependent ligand for TAM receptor tyrosine kinases, especially AXL, and ligand binding activates receptor phosphorylation and downstream signaling. Reason: This term captures the core molecular role of GAS6 better than generic receptor-binding terms. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt describes mouse GAS6 as a ligand for AXL, TYRO3 and MER receptor tyrosine kinases, with roles in cell growth, survival, adhesion, migration, platelet activation, and thrombotic responses. PMID:9395235 Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. PMID:15184064 Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0005615 extracellular space | ISO PMID:8336730 The protein encoded by a growth arrest-specific gene (gas6) ... | ACCEPT | Summary: ACCEPT: extracellular space is the correct functional location for the mature secreted GAS6 ligand. Reason: GAS6 has a signal peptide, is annotated by UniProt as secreted, and acts extracellularly on cell-surface TAM receptors. Supporting Evidence: file:mouse/Gas6/Gas6-uniprot.txt UniProt annotates the mature mouse GAS6 protein as secreted and notes vitamin K-dependent gamma-carboxyglutamate residues required for calcium binding. file:mouse/Gas6/Gas6-deep-research-falcon.md Falcon summarizes mouse GAS6 as a secreted vitamin K-dependent ligand that bridges phosphatidylserine-bearing membranes to TAM receptors and triggers receptor dimerization and kinase activation. |
| GO:0009267 cellular response to starvation | IDA PMID:8336730 The protein encoded by a growth arrest-specific gene (gas6) ... | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: serum starvation induces gas6 expression, but expression context is not the same as a function of the GAS6 protein in cellular response to starvation. Reason: Avoid conflating gene expression regulation with gene product function. Supporting Evidence: PMID:8336730 This finding thus defines a new member of vitamin K-dependent proteins that is expressed in many human and mouse tissues and may be involved in the regulation of a protease cascade relevant in growth regulation. |
| GO:0071363 cellular response to growth factor stimulus | IDA PMID:8336730 The protein encoded by a growth arrest-specific gene (gas6) ... | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Gas6 participates in cellular responses to growth-factor contexts such as Epo and serum-starvation/growth stimulation, but this term is broad and context-dependent. Reason: Retain as non-core because it describes the biological context, not the primary molecular activity. Supporting Evidence: PMID:18188450 Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. PMID:8336730 This finding thus defines a new member of vitamin K-dependent proteins that is expressed in many human and mouse tissues and may be involved in the regulation of a protease cascade relevant in growth regulation. |
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Download this section (compressed HTML)Q: Should GAS6 viral-entry annotations be retained as host-factor annotations for pathogen exploitation of the PtdSer/TAM mechanism, or moved out of core gene-function curation?
Q: Would GO prefer a new molecular-function term for phosphatidylserine-dependent TAM receptor bridging activity, or should this mechanism be represented with receptor ligand activity plus annotation extensions?
Experiment: Compare fully carboxylated recombinant mouse GAS6 with warfarin-produced/non-carboxylated GAS6 in matched AXL-, TYRO3-, and MERTK-expressing phagocyte assays measuring receptor phosphorylation, apoptotic-cell binding, and engulfment.
Hypothesis: Gamma-carboxylated mouse GAS6 activates TAM receptors and promotes apoptotic-cell clearance more effectively than non-carboxylated GAS6.
Type: biochemical receptor activation and efferocytosis assay
Experiment: Use tissue-specific Gas6 perturbation or rescue models with direct TAM signaling readouts to determine whether these high-level phenotypes persist after controlling for general survival/efferocytosis effects.
Hypothesis: Renal, biomineralization, and nuclear-export annotations are secondary context effects rather than direct conserved GAS6 functions.
Type: conditional mouse genetics with pathway readouts
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