GAS6 encodes growth arrest-specific protein 6, a secreted vitamin K-dependent TAM receptor ligand. Its gamma-carboxylated Gla domain binds phosphatidylserine on apoptotic or stressed membranes, while its C-terminal laminin-G/SHBG-like region binds AXL, TYRO3, and MERTK, enabling receptor activation, efferocytosis, immune homeostasis, and context-specific survival, migration, and remodeling signals.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: negative regulation of apoptotic process is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of apoptotic process is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0005615 extracellular space | IBA GO_REF:0000033 | ACCEPT | Summary: Extracellular space is the principal functional location for secreted GAS6. Reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. |
| GO:0007166 cell surface receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Cell surface receptor signaling pathway is supported by GAS6-mediated activation of TAM receptor tyrosine kinases. Reason: cell surface receptor signaling pathway is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of GAS6-TAM receptor activation. Reason: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. PMID:16359517 gamma-carboxylation is also required for both Axl phosphorylation and PI3 kinase activation. |
| GO:0048018 receptor ligand activity | IBA GO_REF:0000033 | ACCEPT | Summary: Receptor ligand activity is the core molecular function of GAS6 as an extracellular TAM receptor ligand. Reason: receptor ligand activity is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. PMID:7854420 We report here the purification of an Axl stimulatory factor, and its identification as the product of growth-arrest-specific gene 6 (ref. 6). |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Calcium ion binding is supported by the vitamin K-dependent Gla domain needed for Ca2+-dependent phospholipid binding. Reason: calcium ion binding is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Extracellular region is supported by GAS6 secretion and extracellular receptor-ligand activity. Reason: extracellular region is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. |
| GO:0005796 Golgi lumen | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Golgi lumen is compatible with GAS6 secretion, maturation, storage, or extracellular-vesicle association but is secondary to extracellular TAM receptor activation. Reason: Golgi lumen is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: Cell surface receptor signaling pathway is supported by GAS6-mediated activation of TAM receptor tyrosine kinases. Reason: cell surface receptor signaling pathway is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. |
| GO:0016477 cell migration | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: cell migration is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: cell migration is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0030154 cell differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: cell differentiation is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: cell differentiation is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0031669 cellular response to nutrient levels | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Cellular response to nutrient levels describes a cellular state rather than the direct function of the GAS6 protein product. Reason: cellular response to nutrient levels overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. |
| GO:0043277 apoptotic cell clearance | IEA GO_REF:0000117 | ACCEPT | Summary: Apoptotic cell clearance is a core biological role of the GAS6/TAM bridging mechanism. Reason: apoptotic cell clearance is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Mechanistically, PS-dependent recruitment of GAS6 to apoptotic/stressed membranes couples “eat-me” recognition (PS exposure) to TAM receptor activation on efferocytes, linking structure/PTM to function. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MODIFY | Summary: Metal ion binding should be narrowed to calcium ion binding because the GAS6 Gla domain supports Ca2+-dependent phospholipid binding. Reason: metal ion binding should be replaced by a term that better matches the GAS6 mechanism. Proposed replacements: calcium ion binding Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:2000270 negative regulation of fibroblast apoptotic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: negative regulation of fibroblast apoptotic process is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of fibroblast apoptotic process is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0003104 positive regulation of glomerular filtration | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Glomerular filtration is a tissue-level phenotype and overstates the direct function of GAS6 relative to its extracellular TAM ligand mechanism. Reason: positive regulation of glomerular filtration overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0005615 extracellular space | IEA GO_REF:0000120 | ACCEPT | Summary: Extracellular space is the principal functional location for secreted GAS6. Reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. |
| GO:0007165 signal transduction | IEA GO_REF:0000107 | MODIFY | Summary: Signal transduction is directionally correct but too generic for GAS6; cell surface receptor signaling better captures TAM receptor activation. Reason: signal transduction should be replaced by a term that better matches the GAS6 mechanism. Proposed replacements: cell surface receptor signaling pathway Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. |
| GO:0031100 animal organ regeneration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: animal organ regeneration is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: animal organ regeneration is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0032008 positive regulation of TOR signaling | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: positive regulation of TOR signaling is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: positive regulation of TOR signaling is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0048018 receptor ligand activity | IEA GO_REF:0000120 | ACCEPT | Summary: Receptor ligand activity is the core molecular function of GAS6 as an extracellular TAM receptor ligand. Reason: receptor ligand activity is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. PMID:7854420 We report here the purification of an Axl stimulatory factor, and its identification as the product of growth-arrest-specific gene 6 (ref. 6). |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IEA GO_REF:0000120 | ACCEPT | Summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of GAS6-TAM receptor activation. Reason: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. PMID:16359517 gamma-carboxylation is also required for both Axl phosphorylation and PI3 kinase activation. |
| GO:0071333 cellular response to glucose stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cellular response to glucose stimulus is an upstream/context annotation and is not a direct GAS6 product function. Reason: cellular response to glucose stimulus overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. |
| GO:0071466 cellular response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cellular response to xenobiotic stimulus is an upstream/context annotation and is not a direct GAS6 product function. Reason: cellular response to xenobiotic stimulus overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:0085029 extracellular matrix assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: extracellular matrix assembly is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: extracellular matrix assembly is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:2000533 negative regulation of renal albumin absorption | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Renal albumin absorption is a tissue-level phenotype and should not be treated as a core molecular function of GAS6. Reason: negative regulation of renal albumin absorption overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-202710 | ACCEPT | Summary: Extracellular region is supported by GAS6 secretion and extracellular receptor-ligand activity. Reason: extracellular region is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-481007 | ACCEPT | Summary: Extracellular region is supported by GAS6 secretion and extracellular receptor-ligand activity. Reason: extracellular region is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-163809 | KEEP AS NON CORE | Summary: endoplasmic reticulum lumen is compatible with GAS6 secretion, maturation, storage, or extracellular-vesicle association but is secondary to extracellular TAM receptor activation. Reason: endoplasmic reticulum lumen is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | KEEP AS NON CORE | Summary: endoplasmic reticulum lumen is compatible with GAS6 secretion, maturation, storage, or extracellular-vesicle association but is secondary to extracellular TAM receptor activation. Reason: endoplasmic reticulum lumen is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-163809 | KEEP AS NON CORE | Summary: Golgi lumen is compatible with GAS6 secretion, maturation, storage, or extracellular-vesicle association but is secondary to extracellular TAM receptor activation. Reason: Golgi lumen is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-163843 | KEEP AS NON CORE | Summary: Golgi lumen is compatible with GAS6 secretion, maturation, storage, or extracellular-vesicle association but is secondary to extracellular TAM receptor activation. Reason: Golgi lumen is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:0031093 platelet alpha granule lumen | TAS Reactome:R-HSA-481007 | KEEP AS NON CORE | Summary: platelet alpha granule lumen is compatible with GAS6 secretion, maturation, storage, or extracellular-vesicle association but is secondary to extracellular TAM receptor activation. Reason: platelet alpha granule lumen is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:0007166 cell surface receptor signaling pathway | IDA PMID:20103767 TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in... | ACCEPT | Summary: Cell surface receptor signaling pathway is supported by GAS6-mediated activation of TAM receptor tyrosine kinases. Reason: cell surface receptor signaling pathway is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. |
| GO:0048018 receptor ligand activity | IDA PMID:20103767 TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in... | ACCEPT | Summary: Receptor ligand activity is the core molecular function of GAS6 as an extracellular TAM receptor ligand. Reason: receptor ligand activity is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. PMID:7854420 We report here the purification of an Axl stimulatory factor, and its identification as the product of growth-arrest-specific gene 6 (ref. 6). |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IDA PMID:20103767 TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in... | ACCEPT | Summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of GAS6-TAM receptor activation. Reason: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. PMID:16359517 gamma-carboxylation is also required for both Axl phosphorylation and PI3 kinase activation. |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:21501828 The soluble serum protein Gas6 bridges virion envelope phosp... | ACCEPT | Summary: Protein-macromolecule adaptor activity captures the bridging mechanism linking phosphatidylserine-bearing membranes to TAM receptors. Reason: protein-macromolecule adaptor activity is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Mechanistically, PS-dependent recruitment of GAS6 to apoptotic/stressed membranes couples “eat-me” recognition (PS exposure) to TAM receptor activation on efferocytes, linking structure/PTM to function. |
| GO:0046827 positive regulation of protein export from nucleus | IDA PMID:18680538 GAS6-induced signaling in human endothelial cells is mediate... | KEEP AS NON CORE | Summary: positive regulation of protein export from nucleus is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: positive regulation of protein export from nucleus is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:2000352 negative regulation of endothelial cell apoptotic process | IDA PMID:18680538 GAS6-induced signaling in human endothelial cells is mediate... | KEEP AS NON CORE | Summary: negative regulation of endothelial cell apoptotic process is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of endothelial cell apoptotic process is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: extracellular exosome is compatible with GAS6 secretion, maturation, storage, or extracellular-vesicle association but is secondary to extracellular TAM receptor activation. Reason: extracellular exosome is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:0070588 calcium ion transmembrane transport | IDA PMID:18395422 Endogenous Gas6 and Ca2+ -channel activation modulate phagoc... | MODIFY | Summary: The evidence connects GAS6 to MerTK-dependent phagocytosis with calcium-channel involvement, but GAS6 is not itself a calcium transporter. Reason: calcium ion transmembrane transport should be replaced by a term that better matches the GAS6 mechanism. Proposed replacements: positive regulation of phagocytosis Supporting Evidence: PMID:18395422 Blocking L-type Ca(2+)-channels with nifedipine inhibited MerTK dependent phagocytosis in vitro. |
| GO:0005615 extracellular space | IDA PMID:18395422 Endogenous Gas6 and Ca2+ -channel activation modulate phagoc... | ACCEPT | Summary: Extracellular space is the principal functional location for secreted GAS6. Reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. |
| GO:0005615 extracellular space | IDA PMID:19922767 GAS6/Mer axis regulates the homing and survival of the E2A/P... | ACCEPT | Summary: Extracellular space is the principal functional location for secreted GAS6. Reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. |
| GO:0005737 cytoplasm | IDA PMID:18395422 Endogenous Gas6 and Ca2+ -channel activation modulate phagoc... | MARK AS OVER ANNOTATED | Summary: Cytoplasm is not the principal functional location for mature GAS6, which acts as a secreted extracellular ligand. Reason: cytoplasm overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. |
| GO:0001934 positive regulation of protein phosphorylation | IDA PMID:7854420 Axl receptor tyrosine kinase stimulated by the vitamin K-dep... | ACCEPT | Summary: Positive regulation of protein phosphorylation is supported because GAS6 activates TAM receptor phosphorylation and downstream kinase signaling. Reason: positive regulation of protein phosphorylation is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: PMID:16359517 gamma-carboxylation is also required for both Axl phosphorylation and PI3 kinase activation. file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. |
| GO:0005102 signaling receptor binding | IPI PMID:7854420 Axl receptor tyrosine kinase stimulated by the vitamin K-dep... | ACCEPT | Summary: Signaling receptor binding is supported by direct GAS6 interaction with TAM receptor ectodomains. Reason: signaling receptor binding is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. PMID:7854420 We report here the purification of an Axl stimulatory factor, and its identification as the product of growth-arrest-specific gene 6 (ref. 6). |
| GO:0007165 signal transduction | IDA PMID:7854420 Axl receptor tyrosine kinase stimulated by the vitamin K-dep... | MODIFY | Summary: Signal transduction is directionally correct but too generic for GAS6; cell surface receptor signaling better captures TAM receptor activation. Reason: signal transduction should be replaced by a term that better matches the GAS6 mechanism. Proposed replacements: cell surface receptor signaling pathway Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. |
| GO:0045860 positive regulation of protein kinase activity | IDA PMID:7854420 Axl receptor tyrosine kinase stimulated by the vitamin K-dep... | ACCEPT | Summary: Positive regulation of protein kinase activity is supported by GAS6-dependent TAM receptor and downstream kinase activation. Reason: positive regulation of protein kinase activity is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: PMID:16359517 gamma-carboxylation is also required for both Axl phosphorylation and PI3 kinase activation. file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. |
| GO:0048146 positive regulation of fibroblast proliferation | IDA PMID:7854420 Axl receptor tyrosine kinase stimulated by the vitamin K-dep... | KEEP AS NON CORE | Summary: positive regulation of fibroblast proliferation is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: positive regulation of fibroblast proliferation is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0032715 negative regulation of interleukin-6 production | IDA PMID:20103767 TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in... | KEEP AS NON CORE | Summary: negative regulation of interleukin-6 production is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of interleukin-6 production is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0019064 fusion of virus membrane with host plasma membrane | IDA PMID:21501828 The soluble serum protein Gas6 bridges virion envelope phosp... | KEEP AS NON CORE | Summary: fusion of virus membrane with host plasma membrane is supported in a viral-entry/apoptotic-mimicry context, but this is not the core host function of GAS6. Reason: fusion of virus membrane with host plasma membrane is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: PMID:21501828 Gas6 mediates binding of the virus to target cells by bridging virion envelope phosphatidylserine to Axl, a TAM receptor tyrosine kinase on target cells. file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. |
| GO:0046813 receptor-mediated virion attachment to host cell | IDA PMID:21501828 The soluble serum protein Gas6 bridges virion envelope phosp... | KEEP AS NON CORE | Summary: receptor-mediated virion attachment to host cell is supported in a viral-entry/apoptotic-mimicry context, but this is not the core host function of GAS6. Reason: receptor-mediated virion attachment to host cell is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: PMID:21501828 Gas6 mediates binding of the virus to target cells by bridging virion envelope phosphatidylserine to Axl, a TAM receptor tyrosine kinase on target cells. file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. |
| GO:0006909 phagocytosis | IDA PMID:21501828 The soluble serum protein Gas6 bridges virion envelope phosp... | ACCEPT | Summary: Phagocytosis is supported in the efferocytosis context where GAS6 bridges phosphatidylserine to TAM receptors on phagocytes. Reason: phagocytosis is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Mechanistically, PS-dependent recruitment of GAS6 to apoptotic/stressed membranes couples “eat-me” recognition (PS exposure) to TAM receptor activation on efferocytes, linking structure/PTM to function. |
| GO:0043277 apoptotic cell clearance | IDA PMID:21501828 The soluble serum protein Gas6 bridges virion envelope phosp... | ACCEPT | Summary: Apoptotic cell clearance is a core biological role of the GAS6/TAM bridging mechanism. Reason: apoptotic cell clearance is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Mechanistically, PS-dependent recruitment of GAS6 to apoptotic/stressed membranes couples “eat-me” recognition (PS exposure) to TAM receptor activation on efferocytes, linking structure/PTM to function. |
| GO:1900142 negative regulation of oligodendrocyte apoptotic process | IDA PMID:16723520 Gas6/Axl signaling activates the phosphatidylinositol 3-kina... | KEEP AS NON CORE | Summary: negative regulation of oligodendrocyte apoptotic process is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of oligodendrocyte apoptotic process is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0001786 phosphatidylserine binding | IDA PMID:21501828 The soluble serum protein Gas6 bridges virion envelope phosp... | ACCEPT | Summary: Phosphatidylserine binding is central to GAS6 function as a bridge between PS-positive membranes and TAM receptors. Reason: phosphatidylserine binding is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Experimental dissection of GAS6 function shows that **γ-carboxylation and PS binding are indispensable for full TAM activation**: warfarin or mutation of key glutamates involved in PS binding eliminates receptor activation despite residual receptor binding; conversely, non-γ-carboxylated or Gla/EGF deletion mutants can bind TAM receptors but behave as **blocking/decoy ligands** rather than agonists. file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. |
| GO:0001961 positive regulation of cytokine-mediated signaling pathway | IMP PMID:18840707 The Axl/Gas6 pathway is required for optimal cytokine signal... | KEEP AS NON CORE | Summary: positive regulation of cytokine-mediated signaling pathway is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: positive regulation of cytokine-mediated signaling pathway is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0005515 protein binding | IPI PMID:18760998 Gas6-mediated signaling is dependent on the engagement of it... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for GAS6; receptor tyrosine kinase binding, receptor ligand activity, phosphatidylserine binding, and adaptor activity better represent the mechanism. Reason: protein binding overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Experimental dissection of GAS6 function shows that **γ-carboxylation and PS binding are indispensable for full TAM activation**: warfarin or mutation of key glutamates involved in PS binding eliminates receptor activation despite residual receptor binding; conversely, non-γ-carboxylated or Gla/EGF deletion mutants can bind TAM receptors but behave as **blocking/decoy ligands** rather than agonists. |
| GO:0005515 protein binding | IPI PMID:20088931 Gas6 is complexed to the soluble tyrosine kinase receptor Ax... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for GAS6; receptor tyrosine kinase binding, receptor ligand activity, phosphatidylserine binding, and adaptor activity better represent the mechanism. Reason: protein binding overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Experimental dissection of GAS6 function shows that **γ-carboxylation and PS binding are indispensable for full TAM activation**: warfarin or mutation of key glutamates involved in PS binding eliminates receptor activation despite residual receptor binding; conversely, non-γ-carboxylated or Gla/EGF deletion mutants can bind TAM receptors but behave as **blocking/decoy ligands** rather than agonists. |
| GO:0005515 protein binding | IPI PMID:20103767 TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for GAS6; receptor tyrosine kinase binding, receptor ligand activity, phosphatidylserine binding, and adaptor activity better represent the mechanism. Reason: protein binding overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Experimental dissection of GAS6 function shows that **γ-carboxylation and PS binding are indispensable for full TAM activation**: warfarin or mutation of key glutamates involved in PS binding eliminates receptor activation despite residual receptor binding; conversely, non-γ-carboxylated or Gla/EGF deletion mutants can bind TAM receptors but behave as **blocking/decoy ligands** rather than agonists. |
| GO:0005615 extracellular space | IDA PMID:20088931 Gas6 is complexed to the soluble tyrosine kinase receptor Ax... | ACCEPT | Summary: Extracellular space is the principal functional location for secreted GAS6. Reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. |
| GO:0007165 signal transduction | IDA PMID:18680538 GAS6-induced signaling in human endothelial cells is mediate... | MODIFY | Summary: Signal transduction is directionally correct but too generic for GAS6; cell surface receptor signaling better captures TAM receptor activation. Reason: signal transduction should be replaced by a term that better matches the GAS6 mechanism. Proposed replacements: cell surface receptor signaling pathway Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. |
| GO:0010628 positive regulation of gene expression | IDA PMID:19657094 Survival and migration of human dendritic cells are regulate... | KEEP AS NON CORE | Summary: positive regulation of gene expression is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: positive regulation of gene expression is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0010804 negative regulation of tumor necrosis factor-mediated signaling pathway | IDA PMID:19657094 Survival and migration of human dendritic cells are regulate... | KEEP AS NON CORE | Summary: negative regulation of tumor necrosis factor-mediated signaling pathway is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of tumor necrosis factor-mediated signaling pathway is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0019079 viral genome replication | IDA PMID:21501828 The soluble serum protein Gas6 bridges virion envelope phosp... | KEEP AS NON CORE | Summary: viral genome replication is supported in a viral-entry/apoptotic-mimicry context, but this is not the core host function of GAS6. Reason: viral genome replication is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: PMID:21501828 Gas6 mediates binding of the virus to target cells by bridging virion envelope phosphatidylserine to Axl, a TAM receptor tyrosine kinase on target cells. file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. |
| GO:0032689 negative regulation of type II interferon production | IDA PMID:18840707 The Axl/Gas6 pathway is required for optimal cytokine signal... | KEEP AS NON CORE | Summary: negative regulation of type II interferon production is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of type II interferon production is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0032692 negative regulation of interleukin-1 production | IDA PMID:20103767 TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in... | KEEP AS NON CORE | Summary: negative regulation of interleukin-1 production is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of interleukin-1 production is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0032715 negative regulation of interleukin-6 production | IDA PMID:19657094 Survival and migration of human dendritic cells are regulate... | KEEP AS NON CORE | Summary: negative regulation of interleukin-6 production is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of interleukin-6 production is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0032720 negative regulation of tumor necrosis factor production | IDA PMID:19657094 Survival and migration of human dendritic cells are regulate... | KEEP AS NON CORE | Summary: negative regulation of tumor necrosis factor production is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of tumor necrosis factor production is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0032720 negative regulation of tumor necrosis factor production | IDA PMID:20103767 TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in... | KEEP AS NON CORE | Summary: negative regulation of tumor necrosis factor production is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of tumor necrosis factor production is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0032825 positive regulation of natural killer cell differentiation | IDA PMID:18840707 The Axl/Gas6 pathway is required for optimal cytokine signal... | KEEP AS NON CORE | Summary: positive regulation of natural killer cell differentiation is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: positive regulation of natural killer cell differentiation is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0035457 cellular response to interferon-alpha | IDA PMID:19657094 Survival and migration of human dendritic cells are regulate... | KEEP AS NON CORE | Summary: cellular response to interferon-alpha is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: cellular response to interferon-alpha is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0035754 B cell chemotaxis | IDA PMID:19922767 GAS6/Mer axis regulates the homing and survival of the E2A/P... | KEEP AS NON CORE | Summary: B cell chemotaxis is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: B cell chemotaxis is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:19922767 GAS6/Mer axis regulates the homing and survival of the E2A/P... | KEEP AS NON CORE | Summary: negative regulation of apoptotic process is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of apoptotic process is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:18680538 GAS6-induced signaling in human endothelial cells is mediate... | KEEP AS NON CORE | Summary: negative regulation of DNA-templated transcription is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of DNA-templated transcription is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0046718 symbiont entry into host cell | IDA PMID:21501828 The soluble serum protein Gas6 bridges virion envelope phosp... | KEEP AS NON CORE | Summary: symbiont entry into host cell is supported in a viral-entry/apoptotic-mimicry context, but this is not the core host function of GAS6. Reason: symbiont entry into host cell is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: PMID:21501828 Gas6 mediates binding of the virus to target cells by bridging virion envelope phosphatidylserine to Axl, a TAM receptor tyrosine kinase on target cells. file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IDA PMID:18680538 GAS6-induced signaling in human endothelial cells is mediate... | ACCEPT | Summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of GAS6-TAM receptor activation. Reason: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. PMID:16359517 gamma-carboxylation is also required for both Axl phosphorylation and PI3 kinase activation. |
| GO:0070168 negative regulation of biomineral tissue development | IDA PMID:20048160 Androgen receptor-dependent transactivation of growth arrest... | KEEP AS NON CORE | Summary: negative regulation of biomineral tissue development is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of biomineral tissue development is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0097028 dendritic cell differentiation | IEP PMID:19657094 Survival and migration of human dendritic cells are regulate... | KEEP AS NON CORE | Summary: dendritic cell differentiation is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: dendritic cell differentiation is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0097241 hematopoietic stem cell migration to bone marrow | IDA PMID:19922767 GAS6/Mer axis regulates the homing and survival of the E2A/P... | KEEP AS NON CORE | Summary: hematopoietic stem cell migration to bone marrow is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: hematopoietic stem cell migration to bone marrow is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:2000352 negative regulation of endothelial cell apoptotic process | IDA PMID:18760998 Gas6-mediated signaling is dependent on the engagement of it... | KEEP AS NON CORE | Summary: negative regulation of endothelial cell apoptotic process is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of endothelial cell apoptotic process is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:2000510 positive regulation of dendritic cell chemotaxis | IDA PMID:19657094 Survival and migration of human dendritic cells are regulate... | KEEP AS NON CORE | Summary: positive regulation of dendritic cell chemotaxis is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: positive regulation of dendritic cell chemotaxis is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:2000669 negative regulation of dendritic cell apoptotic process | IDA PMID:19657094 Survival and migration of human dendritic cells are regulate... | KEEP AS NON CORE | Summary: negative regulation of dendritic cell apoptotic process is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of dendritic cell apoptotic process is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0043027 cysteine-type endopeptidase inhibitor activity involved in apoptotic process | IDA PMID:16723520 Gas6/Axl signaling activates the phosphatidylinositol 3-kina... | MODIFY | Summary: The oligodendrocyte evidence supports anti-apoptotic signaling through AXL/PI3K/AKT, not direct cysteine-type endopeptidase inhibitor activity by GAS6. Reason: cysteine-type endopeptidase inhibitor activity involved in apoptotic process should be replaced by a term that better matches the GAS6 mechanism. 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. |
| GO:0050766 positive regulation of phagocytosis | IDA PMID:18395422 Endogenous Gas6 and Ca2+ -channel activation modulate phagoc... | ACCEPT | Summary: Positive regulation of phagocytosis is supported by GAS6-dependent TAM signaling during apoptotic-cell clearance. Reason: positive regulation of phagocytosis is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. file:human/GAS6/GAS6-deep-research-falcon.md Mechanistically, PS-dependent recruitment of GAS6 to apoptotic/stressed membranes couples “eat-me” recognition (PS exposure) to TAM receptor activation on efferocytes, linking structure/PTM to function. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IDA PMID:16723520 Gas6/Axl signaling activates the phosphatidylinositol 3-kina... | ACCEPT | Summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of GAS6-TAM receptor activation. Reason: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. PMID:16359517 gamma-carboxylation is also required for both Axl phosphorylation and PI3 kinase activation. |
| GO:0001934 positive regulation of protein phosphorylation | ISS GO_REF:0000024 | ACCEPT | Summary: Positive regulation of protein phosphorylation is supported because GAS6 activates TAM receptor phosphorylation and downstream kinase signaling. Reason: positive regulation of protein phosphorylation is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: PMID:16359517 gamma-carboxylation is also required for both Axl phosphorylation and PI3 kinase activation. file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. |
| GO:0003104 positive regulation of glomerular filtration | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Glomerular filtration is a tissue-level phenotype and overstates the direct function of GAS6 relative to its extracellular TAM ligand mechanism. Reason: positive regulation of glomerular filtration overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0032008 positive regulation of TOR signaling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: positive regulation of TOR signaling is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: positive regulation of TOR signaling is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0032148 activation of protein kinase B activity | ISS GO_REF:0000024 | ACCEPT | Summary: Activation of protein kinase B activity is supported by the GAS6-AXL-PI3K/AKT survival pathway. Reason: activation of protein kinase B activity is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. 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:0071333 cellular response to glucose stimulus | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Cellular response to glucose stimulus is an upstream/context annotation and is not a direct GAS6 product function. Reason: cellular response to glucose stimulus overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. |
| GO:0085029 extracellular matrix assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: extracellular matrix assembly is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: extracellular matrix assembly is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:2000533 negative regulation of renal albumin absorption | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Renal albumin absorption is a tissue-level phenotype and should not be treated as a core molecular function of GAS6. Reason: negative regulation of renal albumin absorption overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0005102 signaling receptor binding | IDA PMID:16359517 The role of gamma-carboxylation in the anti-apoptotic functi... | ACCEPT | Summary: Signaling receptor binding is supported by direct GAS6 interaction with TAM receptor ectodomains. Reason: signaling receptor binding is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. PMID:7854420 We report here the purification of an Axl stimulatory factor, and its identification as the product of growth-arrest-specific gene 6 (ref. 6). |
| GO:0006468 protein phosphorylation | IDA PMID:16359517 The role of gamma-carboxylation in the anti-apoptotic functi... | MODIFY | Summary: GAS6 stimulates receptor and downstream kinase phosphorylation rather than catalyzing protein phosphorylation. Reason: protein phosphorylation should be replaced by a term that better matches the GAS6 mechanism. Proposed replacements: positive regulation of protein phosphorylation Supporting Evidence: PMID:16359517 gamma-carboxylation is also required for both Axl phosphorylation and PI3 kinase activation. file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IDA PMID:16359517 The role of gamma-carboxylation in the anti-apoptotic functi... | ACCEPT | Summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of GAS6-TAM receptor activation. Reason: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. PMID:16359517 gamma-carboxylation is also required for both Axl phosphorylation and PI3 kinase activation. |
| GO:0071307 cellular response to vitamin K | IDA PMID:16359517 The role of gamma-carboxylation in the anti-apoptotic functi... | MARK AS OVER ANNOTATED | Summary: Cellular response to vitamin K overstates the role of GAS6; vitamin K-dependent gamma-carboxylation modifies GAS6 rather than defining a GAS6 response pathway. Reason: cellular response to vitamin K overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:0071466 cellular response to xenobiotic stimulus | IDA PMID:16359517 The role of gamma-carboxylation in the anti-apoptotic functi... | MARK AS OVER ANNOTATED | Summary: Cellular response to xenobiotic stimulus is an upstream/context annotation and is not a direct GAS6 product function. Reason: cellular response to xenobiotic stimulus overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md A critical PTM is **vitamin K–dependent γ-carboxylation** of glutamate residues in the Gla domain, which supports Ca2+-dependent binding to anionic phospholipids/PS; pharmacologic blockade (e.g., **warfarin**) inhibits this maturation step and can abrogate GAS6 agonist activity. |
| GO:0072659 protein localization to plasma membrane | IDA PMID:16359517 The role of gamma-carboxylation in the anti-apoptotic functi... | MARK AS OVER ANNOTATED | Summary: Protein localization to plasma membrane is not the direct function of GAS6; the supported mechanism is extracellular ligand bridging and receptor activation. Reason: protein localization to plasma membrane overstates or obscures the direct GAS6 product function. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. |
| GO:2000270 negative regulation of fibroblast apoptotic process | IDA PMID:16359517 The role of gamma-carboxylation in the anti-apoptotic functi... | KEEP AS NON CORE | Summary: negative regulation of fibroblast apoptotic process is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of fibroblast apoptotic process is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:2000352 negative regulation of endothelial cell apoptotic process | IDA PMID:16359517 The role of gamma-carboxylation in the anti-apoptotic functi... | KEEP AS NON CORE | Summary: negative regulation of endothelial cell apoptotic process is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: negative regulation of endothelial cell apoptotic process is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0030971 receptor tyrosine kinase binding | IPI PMID:7634325 Reevaluation of the roles of protein S and Gas6 as ligands f... | ACCEPT | Summary: Receptor tyrosine kinase binding is supported because GAS6 binds and activates TAM-family receptor tyrosine kinases. Reason: receptor tyrosine kinase binding is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. PMID:7854420 We report here the purification of an Axl stimulatory factor, and its identification as the product of growth-arrest-specific gene 6 (ref. 6). |
| GO:0048018 receptor ligand activity | IDA PMID:15184064 Vitamin K-dependent Gas6 activates ERK kinase and stimulates... | ACCEPT | Summary: Receptor ligand activity is the core molecular function of GAS6 as an extracellular TAM receptor ligand. Reason: receptor ligand activity is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md **TAM receptors** (TYRO3, AXL, MERTK) are receptor tyrosine kinases that regulate immune homeostasis, apoptotic-cell clearance (efferocytosis), and tissue repair. Their principal ligands are the vitamin K–dependent proteins **GAS6** and **protein S (PROS1)**. A key concept is that GAS6/PROS1 function as **bridging molecules** that connect **phosphatidylserine (PtdSer/PS)** on apoptotic or stressed membranes to TAM receptors on phagocytes and other cells, thereby promoting receptor activation and downstream signaling. PMID:7854420 We report here the purification of an Axl stimulatory factor, and its identification as the product of growth-arrest-specific gene 6 (ref. 6). |
| GO:0048146 positive regulation of fibroblast proliferation | IDA PMID:15184064 Vitamin K-dependent Gas6 activates ERK kinase and stimulates... | KEEP AS NON CORE | Summary: positive regulation of fibroblast proliferation is supported as a context-specific downstream or tissue-level consequence of GAS6/TAM signaling, not the core molecular function. Reason: positive regulation of fibroblast proliferation is plausible but secondary to the conserved GAS6 ligand/adaptor role. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. file:human/GAS6/GAS6-deep-research-falcon.md Supported functions include **efferocytosis/apoptotic cell clearance**, immune homeostasis and suppression of TLR-driven cytokines via **SOCS1/SOCS3**, vascular integrity, platelet aggregation/thrombo-inflammation, wound repair, and context-dependent regulation of fibrosis and tissue remodeling. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IDA PMID:15184064 Vitamin K-dependent Gas6 activates ERK kinase and stimulates... | ACCEPT | Summary: Positive regulation of ERK1/ERK2 cascade is supported as a GAS6-TAM downstream signaling branch. Reason: positive regulation of ERK1 and ERK2 cascade is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md Downstream, GAS6–TAM activation engages pathways including **PI3K–AKT**, **MEK/ERK**, **NF-κB**, and **JAK/STAT**, supporting context-specific phenotypes such as survival, proliferation, migration, immune suppression, vascular responses, and remodeling. |
| GO:0005615 extracellular space | IDA PMID:8336730 The protein encoded by a growth arrest-specific gene (gas6) ... | ACCEPT | Summary: Extracellular space is the principal functional location for secreted GAS6. Reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and efferocytosis mechanism. Supporting Evidence: file:human/GAS6/GAS6-deep-research-falcon.md GAS6 is predominantly a **secreted extracellular protein** detectable in plasma and experimentally in conditioned media; it can associate with PS-positive membranes/vesicles through its γ-carboxylated Gla domain, thereby acting at the **cell surface interface** between PS-bearing particles/cells and TAM-expressing responders. |
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