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.
|
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The UniProt entry Q14393 is annotated as human (Homo sapiens) Growth arrest-specific protein 6 (GAS6; “GAS-6”), described as an AXL receptor tyrosine kinase ligand and a secreted precursor with a Gla domain and EGF-like modules. This identity is consistent with the core biochemical description in authoritative literature: GAS6 is a vitamin K–dependent secreted protein with an N-terminal γ-carboxyglutamate (Gla) domain, four EGF-like repeats, and a C-terminal SHBG-like/tandem laminin-G region that binds and activates TAM receptors (AXL, TYRO3, MERTK). (wu2018targetinggas6tamin pages 1-2, yanagita2004gas6warfarinand pages 1-2, wu2017molecularinsightsof pages 2-3, rothlin2015tamreceptorsignaling pages 4-6)
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. (geng2017requirementofgammacarboxyglutamic pages 1-2, rothlin2015tamreceptorsignaling pages 4-6, miao2024therapeutictargetingof pages 1-3)
GAS6 is described as a ~678 aa secreted protein (and historically described as ~75 kDa) with: (i) an N-terminal Gla domain containing multiple γ-carboxylated residues, (ii) a loop/disulfide region, (iii) four EGF-like repeats, and (iv) a C-terminal SHBG-like region composed of two laminin-G–like domains that mediate receptor binding. (wu2018targetinggas6tamin pages 1-2, yanagita2004gas6warfarinand pages 1-2, wu2017molecularinsightsof pages 2-3)
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. (geng2017requirementofgammacarboxyglutamic pages 1-2, yanagita2004gas6warfarinand pages 1-2, geng2017requirementofgammacarboxyglutamic pages 2-3, rothlin2015tamreceptorsignaling pages 4-6)
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. PS-positive sources—apoptotic cells, calcium-stressed cells, and exosomes—can serve as platforms that bind GAS6 and promote TAM activation. (geng2017requirementofgammacarboxyglutamic pages 1-2, geng2017requirementofgammacarboxyglutamic pages 11-12, geng2017requirementofgammacarboxyglutamic pages 2-3)
GAS6 binds and activates all three TAM receptors, with a commonly reported affinity/activation hierarchy favoring AXL (AXL > TYRO3 > MERTK/Mer). (wu2018targetinggas6tamin pages 1-2, yanagita2004gas6warfarinand pages 1-2, miao2024therapeutictargetingof pages 1-3)
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. (wu2018targetinggas6tamin pages 1-2, wu2017molecularinsightsof pages 2-3, apostolo2024couldgas6tamaxis pages 4-6, miao2024therapeutictargetingof pages 1-3)
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. (wu2018targetinggas6tamin pages 1-2, geng2017requirementofgammacarboxyglutamic pages 2-3, rothlin2015tamreceptorsignaling pages 4-6)
A 2024 review summarizing expression patterns reports GAS6 as relatively broadly expressed (e.g., vascular smooth muscle cells, kidney, lung, heart, intestine, and monocytes), supporting its potential to act in diverse tissue microenvironments (in contrast to PROS1, described as enriched in liver/endothelium). (apostolo2024couldgas6tamaxis pages 4-6)
A central, repeatedly emphasized role of TAM signaling is to promote efficient clearance of apoptotic cells and suppress excessive inflammatory responses, thereby maintaining immune tolerance. In the immune-homeostasis framework, GAS6/PROS1-TAM signaling induces negative regulators (e.g., SOCS1/3) and suppresses pro-inflammatory cytokine programs downstream of innate immune sensors (e.g., TLR pathways). Genetic loss of all TAM receptors causes severe autoimmunity in mice, consistent with an essential role in immune tolerance. (rothlin2015tamreceptorsignaling pages 4-6, apostolo2024couldgas6tamaxis pages 1-2, apostolo2024couldgas6tamaxis pages 4-6, miao2024therapeutictargetingof pages 1-3)
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. (geng2017requirementofgammacarboxyglutamic pages 1-2, geng2017requirementofgammacarboxyglutamic pages 11-12, geng2017requirementofgammacarboxyglutamic pages 2-3)
GAS6/TAM activity has direct relevance to vascular biology: it is discussed as contributing to endothelial and vascular smooth muscle cell survival responses, leukocyte/platelet interactions, and platelet aggregation (context dependent). A 2024 cardiovascular-focused review provides quantitative context for ligand abundance, reporting plasma PROS1 ~350 nM (with ~40% free form) versus plasma GAS6 ~0.25 nM, and reiterates the need for vitamin K–dependent γ-carboxylation for TAM activation and PS-dependent efferocytosis processes relevant to atherosclerosis biology. (prouse2024functionsoftama pages 3-4)
Recent synthesis work emphasizes that GAS6/TAM signaling can be anti-inflammatory and reparative in some settings (wound repair; resolution via efferocytosis) yet can also contribute to profibrotic programs, including upregulation of TGF-β and activation of fibroblasts. In lung disease/IPF contexts summarized in a 2024 review, GAS6, AXL and TYRO3 are described as elevated, with AXL phosphorylation associated with rapid progression, and AXL inhibitors are described as inhibiting fibroblast activation. (apostolo2024couldgas6tamaxis pages 6-7, apostolo2024couldgas6tamaxis pages 7-9)
A 2023 study in EMBO Molecular Medicine linked a specific macrophage subset to fibrosis in intrauterine adhesion (IUA). In patient samples, flow cytometry (reported n=20/group for IUA vs controls; immunostaining n=5/group) showed an increased proportion of CD301+ macrophages in IUA. Mechanistically, CD301+ macrophages produced GAS6, which activated AXL signaling in endometrial stromal cells (dose/time-dependent phospho-AXL), and pharmacologic AXL inhibition (bemcentinib) was used in the model context to blunt pathology. (lv2023targetingcd301+ pages 4-6)
Interpretation: this work illustrates a contemporary mechanism where GAS6 serves as a paracrine ligand from immune cells that drives a defined receptor pathway (AXL/NF-κB) in stromal cells to promote fibrosis-associated outputs. (lv2023targetingcd301+ pages 4-6)
A 2024 prospective cohort study (Frontiers in Immunology, Apr 2024, URL: https://doi.org/10.3389/fimmu.2024.1362960) evaluated GAS6 and soluble TAM receptors in serum and CSF at diagnosis in 64 patients (treatment-naïve at sampling) and related these measures to disability and short-term severity.
Key quantitative results included:
- Serum sAxl higher in none/low-efficacy DMT vs high-efficacy DMT recipients (p = 0.04). (d’onghia2024gas6tamsystemas pages 1-2)
- Higher CSF GAS6 and higher serum sAXL associated with EDSS <3 at diagnosis (p = 0.04 and p = 0.037, respectively). (d’onghia2024gas6tamsystemas pages 1-2)
- Serum GAS6 inversely correlated with MSSS (r2 = −0.32, p = 0.01). (d’onghia2024gas6tamsystemas pages 1-2)
- Reported median (IQR) concentrations included CSF GAS6 23.49 [12.26–54.65] ng/mL and serum GAS6 7.76 [1.80–32.75] ng/mL (plus soluble receptor measurements). (d’onghia2024gas6tamsystemas pages 3-5)
Interpretation: in this cohort, higher GAS6-axis measures tracked with lower disability/severity, supporting (but not proving) a potentially protective, homeostatic role of GAS6/TAM signaling in demyelinating disease contexts, consistent with the broader immune-homeostasis framework. (d’onghia2024gas6tamsystemas pages 1-2, miao2024therapeutictargetingof pages 1-3)
A 2024 review of systemic sclerosis pathogenesis highlights that AXL and MERTK can be cleaved by ADAM10/17 to generate soluble receptors (sAXL, sMer) that retain GAS6 binding capacity and can modulate signaling by acting as decoys. This mechanism has practical implications for biomarker interpretation (e.g., serum sAXL) and for therapies targeting ligand–receptor engagement. (apostolo2024couldgas6tamaxis pages 6-7, apostolo2024couldgas6tamaxis pages 4-6)
Although the study focuses on AXL, it contextualizes the GAS6/AXL axis in inflammatory/fibrotic responses. In a 2024 study (Frontiers in Immunology, May 2024, URL: https://doi.org/10.3389/fimmu.2024.1394429), serum AXL (and ACE2) were measured longitudinally across time windows after infection. Quantitative highlights:
- Cohort: 358 COVID-19 cases and 71 uninfected controls; time windows 0–7, 8–15, 31–179, and >180 days. (you2024serumaxlis pages 1-2, you2024serumaxlis pages 2-4)
- AXL and ACE2 were decreased in COVID-19 vs controls. (you2024serumaxlis pages 1-2, you2024serumaxlis pages 4-8)
- Discrimination performance: reported AXL ROC AUC 0.752 (early diagnostic cohort) and 0.774 (summary), and higher than ACE2 in the same analysis context (ACE2 AUC 0.714 reported in one excerpt). (you2024serumaxlis pages 1-2, you2024serumaxlis pages 4-8)
- In the first week, only AXL differed between severe and non-severe groups; early cohort for 0–7 days included 84 non-severe and 64 severe patients. (you2024serumaxlis pages 1-2, you2024serumaxlis pages 4-8)
Interpretation: the work suggests AXL is a measurable, time-dependent circulating marker associated with COVID-19 severity trajectories, and supports ongoing interest in the broader GAS6/AXL axis in infection-associated inflammation and tissue remodeling. (you2024serumaxlis pages 1-2)
A directly GAS6-targeting approach is ligand trapping. A ClinicalTrials.gov entry describes a study combining AVB-S6-500 (a GAS6 ligand trap) with durvalumab in platinum-resistant or recurrent ovarian/fallopian tube/primary peritoneal cancer (ClinicalTrials.gov Identifier: NCT04019288, first posted 2019; URL within record context is ClinicalTrials.gov). The protocol explicitly includes measuring “GAS6 suppression” in serum fractions as a molecular endpoint over a reported time frame of 35 months. (NCT04019288 chunk 2)
Multiple clinical development programs target AXL (rather than GAS6). For example, a registry entry documents bemcentinib (BGB324), an AXL inhibitor, tested with erlotinib in NSCLC (NCT02424617, first posted 2015). The record background explicitly discusses GAS6/AXL biology and GAS6-associated prognosis/resistance context, illustrating how GAS6 informs clinical rationale even when the drug target is the receptor kinase. (NCT02424617 chunk 4)
A trial entry (NCT05346536, first posted 2022) evaluates detection of AXL(+) circulating tumor cells (CTC-AXL) in metastatic pancreatic cancer (and breast cancer) using CellSearch® and an investigational platform, emphasizing GAS6/AXL signaling in the biological rationale for EMT/metastasis/resistance. This is an example of the GAS6 axis being operationalized as biomarker logic (AXL expression) in liquid-biopsy implementation rather than a direct GAS6 measurement. (NCT05346536 chunk 1)
A 2024 Nature Reviews Drug Discovery article frames TAM receptors as “functionally elusive” but central to immune/tissue homeostasis: they promote efferocytosis, prevent hyperreactive immune responses, and regulate vascular integrity/permeability. It emphasizes the structural logic whereby vitamin K–dependent ligands (GAS6/PROS1) use a Gla domain for phospholipid/PS binding and receptor-binding domains to drive higher-order receptor complexes (progressing from 1:1 to 2:2), receptor autophosphorylation, and adaptor recruitment (PI3K p85, SRC family, GRB2) leading to MEK–ERK and related signaling. This review also notes that TAM dysregulation is often due to amplification or microenvironmental activation rather than recurrent mutation, shaping therapeutic strategy choices (AXL-focused development, increasing interest in MERTK). (miao2024therapeutictargetingof pages 1-3)
A highly cited immunology review emphasizes the necessity of vitamin K–dependent γ-carboxylation and PS binding for maximal TAM ligand bioactivity and highlights the bridging mechanism as a central organizing principle for how TAM signaling integrates apoptotic-cell recognition with immunoregulatory outputs. (rothlin2015tamreceptorsignaling pages 4-6)
Open Targets lists GAS6 associations across diverse disease ontologies (e.g., metabolic disease and lipid traits), reflecting heterogeneous evidence types and emphasizing the breadth of contexts in which GAS6 biology has been studied; these associations should be interpreted as hypothesis-supporting rather than mechanistic proof. (OpenTargets Search: -GAS6)
| Aspect | Summary | Key evidence/citations |
|---|---|---|
| Identity | UniProt Q14393 corresponds to human GAS6 (growth arrest-specific protein 6), a secreted vitamin K-dependent protein and canonical ligand of the TAM receptor family; GAS6 shows highest receptor affinity for AXL, then TYRO3, then MERTK/Mer. | (wu2018targetinggas6tamin pages 1-2, yanagita2004gas6warfarinand pages 1-2, miao2024therapeutictargetingof pages 1-3) |
| Domains/PTMs | GAS6 is a ~678 aa, ~75 kDa secreted protein with an N-terminal Gla domain containing multiple γ-carboxyglutamate residues, followed by a loop/disulfide region, four EGF-like repeats, and a C-terminal SHBG-like/tandem laminin G domains that bind TAM receptors. Vitamin K-dependent γ-carboxylation of the Gla domain is required for full agonist activity. | (wu2018targetinggas6tamin pages 1-2, yanagita2004gas6warfarinand pages 1-2, wu2017molecularinsightsof pages 2-3, rothlin2015tamreceptorsignaling pages 4-6) |
| Localization | GAS6 functions primarily as an extracellular/secreted ligand present in plasma and conditioned media; it associates with negatively charged membranes and phosphatidylserine-positive apoptotic/stressed cells or vesicles via its Gla domain. Broad tissue expression is reported, including vascular smooth muscle, kidney, lung, heart, intestine, and monocytes. | (wu2018targetinggas6tamin pages 1-2, geng2017requirementofgammacarboxyglutamic pages 2-3, apostolo2024couldgas6tamaxis pages 6-7, apostolo2024couldgas6tamaxis pages 4-6) |
| Receptors/ligand mechanism | GAS6 activates AXL, TYRO3, and MERTK by binding receptor ectodomains through its SHBG-like C-terminus while its γ-carboxylated Gla domain binds phosphatidylserine (PtdSer/PS) on apoptotic cells, stressed cells, liposomes, or exosomes. This bridging is required for strong TAM activation; non-γ-carboxylated or Gla-deficient GAS6 can still bind receptors but may act as decoy/blocking ligands. | (geng2017requirementofgammacarboxyglutamic pages 1-2, geng2017requirementofgammacarboxyglutamic pages 11-12, geng2017requirementofgammacarboxyglutamic pages 2-3, rothlin2015tamreceptorsignaling pages 4-6, miao2024therapeutictargetingof pages 1-3) |
| Downstream signaling | Upon TAM dimerization/autophosphorylation, GAS6 signaling recruits PI3K, SRC-family proteins, and GRB2 and activates PI3K-AKT, MEK/ERK, NF-κB, JAK/STAT, and related pathways; context-specific outputs include survival, proliferation, migration, immune suppression, and endothelial/vascular responses. | (wu2018targetinggas6tamin pages 1-2, wu2017molecularinsightsof pages 2-3, apostolo2024couldgas6tamaxis pages 6-7, apostolo2024couldgas6tamaxis pages 4-6, miao2024therapeutictargetingof pages 1-3) |
| Key biological processes | 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. TAM-null mice develop broad autoimmunity, supporting pathway importance in immune tolerance. | (rothlin2015tamreceptorsignaling pages 4-6, apostolo2024couldgas6tamaxis pages 6-7, prouse2024functionsoftama pages 3-4, apostolo2024couldgas6tamaxis pages 1-2, miao2024therapeutictargetingof pages 1-3) |
| Disease associations | Recent literature links GAS6/TAM signaling to fibrosis (liver, lung/IPF, endometrium), autoimmune/inflammatory disease (systemic sclerosis, multiple sclerosis), cardiovascular disease/atherosclerosis, infection/COVID-19, and many AXL-positive cancers. Effects are context dependent: GAS6 can support repair and anti-inflammatory efferocytosis but can also drive profibrotic and tumor-promoting programs. | (prouse2024functionsoftama pages 1-3, apostolo2024couldgas6tamaxis pages 6-7, apostolo2024couldgas6tamaxis pages 7-9, apostolo2024couldgas6tamaxis pages 1-2, miao2024therapeutictargetingof pages 1-3) |
| Therapeutics/biomarkers | The pathway is being targeted mainly at the receptor or ligand-interface level: AVB-S6-500 is a GAS6 ligand trap evaluated with durvalumab in platinum-resistant/recurrent ovarian, fallopian tube, or primary peritoneal cancer, with on-study measurement of serum GAS6 suppression. Bemcentinib/BGB324 targets AXL rather than GAS6 directly. AXL-positive CTC detection is under study as a liquid-biopsy biomarker in pancreatic cancer. | (NCT04019288 chunk 2, NCT05346536 chunk 1, NCT02424617 chunk 4) |
| Quantitative 2023-2024 data | Multiple sclerosis (2024): prospective cohort n=64; serum sAxl higher in none/low-efficacy vs high-efficacy DMT groups (p=0.04); higher CSF Gas6 and serum sAxl associated with EDSS <3 (p=0.04, p=0.037); serum Gas6 inversely correlated with MSSS (r2=-0.32, p=0.01). COVID-19 (2024): 358 patients + 71 controls; AXL lower in COVID-19 vs controls, with AUC 0.774 in one summary and 0.752 in the early diagnostic cohort; during days 0-7, only AXL differed between severe and non-severe cases; early cohort included 84 non-severe and 64 severe patients. Endometrial fibrosis (2023): human IUA flow-cytometry cohort n=20/group and immunostaining n=5/group showed increased CD301+ macrophages; macrophage-derived GAS6 activated AXL in stromal cells in dose/time-dependent fashion. | (d’onghia2024gas6tamsystemas pages 1-2, d’onghia2024gas6tamsystemas pages 3-5, you2024serumaxlis pages 1-2, you2024serumaxlis pages 4-8, lv2023targetingcd301+ pages 4-6) |
Table: This table summarizes the validated identity, mechanism, signaling, and disease relevance of human GAS6 (UniProt Q14393), emphasizing recent 2023-2024 findings and clinically relevant biomarker/therapeutic evidence. It is designed as a compact reference for functional annotation with direct citation to the provided evidence snippets.
References
(wu2018targetinggas6tamin pages 1-2): Guiling Wu, Zhiqiang Ma, Yicheng Cheng, Wei Hu, Chao Deng, Shuai Jiang, Tian Li, Fulin Chen, and Yang Yang. Targeting gas6/tam in cancer cells and tumor microenvironment. Molecular Cancer, Jan 2018. URL: https://doi.org/10.1186/s12943-018-0769-1, doi:10.1186/s12943-018-0769-1. This article has 198 citations and is from a highest quality peer-reviewed journal.
(yanagita2004gas6warfarinand pages 1-2): Motoko Yanagita. Gas6, warfarin, and kidney diseases. Journal of Clinical and Experimental Nephrology, 8:304-309, Dec 2004. URL: https://doi.org/10.1007/s10157-004-0305-z, doi:10.1007/s10157-004-0305-z. This article has 75 citations.
(wu2017molecularinsightsof pages 2-3): Guiling Wu, Zhiqiang Ma, Wei Hu, Dongjin Wang, Bing Gong, Chongxi Fan, Shuai Jiang, Tian Li, Jianyuan Gao, and Yang Yang. Molecular insights of gas6/tam in cancer development and therapy. Cell Death & Disease, 8:e2700-e2700, Mar 2017. URL: https://doi.org/10.1038/cddis.2017.113, doi:10.1038/cddis.2017.113. This article has 126 citations and is from a peer-reviewed journal.
(rothlin2015tamreceptorsignaling pages 4-6): Carla V. Rothlin, Eugenio A. Carrera-Silva, Lidia Bosurgi, and Sourav Ghosh. Tam receptor signaling in immune homeostasis. Annual review of immunology, 33:355-91, Apr 2015. URL: https://doi.org/10.1146/annurev-immunol-032414-112103, doi:10.1146/annurev-immunol-032414-112103. This article has 543 citations and is from a highest quality peer-reviewed journal.
(geng2017requirementofgammacarboxyglutamic pages 1-2): Ke Geng, Sushil Kumar, Stanley G. Kimani, Vladyslav Kholodovych, Canan Kasikara, Kensaku Mizuno, Oleta Sandiford, Pranela Rameshwar, Sergei V. Kotenko, and Raymond B. Birge. Requirement of gamma-carboxyglutamic acid modification and phosphatidylserine binding for the activation of tyro3, axl, and mertk receptors by growth arrest-specific 6. Frontiers in Immunology, Nov 2017. URL: https://doi.org/10.3389/fimmu.2017.01521, doi:10.3389/fimmu.2017.01521. This article has 97 citations and is from a peer-reviewed journal.
(miao2024therapeutictargetingof pages 1-3): Yu Rebecca Miao, Erinn B. Rankin, and Amato J. Giaccia. Therapeutic targeting of the functionally elusive tam receptor family. Nature reviews. Drug discovery, 23:201-217, Dec 2024. URL: https://doi.org/10.1038/s41573-023-00846-8, doi:10.1038/s41573-023-00846-8. This article has 69 citations.
(geng2017requirementofgammacarboxyglutamic pages 2-3): Ke Geng, Sushil Kumar, Stanley G. Kimani, Vladyslav Kholodovych, Canan Kasikara, Kensaku Mizuno, Oleta Sandiford, Pranela Rameshwar, Sergei V. Kotenko, and Raymond B. Birge. Requirement of gamma-carboxyglutamic acid modification and phosphatidylserine binding for the activation of tyro3, axl, and mertk receptors by growth arrest-specific 6. Frontiers in Immunology, Nov 2017. URL: https://doi.org/10.3389/fimmu.2017.01521, doi:10.3389/fimmu.2017.01521. This article has 97 citations and is from a peer-reviewed journal.
(geng2017requirementofgammacarboxyglutamic pages 11-12): Ke Geng, Sushil Kumar, Stanley G. Kimani, Vladyslav Kholodovych, Canan Kasikara, Kensaku Mizuno, Oleta Sandiford, Pranela Rameshwar, Sergei V. Kotenko, and Raymond B. Birge. Requirement of gamma-carboxyglutamic acid modification and phosphatidylserine binding for the activation of tyro3, axl, and mertk receptors by growth arrest-specific 6. Frontiers in Immunology, Nov 2017. URL: https://doi.org/10.3389/fimmu.2017.01521, doi:10.3389/fimmu.2017.01521. This article has 97 citations and is from a peer-reviewed journal.
(apostolo2024couldgas6tamaxis pages 4-6): Daria Apostolo, Davide D’Onghia, Alessandra Nerviani, Giulia Maria Ghirardi, Daniele Sola, Mattia Perazzi, Stelvio Tonello, Donato Colangelo, Pier Paolo Sainaghi, and Mattia Bellan. Could gas6/tam axis provide valuable insights into the pathogenesis of systemic sclerosis? Current Issues in Molecular Biology, 46:7486-7504, Jul 2024. URL: https://doi.org/10.3390/cimb46070444, doi:10.3390/cimb46070444. This article has 5 citations.
(apostolo2024couldgas6tamaxis pages 1-2): Daria Apostolo, Davide D’Onghia, Alessandra Nerviani, Giulia Maria Ghirardi, Daniele Sola, Mattia Perazzi, Stelvio Tonello, Donato Colangelo, Pier Paolo Sainaghi, and Mattia Bellan. Could gas6/tam axis provide valuable insights into the pathogenesis of systemic sclerosis? Current Issues in Molecular Biology, 46:7486-7504, Jul 2024. URL: https://doi.org/10.3390/cimb46070444, doi:10.3390/cimb46070444. This article has 5 citations.
(prouse2024functionsoftama pages 3-4): Teagan Prouse, Samarpan Majumder, and Rinku Majumder. Functions of tam receptors and ligands protein s and gas6 in atherosclerosis and cardiovascular disease. International Journal of Molecular Sciences, 25:12736, Nov 2024. URL: https://doi.org/10.3390/ijms252312736, doi:10.3390/ijms252312736. This article has 16 citations.
(apostolo2024couldgas6tamaxis pages 6-7): Daria Apostolo, Davide D’Onghia, Alessandra Nerviani, Giulia Maria Ghirardi, Daniele Sola, Mattia Perazzi, Stelvio Tonello, Donato Colangelo, Pier Paolo Sainaghi, and Mattia Bellan. Could gas6/tam axis provide valuable insights into the pathogenesis of systemic sclerosis? Current Issues in Molecular Biology, 46:7486-7504, Jul 2024. URL: https://doi.org/10.3390/cimb46070444, doi:10.3390/cimb46070444. This article has 5 citations.
(apostolo2024couldgas6tamaxis pages 7-9): Daria Apostolo, Davide D’Onghia, Alessandra Nerviani, Giulia Maria Ghirardi, Daniele Sola, Mattia Perazzi, Stelvio Tonello, Donato Colangelo, Pier Paolo Sainaghi, and Mattia Bellan. Could gas6/tam axis provide valuable insights into the pathogenesis of systemic sclerosis? Current Issues in Molecular Biology, 46:7486-7504, Jul 2024. URL: https://doi.org/10.3390/cimb46070444, doi:10.3390/cimb46070444. This article has 5 citations.
(lv2023targetingcd301+ pages 4-6): Haining Lv, Haixiang Sun, Limin Wang, Simin Yao, Dan Liu, Xiwen Zhang, Zhongrui Pei, Jianjun Zhou, Huiyan Wang, Jianwu Dai, Guijun Yan, Lijun Ding, Zhiyin Wang, Chenrui Cao, Guangfeng Zhao, and Yali Hu. Targeting cd301 + macrophages inhibits endometrial fibrosis and improves pregnancy outcome. EMBO Molecular Medicine, Jul 2023. URL: https://doi.org/10.15252/emmm.202317601, doi:10.15252/emmm.202317601. This article has 51 citations and is from a highest quality peer-reviewed journal.
(d’onghia2024gas6tamsystemas pages 1-2): Davide D’Onghia, Donato Colangelo, Mattia Bellan, Stelvio Tonello, Chiara Puricelli, Eleonora Virgilio, Daria Apostolo, Rosalba Minisini, Luciana L. Ferreira, Leonardo Sozzi, Federica Vincenzi, Roberto Cantello, Cristoforo Comi, Mario Pirisi, Domizia Vecchio, and Pier Paolo Sainaghi. Gas6/tam system as potential biomarker for multiple sclerosis prognosis. Frontiers in Immunology, Apr 2024. URL: https://doi.org/10.3389/fimmu.2024.1362960, doi:10.3389/fimmu.2024.1362960. This article has 9 citations and is from a peer-reviewed journal.
(d’onghia2024gas6tamsystemas pages 3-5): Davide D’Onghia, Donato Colangelo, Mattia Bellan, Stelvio Tonello, Chiara Puricelli, Eleonora Virgilio, Daria Apostolo, Rosalba Minisini, Luciana L. Ferreira, Leonardo Sozzi, Federica Vincenzi, Roberto Cantello, Cristoforo Comi, Mario Pirisi, Domizia Vecchio, and Pier Paolo Sainaghi. Gas6/tam system as potential biomarker for multiple sclerosis prognosis. Frontiers in Immunology, Apr 2024. URL: https://doi.org/10.3389/fimmu.2024.1362960, doi:10.3389/fimmu.2024.1362960. This article has 9 citations and is from a peer-reviewed journal.
(you2024serumaxlis pages 1-2): Jianbin You, Rongbin Huang, Ruifang Zhong, Jing Shen, Shuhang Huang, Jinhua Chen, Falin Chen, Yanli Kang, and Liangyuan Chen. Serum axl is a potential molecular marker for predicting covid-19 progression. Frontiers in Immunology, May 2024. URL: https://doi.org/10.3389/fimmu.2024.1394429, doi:10.3389/fimmu.2024.1394429. This article has 6 citations and is from a peer-reviewed journal.
(you2024serumaxlis pages 2-4): Jianbin You, Rongbin Huang, Ruifang Zhong, Jing Shen, Shuhang Huang, Jinhua Chen, Falin Chen, Yanli Kang, and Liangyuan Chen. Serum axl is a potential molecular marker for predicting covid-19 progression. Frontiers in Immunology, May 2024. URL: https://doi.org/10.3389/fimmu.2024.1394429, doi:10.3389/fimmu.2024.1394429. This article has 6 citations and is from a peer-reviewed journal.
(you2024serumaxlis pages 4-8): Jianbin You, Rongbin Huang, Ruifang Zhong, Jing Shen, Shuhang Huang, Jinhua Chen, Falin Chen, Yanli Kang, and Liangyuan Chen. Serum axl is a potential molecular marker for predicting covid-19 progression. Frontiers in Immunology, May 2024. URL: https://doi.org/10.3389/fimmu.2024.1394429, doi:10.3389/fimmu.2024.1394429. This article has 6 citations and is from a peer-reviewed journal.
(NCT04019288 chunk 2): AVB-S6-500 and Durvalumab in Treating Patients With Platinum-Resistant or Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. M.D. Anderson Cancer Center. 2019. ClinicalTrials.gov Identifier: NCT04019288
(NCT02424617 chunk 4): A Study of BGB324 (Bemcentinib) in Combination With Erlotinib in Patients With Non-Small Cell Lung Cancer. BerGenBio ASA. 2015. ClinicalTrials.gov Identifier: NCT02424617
(NCT05346536 chunk 1): Liquid Biopsy and Pancreas Cancer: Detection of AXL(+) CTCs (CTC-AXL-PANC). University Hospital, Montpellier. 2022. ClinicalTrials.gov Identifier: NCT05346536
(OpenTargets Search: -GAS6): Open Targets Query (-GAS6, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(prouse2024functionsoftama pages 1-3): Teagan Prouse, Samarpan Majumder, and Rinku Majumder. Functions of tam receptors and ligands protein s and gas6 in atherosclerosis and cardiovascular disease. International Journal of Molecular Sciences, 25:12736, Nov 2024. URL: https://doi.org/10.3390/ijms252312736, doi:10.3390/ijms252312736. This article has 16 citations.
id: Q14393
gene_symbol: GAS6
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: '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.'
existing_annotations:
- term:
id: GO:0043066
label: negative regulation of apoptotic process
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of apoptotic process is plausible but secondary to the conserved
GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005615
label: extracellular space
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Extracellular space is the principal functional location for secreted GAS6.
action: ACCEPT
reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0007166
label: cell surface receptor signaling pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Cell surface receptor signaling pathway is supported by GAS6-mediated activation of
TAM receptor tyrosine kinases.
action: ACCEPT
reason: cell surface receptor signaling pathway is supported as part of the core GAS6-TAM
receptor ligand and efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0051897
label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal
transduction
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of
GAS6-TAM receptor activation.
action: ACCEPT
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.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:16359517
supporting_text: gamma-carboxylation is also required for both Axl phosphorylation and PI3
kinase activation.
- term:
id: GO:0048018
label: receptor ligand activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Receptor ligand activity is the core molecular function of GAS6 as an extracellular
TAM receptor ligand.
action: ACCEPT
reason: receptor ligand activity is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: PMID:7854420
supporting_text: We report here the purification of an Axl stimulatory factor, and its
identification as the product of growth-arrest-specific gene 6 (ref. 6).
- term:
id: GO:0005509
label: calcium ion binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: Calcium ion binding is supported by the vitamin K-dependent Gla domain needed for
Ca2+-dependent phospholipid binding.
action: ACCEPT
reason: calcium ion binding is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005576
label: extracellular region
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Extracellular region is supported by GAS6 secretion and extracellular receptor-ligand
activity.
action: ACCEPT
reason: extracellular region is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005796
label: Golgi lumen
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Golgi lumen is compatible with GAS6 secretion, maturation, storage, or
extracellular-vesicle association but is secondary to extracellular TAM receptor activation.
action: KEEP_AS_NON_CORE
reason: Golgi lumen is plausible but secondary to the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0007166
label: cell surface receptor signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Cell surface receptor signaling pathway is supported by GAS6-mediated activation of
TAM receptor tyrosine kinases.
action: ACCEPT
reason: cell surface receptor signaling pathway is supported as part of the core GAS6-TAM
receptor ligand and efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0016477
label: cell migration
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: cell migration is supported as a context-specific downstream or tissue-level
consequence of GAS6/TAM signaling, not the core molecular function.
action: KEEP_AS_NON_CORE
reason: cell migration is plausible but secondary to the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0030154
label: cell differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: cell differentiation is supported as a context-specific downstream or tissue-level
consequence of GAS6/TAM signaling, not the core molecular function.
action: KEEP_AS_NON_CORE
reason: cell differentiation is plausible but secondary to the conserved GAS6 ligand/adaptor
role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0031669
label: cellular response to nutrient levels
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Cellular response to nutrient levels describes a cellular state rather than the
direct function of the GAS6 protein product.
action: MARK_AS_OVER_ANNOTATED
reason: cellular response to nutrient levels overstates or obscures the direct GAS6 product
function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- term:
id: GO:0043277
label: apoptotic cell clearance
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Apoptotic cell clearance is a core biological role of the GAS6/TAM bridging
mechanism.
action: ACCEPT
reason: apoptotic cell clearance is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0046872
label: metal ion binding
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: Metal ion binding should be narrowed to calcium ion binding because the GAS6 Gla
domain supports Ca2+-dependent phospholipid binding.
action: MODIFY
reason: metal ion binding should be replaced by a term that better matches the GAS6 mechanism.
proposed_replacement_terms:
- id: GO:0005509
label: calcium ion binding
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:2000270
label: negative regulation of fibroblast apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of fibroblast apoptotic process is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0003104
label: positive regulation of glomerular filtration
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Glomerular filtration is a tissue-level phenotype and overstates the direct function
of GAS6 relative to its extracellular TAM ligand mechanism.
action: MARK_AS_OVER_ANNOTATED
reason: positive regulation of glomerular filtration overstates or obscures the direct GAS6
product function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005615
label: extracellular space
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Extracellular space is the principal functional location for secreted GAS6.
action: ACCEPT
reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0007165
label: signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Signal transduction is directionally correct but too generic for GAS6; cell surface
receptor signaling better captures TAM receptor activation.
action: MODIFY
reason: signal transduction should be replaced by a term that better matches the GAS6
mechanism.
proposed_replacement_terms:
- id: GO:0007166
label: cell surface receptor signaling pathway
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0031100
label: animal organ regeneration
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: animal organ regeneration is supported as a context-specific downstream or
tissue-level consequence of GAS6/TAM signaling, not the core molecular function.
action: KEEP_AS_NON_CORE
reason: animal organ regeneration is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0032008
label: positive regulation of TOR signaling
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
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.
action: KEEP_AS_NON_CORE
reason: positive regulation of TOR signaling is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0048018
label: receptor ligand activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Receptor ligand activity is the core molecular function of GAS6 as an extracellular
TAM receptor ligand.
action: ACCEPT
reason: receptor ligand activity is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: PMID:7854420
supporting_text: We report here the purification of an Axl stimulatory factor, and its
identification as the product of growth-arrest-specific gene 6 (ref. 6).
- term:
id: GO:0051897
label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal
transduction
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of
GAS6-TAM receptor activation.
action: ACCEPT
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.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:16359517
supporting_text: gamma-carboxylation is also required for both Axl phosphorylation and PI3
kinase activation.
- term:
id: GO:0071333
label: cellular response to glucose stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Cellular response to glucose stimulus is an upstream/context annotation and is not a
direct GAS6 product function.
action: MARK_AS_OVER_ANNOTATED
reason: cellular response to glucose stimulus overstates or obscures the direct GAS6 product
function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- term:
id: GO:0071466
label: cellular response to xenobiotic stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Cellular response to xenobiotic stimulus is an upstream/context annotation and is not
a direct GAS6 product function.
action: MARK_AS_OVER_ANNOTATED
reason: cellular response to xenobiotic stimulus overstates or obscures the direct GAS6
product function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0085029
label: extracellular matrix assembly
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: extracellular matrix assembly is supported as a context-specific downstream or
tissue-level consequence of GAS6/TAM signaling, not the core molecular function.
action: KEEP_AS_NON_CORE
reason: extracellular matrix assembly is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:2000533
label: negative regulation of renal albumin absorption
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Renal albumin absorption is a tissue-level phenotype and should not be treated as a
core molecular function of GAS6.
action: MARK_AS_OVER_ANNOTATED
reason: negative regulation of renal albumin absorption overstates or obscures the direct GAS6
product function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-202710
review:
summary: Extracellular region is supported by GAS6 secretion and extracellular receptor-ligand
activity.
action: ACCEPT
reason: extracellular region is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-481007
review:
summary: Extracellular region is supported by GAS6 secretion and extracellular receptor-ligand
activity.
action: ACCEPT
reason: extracellular region is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005788
label: endoplasmic reticulum lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-163809
review:
summary: endoplasmic reticulum lumen is compatible with GAS6 secretion, maturation, storage,
or extracellular-vesicle association but is secondary to extracellular TAM receptor
activation.
action: KEEP_AS_NON_CORE
reason: endoplasmic reticulum lumen is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005788
label: endoplasmic reticulum lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8952289
review:
summary: endoplasmic reticulum lumen is compatible with GAS6 secretion, maturation, storage,
or extracellular-vesicle association but is secondary to extracellular TAM receptor
activation.
action: KEEP_AS_NON_CORE
reason: endoplasmic reticulum lumen is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005796
label: Golgi lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-163809
review:
summary: Golgi lumen is compatible with GAS6 secretion, maturation, storage, or
extracellular-vesicle association but is secondary to extracellular TAM receptor activation.
action: KEEP_AS_NON_CORE
reason: Golgi lumen is plausible but secondary to the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005796
label: Golgi lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-163843
review:
summary: Golgi lumen is compatible with GAS6 secretion, maturation, storage, or
extracellular-vesicle association but is secondary to extracellular TAM receptor activation.
action: KEEP_AS_NON_CORE
reason: Golgi lumen is plausible but secondary to the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0031093
label: platelet alpha granule lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-481007
review:
summary: platelet alpha granule lumen is compatible with GAS6 secretion, maturation, storage,
or extracellular-vesicle association but is secondary to extracellular TAM receptor
activation.
action: KEEP_AS_NON_CORE
reason: platelet alpha granule lumen is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0007166
label: cell surface receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:20103767
review:
summary: Cell surface receptor signaling pathway is supported by GAS6-mediated activation of
TAM receptor tyrosine kinases.
action: ACCEPT
reason: cell surface receptor signaling pathway is supported as part of the core GAS6-TAM
receptor ligand and efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0048018
label: receptor ligand activity
evidence_type: IDA
original_reference_id: PMID:20103767
review:
summary: Receptor ligand activity is the core molecular function of GAS6 as an extracellular
TAM receptor ligand.
action: ACCEPT
reason: receptor ligand activity is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: PMID:7854420
supporting_text: We report here the purification of an Axl stimulatory factor, and its
identification as the product of growth-arrest-specific gene 6 (ref. 6).
- term:
id: GO:0051897
label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal
transduction
evidence_type: IDA
original_reference_id: PMID:20103767
review:
summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of
GAS6-TAM receptor activation.
action: ACCEPT
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.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:16359517
supporting_text: gamma-carboxylation is also required for both Axl phosphorylation and PI3
kinase activation.
- term:
id: GO:0030674
label: protein-macromolecule adaptor activity
evidence_type: IDA
original_reference_id: PMID:21501828
review:
summary: Protein-macromolecule adaptor activity captures the bridging mechanism linking
phosphatidylserine-bearing membranes to TAM receptors.
action: ACCEPT
reason: protein-macromolecule adaptor activity is supported as part of the core GAS6-TAM
receptor ligand and efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0046827
label: positive regulation of protein export from nucleus
evidence_type: IDA
original_reference_id: PMID:18680538
review:
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.
action: KEEP_AS_NON_CORE
reason: positive regulation of protein export from nucleus is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:2000352
label: negative regulation of endothelial cell apoptotic process
evidence_type: IDA
original_reference_id: PMID:18680538
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of endothelial cell apoptotic process is plausible but secondary
to the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0070062
label: extracellular exosome
evidence_type: HDA
original_reference_id: PMID:23533145
review:
summary: extracellular exosome is compatible with GAS6 secretion, maturation, storage, or
extracellular-vesicle association but is secondary to extracellular TAM receptor activation.
action: KEEP_AS_NON_CORE
reason: extracellular exosome is plausible but secondary to the conserved GAS6 ligand/adaptor
role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0070588
label: calcium ion transmembrane transport
evidence_type: IDA
original_reference_id: PMID:18395422
review:
summary: The evidence connects GAS6 to MerTK-dependent phagocytosis with calcium-channel
involvement, but GAS6 is not itself a calcium transporter.
action: MODIFY
reason: calcium ion transmembrane transport should be replaced by a term that better matches
the GAS6 mechanism.
proposed_replacement_terms:
- id: GO:0050766
label: positive regulation of phagocytosis
supported_by:
- reference_id: PMID:18395422
supporting_text: Blocking L-type Ca(2+)-channels with nifedipine inhibited MerTK dependent
phagocytosis in vitro.
- term:
id: GO:0005615
label: extracellular space
evidence_type: IDA
original_reference_id: PMID:18395422
review:
summary: Extracellular space is the principal functional location for secreted GAS6.
action: ACCEPT
reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005615
label: extracellular space
evidence_type: IDA
original_reference_id: PMID:19922767
review:
summary: Extracellular space is the principal functional location for secreted GAS6.
action: ACCEPT
reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:18395422
review:
summary: Cytoplasm is not the principal functional location for mature GAS6, which acts as a
secreted extracellular ligand.
action: MARK_AS_OVER_ANNOTATED
reason: cytoplasm overstates or obscures the direct GAS6 product function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0001934
label: positive regulation of protein phosphorylation
evidence_type: IDA
original_reference_id: PMID:7854420
review:
summary: Positive regulation of protein phosphorylation is supported because GAS6 activates
TAM receptor phosphorylation and downstream kinase signaling.
action: ACCEPT
reason: positive regulation of protein phosphorylation is supported as part of the core
GAS6-TAM receptor ligand and efferocytosis mechanism.
supported_by:
- reference_id: PMID:16359517
supporting_text: gamma-carboxylation is also required for both Axl phosphorylation and PI3
kinase activation.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005102
label: signaling receptor binding
evidence_type: IPI
original_reference_id: PMID:7854420
review:
summary: Signaling receptor binding is supported by direct GAS6 interaction with TAM receptor
ectodomains.
action: ACCEPT
reason: signaling receptor binding is supported as part of the core GAS6-TAM receptor ligand
and efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: PMID:7854420
supporting_text: We report here the purification of an Axl stimulatory factor, and its
identification as the product of growth-arrest-specific gene 6 (ref. 6).
- term:
id: GO:0007165
label: signal transduction
evidence_type: IDA
original_reference_id: PMID:7854420
review:
summary: Signal transduction is directionally correct but too generic for GAS6; cell surface
receptor signaling better captures TAM receptor activation.
action: MODIFY
reason: signal transduction should be replaced by a term that better matches the GAS6
mechanism.
proposed_replacement_terms:
- id: GO:0007166
label: cell surface receptor signaling pathway
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0045860
label: positive regulation of protein kinase activity
evidence_type: IDA
original_reference_id: PMID:7854420
review:
summary: Positive regulation of protein kinase activity is supported by GAS6-dependent TAM
receptor and downstream kinase activation.
action: ACCEPT
reason: positive regulation of protein kinase activity is supported as part of the core
GAS6-TAM receptor ligand and efferocytosis mechanism.
supported_by:
- reference_id: PMID:16359517
supporting_text: gamma-carboxylation is also required for both Axl phosphorylation and PI3
kinase activation.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0048146
label: positive regulation of fibroblast proliferation
evidence_type: IDA
original_reference_id: PMID:7854420
review:
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.
action: KEEP_AS_NON_CORE
reason: positive regulation of fibroblast proliferation is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0032715
label: negative regulation of interleukin-6 production
evidence_type: IDA
original_reference_id: PMID:20103767
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of interleukin-6 production is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0019064
label: fusion of virus membrane with host plasma membrane
evidence_type: IDA
original_reference_id: PMID:21501828
review:
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.
action: KEEP_AS_NON_CORE
reason: fusion of virus membrane with host plasma membrane is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: PMID:21501828
supporting_text: Gas6 mediates binding of the virus to target cells by bridging virion
envelope phosphatidylserine to Axl, a TAM receptor tyrosine kinase on target cells.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- term:
id: GO:0046813
label: receptor-mediated virion attachment to host cell
evidence_type: IDA
original_reference_id: PMID:21501828
review:
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.
action: KEEP_AS_NON_CORE
reason: receptor-mediated virion attachment to host cell is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: PMID:21501828
supporting_text: Gas6 mediates binding of the virus to target cells by bridging virion
envelope phosphatidylserine to Axl, a TAM receptor tyrosine kinase on target cells.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- term:
id: GO:0006909
label: phagocytosis
evidence_type: IDA
original_reference_id: PMID:21501828
review:
summary: Phagocytosis is supported in the efferocytosis context where GAS6 bridges
phosphatidylserine to TAM receptors on phagocytes.
action: ACCEPT
reason: phagocytosis is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0043277
label: apoptotic cell clearance
evidence_type: IDA
original_reference_id: PMID:21501828
review:
summary: Apoptotic cell clearance is a core biological role of the GAS6/TAM bridging
mechanism.
action: ACCEPT
reason: apoptotic cell clearance is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:1900142
label: negative regulation of oligodendrocyte apoptotic process
evidence_type: IDA
original_reference_id: PMID:16723520
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of oligodendrocyte apoptotic process is plausible but secondary to
the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0001786
label: phosphatidylserine binding
evidence_type: IDA
original_reference_id: PMID:21501828
review:
summary: Phosphatidylserine binding is central to GAS6 function as a bridge between
PS-positive membranes and TAM receptors.
action: ACCEPT
reason: phosphatidylserine binding is supported as part of the core GAS6-TAM receptor ligand
and efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- term:
id: GO:0001961
label: positive regulation of cytokine-mediated signaling pathway
evidence_type: IMP
original_reference_id: PMID:18840707
review:
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.
action: KEEP_AS_NON_CORE
reason: positive regulation of cytokine-mediated signaling pathway is plausible but secondary
to the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18760998
review:
summary: Protein binding is too generic for GAS6; receptor tyrosine kinase binding, receptor
ligand activity, phosphatidylserine binding, and adaptor activity better represent the
mechanism.
action: MARK_AS_OVER_ANNOTATED
reason: protein binding overstates or obscures the direct GAS6 product function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20088931
review:
summary: Protein binding is too generic for GAS6; receptor tyrosine kinase binding, receptor
ligand activity, phosphatidylserine binding, and adaptor activity better represent the
mechanism.
action: MARK_AS_OVER_ANNOTATED
reason: protein binding overstates or obscures the direct GAS6 product function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20103767
review:
summary: Protein binding is too generic for GAS6; receptor tyrosine kinase binding, receptor
ligand activity, phosphatidylserine binding, and adaptor activity better represent the
mechanism.
action: MARK_AS_OVER_ANNOTATED
reason: protein binding overstates or obscures the direct GAS6 product function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '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.'
- term:
id: GO:0005615
label: extracellular space
evidence_type: IDA
original_reference_id: PMID:20088931
review:
summary: Extracellular space is the principal functional location for secreted GAS6.
action: ACCEPT
reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0007165
label: signal transduction
evidence_type: IDA
original_reference_id: PMID:18680538
review:
summary: Signal transduction is directionally correct but too generic for GAS6; cell surface
receptor signaling better captures TAM receptor activation.
action: MODIFY
reason: signal transduction should be replaced by a term that better matches the GAS6
mechanism.
proposed_replacement_terms:
- id: GO:0007166
label: cell surface receptor signaling pathway
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IDA
original_reference_id: PMID:19657094
review:
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.
action: KEEP_AS_NON_CORE
reason: positive regulation of gene expression is plausible but secondary to the conserved
GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0010804
label: negative regulation of tumor necrosis factor-mediated signaling pathway
evidence_type: IDA
original_reference_id: PMID:19657094
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of tumor necrosis factor-mediated signaling pathway is plausible
but secondary to the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0019079
label: viral genome replication
evidence_type: IDA
original_reference_id: PMID:21501828
review:
summary: viral genome replication is supported in a viral-entry/apoptotic-mimicry context, but
this is not the core host function of GAS6.
action: KEEP_AS_NON_CORE
reason: viral genome replication is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: PMID:21501828
supporting_text: Gas6 mediates binding of the virus to target cells by bridging virion
envelope phosphatidylserine to Axl, a TAM receptor tyrosine kinase on target cells.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- term:
id: GO:0032689
label: negative regulation of type II interferon production
evidence_type: IDA
original_reference_id: PMID:18840707
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of type II interferon production is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0032692
label: negative regulation of interleukin-1 production
evidence_type: IDA
original_reference_id: PMID:20103767
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of interleukin-1 production is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0032715
label: negative regulation of interleukin-6 production
evidence_type: IDA
original_reference_id: PMID:19657094
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of interleukin-6 production is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0032720
label: negative regulation of tumor necrosis factor production
evidence_type: IDA
original_reference_id: PMID:19657094
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of tumor necrosis factor production is plausible but secondary to
the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0032720
label: negative regulation of tumor necrosis factor production
evidence_type: IDA
original_reference_id: PMID:20103767
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of tumor necrosis factor production is plausible but secondary to
the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0032825
label: positive regulation of natural killer cell differentiation
evidence_type: IDA
original_reference_id: PMID:18840707
review:
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.
action: KEEP_AS_NON_CORE
reason: positive regulation of natural killer cell differentiation is plausible but secondary
to the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0035457
label: cellular response to interferon-alpha
evidence_type: IDA
original_reference_id: PMID:19657094
review:
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.
action: KEEP_AS_NON_CORE
reason: cellular response to interferon-alpha is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0035754
label: B cell chemotaxis
evidence_type: IDA
original_reference_id: PMID:19922767
review:
summary: B cell chemotaxis is supported as a context-specific downstream or tissue-level
consequence of GAS6/TAM signaling, not the core molecular function.
action: KEEP_AS_NON_CORE
reason: B cell chemotaxis is plausible but secondary to the conserved GAS6 ligand/adaptor
role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0043066
label: negative regulation of apoptotic process
evidence_type: IDA
original_reference_id: PMID:19922767
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of apoptotic process is plausible but secondary to the conserved
GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:18680538
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of DNA-templated transcription is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0046718
label: symbiont entry into host cell
evidence_type: IDA
original_reference_id: PMID:21501828
review:
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.
action: KEEP_AS_NON_CORE
reason: symbiont entry into host cell is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: PMID:21501828
supporting_text: Gas6 mediates binding of the virus to target cells by bridging virion
envelope phosphatidylserine to Axl, a TAM receptor tyrosine kinase on target cells.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- term:
id: GO:0051897
label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal
transduction
evidence_type: IDA
original_reference_id: PMID:18680538
review:
summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of
GAS6-TAM receptor activation.
action: ACCEPT
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.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:16359517
supporting_text: gamma-carboxylation is also required for both Axl phosphorylation and PI3
kinase activation.
- term:
id: GO:0070168
label: negative regulation of biomineral tissue development
evidence_type: IDA
original_reference_id: PMID:20048160
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of biomineral tissue development is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0097028
label: dendritic cell differentiation
evidence_type: IEP
original_reference_id: PMID:19657094
review:
summary: dendritic cell differentiation is supported as a context-specific downstream or
tissue-level consequence of GAS6/TAM signaling, not the core molecular function.
action: KEEP_AS_NON_CORE
reason: dendritic cell differentiation is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0097241
label: hematopoietic stem cell migration to bone marrow
evidence_type: IDA
original_reference_id: PMID:19922767
review:
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.
action: KEEP_AS_NON_CORE
reason: hematopoietic stem cell migration to bone marrow is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:2000352
label: negative regulation of endothelial cell apoptotic process
evidence_type: IDA
original_reference_id: PMID:18760998
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of endothelial cell apoptotic process is plausible but secondary
to the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:2000510
label: positive regulation of dendritic cell chemotaxis
evidence_type: IDA
original_reference_id: PMID:19657094
review:
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.
action: KEEP_AS_NON_CORE
reason: positive regulation of dendritic cell chemotaxis is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:2000669
label: negative regulation of dendritic cell apoptotic process
evidence_type: IDA
original_reference_id: PMID:19657094
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of dendritic cell apoptotic process is plausible but secondary to
the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0043027
label: cysteine-type endopeptidase inhibitor activity involved in apoptotic process
evidence_type: IDA
original_reference_id: PMID:16723520
review:
summary: The oligodendrocyte evidence supports anti-apoptotic signaling through AXL/PI3K/AKT,
not direct cysteine-type endopeptidase inhibitor activity by GAS6.
action: MODIFY
reason: cysteine-type endopeptidase inhibitor activity involved in apoptotic process should be
replaced by a term that better matches the GAS6 mechanism.
proposed_replacement_terms:
- id: GO:0043066
label: negative regulation of apoptotic process
supported_by:
- reference_id: PMID:16723520
supporting_text: 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.
- term:
id: GO:0050766
label: positive regulation of phagocytosis
evidence_type: IDA
original_reference_id: PMID:18395422
review:
summary: Positive regulation of phagocytosis is supported by GAS6-dependent TAM signaling
during apoptotic-cell clearance.
action: ACCEPT
reason: positive regulation of phagocytosis is supported as part of the core GAS6-TAM receptor
ligand and efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0051897
label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal
transduction
evidence_type: IDA
original_reference_id: PMID:16723520
review:
summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of
GAS6-TAM receptor activation.
action: ACCEPT
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.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:16359517
supporting_text: gamma-carboxylation is also required for both Axl phosphorylation and PI3
kinase activation.
- term:
id: GO:0001934
label: positive regulation of protein phosphorylation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Positive regulation of protein phosphorylation is supported because GAS6 activates
TAM receptor phosphorylation and downstream kinase signaling.
action: ACCEPT
reason: positive regulation of protein phosphorylation is supported as part of the core
GAS6-TAM receptor ligand and efferocytosis mechanism.
supported_by:
- reference_id: PMID:16359517
supporting_text: gamma-carboxylation is also required for both Axl phosphorylation and PI3
kinase activation.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0003104
label: positive regulation of glomerular filtration
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Glomerular filtration is a tissue-level phenotype and overstates the direct function
of GAS6 relative to its extracellular TAM ligand mechanism.
action: MARK_AS_OVER_ANNOTATED
reason: positive regulation of glomerular filtration overstates or obscures the direct GAS6
product function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0032008
label: positive regulation of TOR signaling
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
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.
action: KEEP_AS_NON_CORE
reason: positive regulation of TOR signaling is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0032148
label: activation of protein kinase B activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Activation of protein kinase B activity is supported by the GAS6-AXL-PI3K/AKT
survival pathway.
action: ACCEPT
reason: activation of protein kinase B activity is supported as part of the core GAS6-TAM
receptor ligand and efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:16723520
supporting_text: 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.
- term:
id: GO:0071333
label: cellular response to glucose stimulus
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Cellular response to glucose stimulus is an upstream/context annotation and is not a
direct GAS6 product function.
action: MARK_AS_OVER_ANNOTATED
reason: cellular response to glucose stimulus overstates or obscures the direct GAS6 product
function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- term:
id: GO:0085029
label: extracellular matrix assembly
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: extracellular matrix assembly is supported as a context-specific downstream or
tissue-level consequence of GAS6/TAM signaling, not the core molecular function.
action: KEEP_AS_NON_CORE
reason: extracellular matrix assembly is plausible but secondary to the conserved GAS6
ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:2000533
label: negative regulation of renal albumin absorption
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Renal albumin absorption is a tissue-level phenotype and should not be treated as a
core molecular function of GAS6.
action: MARK_AS_OVER_ANNOTATED
reason: negative regulation of renal albumin absorption overstates or obscures the direct GAS6
product function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005102
label: signaling receptor binding
evidence_type: IDA
original_reference_id: PMID:16359517
review:
summary: Signaling receptor binding is supported by direct GAS6 interaction with TAM receptor
ectodomains.
action: ACCEPT
reason: signaling receptor binding is supported as part of the core GAS6-TAM receptor ligand
and efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: PMID:7854420
supporting_text: We report here the purification of an Axl stimulatory factor, and its
identification as the product of growth-arrest-specific gene 6 (ref. 6).
- term:
id: GO:0006468
label: protein phosphorylation
evidence_type: IDA
original_reference_id: PMID:16359517
review:
summary: GAS6 stimulates receptor and downstream kinase phosphorylation rather than catalyzing
protein phosphorylation.
action: MODIFY
reason: protein phosphorylation should be replaced by a term that better matches the GAS6
mechanism.
proposed_replacement_terms:
- id: GO:0001934
label: positive regulation of protein phosphorylation
supported_by:
- reference_id: PMID:16359517
supporting_text: gamma-carboxylation is also required for both Axl phosphorylation and PI3
kinase activation.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0051897
label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal
transduction
evidence_type: IDA
original_reference_id: PMID:16359517
review:
summary: Positive regulation of PI3K/AKT signaling is supported as a downstream consequence of
GAS6-TAM receptor activation.
action: ACCEPT
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.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:16359517
supporting_text: gamma-carboxylation is also required for both Axl phosphorylation and PI3
kinase activation.
- term:
id: GO:0071307
label: cellular response to vitamin K
evidence_type: IDA
original_reference_id: PMID:16359517
review:
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.
action: MARK_AS_OVER_ANNOTATED
reason: cellular response to vitamin K overstates or obscures the direct GAS6 product
function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0071466
label: cellular response to xenobiotic stimulus
evidence_type: IDA
original_reference_id: PMID:16359517
review:
summary: Cellular response to xenobiotic stimulus is an upstream/context annotation and is not
a direct GAS6 product function.
action: MARK_AS_OVER_ANNOTATED
reason: cellular response to xenobiotic stimulus overstates or obscures the direct GAS6
product function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0072659
label: protein localization to plasma membrane
evidence_type: IDA
original_reference_id: PMID:16359517
review:
summary: Protein localization to plasma membrane is not the direct function of GAS6; the
supported mechanism is extracellular ligand bridging and receptor activation.
action: MARK_AS_OVER_ANNOTATED
reason: protein localization to plasma membrane overstates or obscures the direct GAS6 product
function.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- term:
id: GO:2000270
label: negative regulation of fibroblast apoptotic process
evidence_type: IDA
original_reference_id: PMID:16359517
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of fibroblast apoptotic process is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:2000352
label: negative regulation of endothelial cell apoptotic process
evidence_type: IDA
original_reference_id: PMID:16359517
review:
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.
action: KEEP_AS_NON_CORE
reason: negative regulation of endothelial cell apoptotic process is plausible but secondary
to the conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0030971
label: receptor tyrosine kinase binding
evidence_type: IPI
original_reference_id: PMID:7634325
review:
summary: Receptor tyrosine kinase binding is supported because GAS6 binds and activates
TAM-family receptor tyrosine kinases.
action: ACCEPT
reason: receptor tyrosine kinase binding is supported as part of the core GAS6-TAM receptor
ligand and efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: PMID:7854420
supporting_text: We report here the purification of an Axl stimulatory factor, and its
identification as the product of growth-arrest-specific gene 6 (ref. 6).
- term:
id: GO:0048018
label: receptor ligand activity
evidence_type: IDA
original_reference_id: PMID:15184064
review:
summary: Receptor ligand activity is the core molecular function of GAS6 as an extracellular
TAM receptor ligand.
action: ACCEPT
reason: receptor ligand activity is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: PMID:7854420
supporting_text: We report here the purification of an Axl stimulatory factor, and its
identification as the product of growth-arrest-specific gene 6 (ref. 6).
- term:
id: GO:0048146
label: positive regulation of fibroblast proliferation
evidence_type: IDA
original_reference_id: PMID:15184064
review:
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.
action: KEEP_AS_NON_CORE
reason: positive regulation of fibroblast proliferation is plausible but secondary to the
conserved GAS6 ligand/adaptor role.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0070374
label: positive regulation of ERK1 and ERK2 cascade
evidence_type: IDA
original_reference_id: PMID:15184064
review:
summary: Positive regulation of ERK1/ERK2 cascade is supported as a GAS6-TAM downstream
signaling branch.
action: ACCEPT
reason: positive regulation of ERK1 and ERK2 cascade is supported as part of the core GAS6-TAM
receptor ligand and efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005615
label: extracellular space
evidence_type: IDA
original_reference_id: PMID:8336730
review:
summary: Extracellular space is the principal functional location for secreted GAS6.
action: ACCEPT
reason: extracellular space is supported as part of the core GAS6-TAM receptor ligand and
efferocytosis mechanism.
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by
curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to orthologs
using Ensembl Compara
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:15184064
title: Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac
fibroblasts.
findings: []
- id: PMID:16359517
title: The role of gamma-carboxylation in the anti-apoptotic function of gas6.
findings: []
- id: PMID:16723520
title: Gas6/Axl signaling activates the phosphatidylinositol 3-kinase/Akt1 survival pathway to
protect oligodendrocytes from tumor necrosis factor alpha-induced apoptosis.
findings: []
- id: PMID:18395422
title: Endogenous Gas6 and Ca2+ -channel activation modulate phagocytosis by retinal pigment
epithelium.
findings: []
- id: PMID:18680538
title: GAS6-induced signaling in human endothelial cells is mediated by FOXO1a.
findings: []
- id: PMID:18760998
title: Gas6-mediated signaling is dependent on the engagement of its gamma-carboxyglutamic acid
domain with phosphatidylserine.
findings: []
- id: PMID:18840707
title: The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural
killer cell development.
findings: []
- id: PMID:19657094
title: Survival and migration of human dendritic cells are regulated by an IFN-alpha-inducible
Axl/Gas6 pathway.
findings: []
- id: PMID:19922767
title: GAS6/Mer axis regulates the homing and survival of the E2A/PBX1-positive B-cell precursor
acute lymphoblastic leukemia in the bone marrow niche.
findings: []
- id: PMID:20048160
title: Androgen receptor-dependent transactivation of growth arrest-specific gene 6 mediates
inhibitory effects of testosterone on vascular calcification.
findings: []
- id: PMID:20088931
title: Gas6 is complexed to the soluble tyrosine kinase receptor Axl in human blood.
findings: []
- id: PMID:20103767
title: TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages.
findings: []
- id: PMID:21501828
title: The soluble serum protein Gas6 bridges virion envelope phosphatidylserine to the TAM
receptor tyrosine kinase Axl to mediate viral entry.
findings: []
- id: PMID:23533145
title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in
urine.
findings: []
- id: PMID:7634325
title: Reevaluation of the roles of protein S and Gas6 as ligands for the receptor tyrosine
kinase Rse/Tyro 3.
findings: []
- id: PMID:7854420
title: Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by
growth-arrest-specific gene 6.
findings: []
- id: PMID:8336730
title: The protein encoded by a growth arrest-specific gene (gas6) is a new member of the
vitamin K-dependent proteins related to protein S, a negative coregulator in the blood
coagulation cascade.
findings: []
- id: Reactome:R-HSA-163809
title: Gamma-carboxy pro-GAS6 transport from the endoplasmic reticulum to the Golgi apparatus
findings: []
- id: Reactome:R-HSA-163843
title: Furin cleaves pro-GAS6 to GAS6
findings: []
- id: Reactome:R-HSA-202710
title: MERTK receptor binds ligands (Gas6 or Protein S)
findings: []
- id: Reactome:R-HSA-481007
title: Exocytosis of platelet alpha granule contents
findings: []
- id: Reactome:R-HSA-8952289
title: FAM20C phosphorylates FAM20C substrates
findings: []
- id: file:human/GAS6/GAS6-deep-research-falcon.md
title: Falcon deep research synthesis for GAS6
findings: []
core_functions:
- description: Extracellular TAM receptor ligand activity that activates AXL, TYRO3, and MERTK at
phosphatidylserine-positive cell-surface interfaces.
molecular_function:
id: GO:0048018
label: receptor ligand activity
directly_involved_in:
- id: GO:0007166
label: cell surface receptor signaling pathway
- id: GO:0051897
label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal
transduction
- id: GO:0001934
label: positive regulation of protein phosphorylation
locations:
- id: GO:0005576
label: extracellular region
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- description: Phosphatidylserine-dependent bridging of apoptotic or stressed membranes to TAM
receptors to promote efferocytosis and immune homeostasis.
molecular_function:
id: GO:0001786
label: phosphatidylserine binding
directly_involved_in:
- id: GO:0043277
label: apoptotic cell clearance
- id: GO:0006909
label: phagocytosis
- id: GO:0050766
label: positive regulation of phagocytosis
locations:
- id: GO:0005576
label: extracellular region
supported_by:
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: '**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.'
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/GAS6/GAS6-deep-research-falcon.md
supporting_text: 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.
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []