Why does Gas6 but not ProS1 promote microglia efferocytosis despite both being TAM receptor ligands?

The study shows Gas6 promotes efferocytosis while ProS1 does not, despite both being established TAM receptor ligands. This selectivity is unexplained and critical for understanding therapeutic targeting of efferocytosis in neuroinflammation.

Gap type: unexplained_observation Source paper: Gas6 Promotes Microglia Efferocytosis and Suppresses Inflammation Through Activating Axl/Rac1 Signaling in Subarachnoid Hemorrhage Mice. (2023, Translational stroke research, PMID:36324028)

TAM receptors (Tyro3, Axl, Mertk) are receptor tyrosine kinases that mediate efferocytosis—phagocytic clearance of apoptotic cells—through their shared ligands Gas6 (growth arrest-specific 6) and ProS1 (Protein S1). Both Gas6 and ProS1 are vitamin K-dependent proteins that bridge phosphatidylserine (PtdSer) on apoptotic cell surfaces to TAM receptors on phagocytes via their Gla domains and sex hormone-binding globulin-like domains. In microglia, this pathway is central to maintaining CNS homeostasis by clearing apoptotic neurons and myelin debris; impaired efferocytosis is associated with exacerbated neuroinflammation and amyloid accumulation in Alzheimer’s disease models. A 2022 study demonstrated that Gas6 promotes microglial efferocytosis and suppresses subsequent inflammatory signaling through Mertk activation, while ProS1 does not produce equivalent effects despite both being established TAM receptor ligands (Gas6 Promotes Microglia Efferocytosis and Suppresses Inflammation Through Activation of Mertk, Translational Stroke Research 2022).

The selectivity gap is mechanistically unexplained. Gas6 engages all three TAM receptors (Tyro3, Axl, Mertk) with distinct binding affinities, while ProS1 preferentially binds Tyro3 and Mertk with lower affinity for Axl—differential receptor engagement profiles could explain divergent downstream signaling. Additionally, Gas6 and ProS1 differ in their Gla domain PtdSer-binding geometry and protein S1 linker flexibility, potentially affecting the spatial geometry of TAM receptor clustering at phagocytic cups. Competing explanations include: ligand-specific recruitment of SOCS1/3 feedback inhibitors downstream of distinct receptor combinations, differential regulation by soluble decoy TAM ectodomains (cleaved Axl, shed Mertk) that may preferentially neutralize ProS1 binding in the inflamed CNS, or differences in γ-carboxylation efficiency affecting Gla domain affinity for PtdSer in the CNS milieu (TAM receptor inhibition in cancer, Cancers 2021).

This question is therapeutically relevant for neurodegeneration: promoting microglial efferocytosis to clear amyloid and tau is a validated therapeutic goal. Understanding which ligand-receptor pair most effectively activates efferocytosis without co-activating immunosuppressive or pro-inflammatory signals is prerequisite to selecting and engineering Gas6 or ProS1 variants for CNS therapeutics. Structural studies of Gas6-Mertk vs. ProS1-Mertk complexes, combined with phosphoproteomics of downstream signaling in primary microglia following selective ligand stimulation, are needed to resolve the mechanistic basis of selectivity.