Photoreceptor Cell Maintenance Depends on the TAM Ligands Protein S and Gas6

A recent paper described the role of the two TAM ligand proteins, Gas6 and Protein S, which are important players in immune regulation, cancer metastasis, and viral infection in maintaining the health of photoreceptor cells in the eye.

Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs) characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. This small family of RTKs regulates several processes, including cell proliferation/survival, cell adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Defects in TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer.

Protein S is a vitamin K-dependent plasma protein that functions as a cofactor for the anticoagulant protease, activated protein C (APC) to inhibit blood coagulation. It is found in plasma in both a free, functionally active form and also in an inactive form complexed with C4b-binding protein. Gas6 (growth arrest-specific 6) is similar to Protein S with the same domain organization and 43% amino acid identity. It is a gamma-carboxyglutamic acid (Gla) domain-containing protein thought to be involved in the stimulation of cell proliferation.

Investigators at the Hebrew University of Jerusalem (Israel) and their collaborators at the Salk Institute (La Jolla, CA, USA) chose to study the function of Protein S and Gas6 in photoreceptor maintenance due to their relation to Mer, which is required for the regular phagocytosis of photoreceptor outer segments by retinal pigment epithelial cells. For this purpose they worked with Mer mutant mice, a model system in which the process of photoreceptor phagocytosis is severely attenuated, which leads to photoreceptor death.

They reported in the December 20, 2012, issue of the journal Neuron that deletion of either Gas6 or Protein S alone from the mouse retina yielded eyes with a normal number of photoreceptors. However, concerted deletion of both ligands fully reproduced the photoreceptor death seen in Mer mutants.

These results demonstrated that Protein S and Gas6 functioned as independent, bona fide Mer ligands, and were interchangeable with respect to Mer-driven phagocytosis in the retina.

Related Links:
Hebrew University of Jerusalem
Salk Institute