GAS6 and AXL promote insulin resistance by rewiring insulin signaling and increasing insulin receptor trafficking to late endosomes

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Abstract

Growth-arrest specific 6 (GAS6) is a secreted protein that acts as a ligand for TAM receptors (TYRO3, AXL and MERTK). In humans, GAS6 circulating levels and genetic variations in GAS6 are associated with hyperglycemia and increased risk of type 2 diabetes. However, the mechanisms by which GAS6 influences glucose metabolism are not understood. Here, we show that Gas6 deficiency in mice increases insulin sensitivity and protects from diet-induced insulin resistance. Conversely, increasing GAS6 circulating levels is sufficient to reduce insulin sensitivity in vivo . Recombinant GAS6 inhibits the activation of the insulin receptor (IR) and reduces insulin response in muscle cells. Mechanistically, AXL heterodimerizes with the IR, while GAS6 reprograms signaling pathways downstream of IR. This results in increased trafficking of the IR to Rab7a-positive late endosomes following insulin treatment. Together, these results contribute to a better understanding of the cellular and molecular mechanisms by which GAS6 and AXL influence insulin sensitivity.

ARTICLE HIGHLIGHTS

  • GAS6 deficient mice are characterized by improved glucose tolerance, increased insulin sensitivity and are protected from diet-induced insulin resistance.

  • The GAS6 receptor AXL is expressed in muscle cells and physically interacts with the insulin receptor.

  • GAS6 reprograms insulin signaling by modulating the phosphorylation of proteins implicated in endocytosis, vesicle-mediated transport, and membrane trafficking.

  • AXL promotes insulin receptor trafficking to late endosome following insulin treatment.

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