GDNF Family Receptor Alpha Like (GFRAL)

GFRAL (GDNF Family Receptor Alpha Like) is a single-pass membrane protein that localizes to the plasma membrane and is primarily expressed in the hindbrain. It functions as the exclusive receptor for the GDF15 hormone, forming a complex that interacts with the RET tyrosine kinase co-receptor to activate downstream signaling pathways including Ras/MAPK, PI3K/Akt, and PLC-γ. These pathways promote cell cycle progression, proliferation, migration, survival, and differentiation. The GDF15-GFRAL signaling axis plays a crucial role in metabolism regulation, particularly lipid metabolism in adipose tissues, and triggers aversive responses to various stresses. Elevated expression of GFRAL has been observed in certain cancers, such as gastric cancer, and it has been implicated in cancer cachexia. Therapeutic approaches targeting GFRAL, such as the antagonistic monoclonal antibody 3P10, have shown promise in reversing cancer cachexia in experimental models by inhibiting RET signaling through prevention of the GDF15-driven interaction of RET with GFRAL on the cell surface.

Other names

C6orf144GDNF family receptor alpha-like

GFRAL is the brainstem-restricted receptor for GDF15 hormone. Forms a complex with GDF15 that interacts with RET tyrosine kinase co-receptor to activate intracellular signaling. Activation of the GFRAL-RET pathway induces expression of genes involved in lipid metabolism in adipose tissues. Triggers an aversive response characterized by nausea, vomiting, and/or loss of appetite in response to various stresses.