Recombinant Mouse GDNF family receptor alpha-like (Gfral), partial (Active)

Function

Brainstem-restricted receptor for GDF15 hormone, which triggers an aversive response, characterized by nausea, vomiting, and/or loss of appetite in response to various stresses (PubMed:28846097, PubMed:28846098, PubMed:28846099, PubMed:28953886, PubMed:31152154, PubMed:31928886, PubMed:32723474, PubMed:33593916, PubMed:35202387, PubMed:36630958, PubMed:37380764). The aversive response is both required to reduce continuing exposure to those stresses at the time of exposure and to promote avoidance behavior in the future (PubMed:28846097, PubMed:28846098, PubMed:28846099, PubMed:28953886, PubMed:31928886, PubMed:32723474, PubMed:33593916, PubMed:35202387, PubMed:36630958). The GDF15-GFRAL aversive response is triggered by stresses, such as anticancer drugs (camptothecin or cisplatin), cancers or drugs such as metformin (PubMed:31875646, PubMed:31928886, PubMed:32661391, PubMed:32723474). Upon interaction with its ligand, GDF15, mediates the GDF15-induced autophosphorylation and activation of the RET tyrosine kinase receptor, leading to activation of MAPK- and AKT- signaling pathways (PubMed:28846098, PubMed:28846099, PubMed:32723474, PubMed:33593916). Ligand-binding activates GFRAL-expressing neurons localized in the area postrema and nucleus tractus solitarius of the brainstem (PubMed:28846098, PubMed:28846099, PubMed:31152154, PubMed:32723474). The GDF15-GFRAL signal induces expression of genes involved in metabolism, such as lipid metabolism in adipose tissues (PubMed:32661391)

Subcellular Location

Cell membrane (Single-pass membrane protein)

Tissue Specificity

Expressed in the brainstem, restricted to cells in the area postrema and the immediately adjacent region of the nucleus tractus solitarius

Subunit

Interacts (via the extracellular domain) with GDF15 and RET; receptor of GDF15, mediates cellular signaling through interaction with RET after GDF15-binding (PubMed:28846098, PubMed:28846099). Interaction with RET requires previous GDF15-binding (PubMed:28846099)

• Li Z. et al. Molecular cloning and characterization of GRAL, a novel GDNF receptor alpha-like gene. (JUN-)
• Hsu J.Y. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. — Nature (2017)
• Hsu J.Y. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. — Nature (2017)
• Emmerson P.J. et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. — Nat. Med. (2017)
• Yang L. et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. — Nat. Med. (2017)
• Mullican S.E. et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. — Nat. Med. (2017)
• Tsai V.W. et al. GDF15 mediates adiposity resistance through actions on GFRAL neurons in the hindbrain AP/NTS. — Int. J. Obes. Relat. Metab. Disord. (2019)
• Borner T. et al. GDF15 induces anorexia through nausea and emesis. — Cell Metab. (2020)