Recombinant Human GDNF family receptor alpha-like (GFRAL), partial

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:36630958). 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:36630958). The GDF15-GFRAL aversive response is triggered by stresses, such as anticancer drugs (camptothecin or cisplatin), cancers or drugs such as metformin (PubMed:32661391). 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:31535977, PubMed:32661391). Ligand-binding activates GFRAL-expressing neurons localized in the area postrema and nucleus tractus solitarius of the brainstem (By similarity). 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 (at protein level) (PubMed:28846097, PubMed:28846098). Detected at low levels in testis and adipose tissue (PubMed:28846097)

Subunit

Interacts (via the extracellular domain) with GDF15 and RET; receptor of GDF15, mediates cellular signaling through interaction with RET after GDF15-binding (PubMed:28846097, PubMed:28846099, PubMed:28953886, PubMed:31535977). Interaction with RET requires previous GDF15-binding (PubMed:28846097, PubMed:28846099)

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• Mungall A.J. et al. The DNA sequence and analysis of human chromosome 6. — Nature (2003)
• 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)
• Yang L. et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. — Nat. Med. (2017)
• Emmerson P.J. et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. — Nat. Med. (2017)
• Chow C.F.W. et al. Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. — Nat. Metab. (2022)
• Benichou O. et al. Discovery, development, and clinical proof of mechanism of LY3463251, a long-acting GDF15 receptor agonist. — Cell Metab. (2023)
• Hsu J.Y. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. — Nature (2017)