Neudesin, a secreted protein implicated in diverse physiological processes, such as metabolism and immunity, lacks an identified receptor, which has prevented a detailed understanding of its molecular mechanisms. In this study, we aimed to elucidate the function of neudesin by identifying its cognate receptor and investigating its effects on cellular signaling. Using a combination of phage display, bioinformatics, and biochemical analysis, we identified insulin‐like growth factor 1 receptor (IGF1R) as a high‐affinity receptor for neudesin, with a binding affinity of 1.78 ± 1.87 n m . This interaction was mediated by a conserved tryptophan‐proline‐glutamic acid (WPE) motif in the IGF1R extracellular domain. Our cellular assays revealed that, while neudesin binding to IGF1R induces basal phosphorylation of the downstream signaling molecules extracellular signal‐regulated kinase (ERK) and AKT (also known as Protein Kinase B, or PKB) in a cell‐line‐specific manner, it consistently acts as a negative modulator, attenuating both IGF1‐ and insulin‐induced signaling. Mechanistically, neudesin promoted the downregulation of cell surface IGF1R, thereby reducing the receptor pool available for ligand stimulation. Furthermore, neudesin inhibited insulin signaling, likely through the co‐internalization of IGF1R/insulin receptor (INSR) hybrid complexes. The physiological significance of this role was underscored in 3 T3‐L1 adipocytes, where neudesin knockdown enhanced insulin‐induced signaling and accelerated triglyceride accumulation. These results establish a novel molecular link between neudesin and the IGF1/insulin signaling axis, suggesting that neudesin may serve as an endogenous modulator of IGF1R/insulin activity, with potential implications for metabolic and growth‐related diseases.
Nakayama et al. (Sat,) studied this question.