Fibroblast growth factor receptor 2c-Klotho beta receptor complex (FGFR2c-KLB) (FGFR2c-KLB)

The Fibroblast growth factor receptor 2c-Klotho beta (FGFR2c-KLB) receptor complex is a specialized heterodimeric signaling unit essential for the biological activity of the endocrine hormone fibroblast growth factor 21 (FGF21) (Geng et al., 2018, PMID: 29343501). While FGFR2c is a receptor tyrosine kinase, it lacks high affinity for FGF21 unless it is physically associated with the transmembrane protein Klotho beta (KLB), which acts as a mandatory co-receptor (Suga et al., 2019, PMID: 30655315). This complex is primarily involved in the regulation of systemic metabolism, including glucose uptake, lipid oxidation, and energy expenditure (Kharitonenkov & DiMarchi, 2015, PMID: 25971109). Signaling through this complex activates the MAPK/ERK pathway and FRS2 phosphorylation to modulate gene expression related to metabolic homeostasis (UniProt P21802). Dysregulation of the FGF21-FGFR-KLB signaling axis is strongly implicated in metabolic disorders such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH) (Tillman & Rolph, 2020, PMID: 32124131). Therapeutic strategies focus on the development of FGF21 mimetics or long-acting analogs that target the FGFR-KLB complex to treat chronic metabolic and fibrotic diseases. Clinical candidates targeting this complex, such as efruxifermin and pegozafermin, have demonstrated significant efficacy in reducing hepatic fat content and improving insulin sensitivity in clinical trials (Harrison et al., 2021, PMID: 33444265). Safety considerations for drugs targeting this complex include potential effects on bone mineral density and gastrointestinal tolerability.

Other names

FGFR2IIIc-KLB complexFGFR2c-Beta-klotho complexFGF21 receptor complex (FGFR2c variant)Fibroblast growth factor receptor 2 isoform IIIc-Klotho beta complex

Agonism of the FGFR2c-KLB complex to activate downstream metabolic signaling pathways