Fibroblast growth factor receptor 1c–β-Klotho complex (FGFR1c–β-Klotho)

The fibroblast growth factor receptor family via β‑Klotho co-receptor refers specifically to a cell-surface signaling system where certain endocrine fibroblast growth factors—primarily FGF19 and FGF21—require both a classical fibroblast growth factor receptor (FGFR, especially isoform FGFR1c) and the single-pass membrane protein β‑Klotho (KLB) for high-affinity binding and signal initiation. Unlike canonical paracrine/autocrine FGFs that use heparan sulfate proteoglycan co-receptors, these endocrine hormones circulate systemically to regulate key aspects of energy homeostasis—including glucose uptake, insulin sensitivity, lipid metabolism—and exert their effects predominantly on tissues expressing both components. In this system: • The ligand (FGF19 or FGF21) binds first with high affinity to extracellular domains on β‑Klotho. • This interaction recruits an appropriate isoform of the fibroblast growth factor receptor (usually FGFR1c or sometimes FGFR4) into a ternary ligand–co-receptor–receptor assembly. • The resulting active complex triggers intracellular kinase cascades such as RAS-MAPK/ERK pathways leading to diverse metabolic responses including increased insulin sensitivity, reduced body weight/fat mass, improved lipid profiles, suppression of bile acid synthesis (for FGF19) etc. This target is under intense investigation for its therapeutic potential against type 2 diabetes mellitus (T2D), non-alcoholic fatty liver disease (NAFLD), obesity/metabolic syndrome—and possibly cardiovascular diseases—via pharmacologic modulation using recombinant proteins/mimetics or peptide antagonists designed either to enhance beneficial actions (agonism) or block excessive/harmful activity (antagonism) depending on context.

Other names

FGFR1c/β-KlothoFGFR/β-KlothoβKlotho-FGFR complexKLB-FGFR1c complex

Agonists (e.g., FGF21 mimetics) bind to β-Klotho and recruit FGFR1c to form an active signaling complex that triggers downstream MAPK/ERK pathways for metabolic regulation. Antagonists block the interaction between endocrine FGFs and the β-Klotho co-receptor, inhibiting signal transduction through the receptor complex.