Fibroblast growth factor receptor 1c–beta-Klotho protein complex (FGFR1c–KLB complex)

The **fibroblast growth factor receptor 1c–beta-Klotho protein complex** (FGFR1c–KLB complex) is a cell surface signaling unit that mediates the action of endocrine fibroblast growth factors, primarily FGF19 and FGF21. FGFR1c is a receptor tyrosine kinase, while beta-Klotho (KLB) acts as an essential co-receptor conferring high-affinity and specificity to the complex for metabolic FGFs. In the absence of KLB, FGF21 (and to a lesser extent FGF19) does not efficiently activate FGFR1c[2][3][6][7]. Interaction between KLB and FGFR1c forms a 1:1 heterocomplex at the plasma membrane, which, upon ligand (FGF21) binding, promotes dimerization of FGFR1c and initiates downstream signaling[1][3][6]. This complex is crucial for the regulation of glucose and lipid metabolism, energy balance, and has therapeutic relevance in conditions such as type 2 diabetes, obesity, and dyslipidemia. Multiple FGF21 and FGF19 analogs—potential drugs—target the FGFR1c–KLB complex to harness these metabolic effects. Abnormalities or dysregulation of this signaling axis are implicated in metabolic and possibly cardiovascular diseases. The FGFR1c–KLB complex can be the target of agonistic therapies (mainly FGF21 analogs) aiming to improve insulin sensitivity, lower lipid levels, and reduce body weight. The safety and efficacy of such interventions are under ongoing investigation, with liver and cardiovascular safety being primary concerns[2][7].

Other names

FGFR1c–beta-Klotho complexFGFR1c–KLB heterocomplexFGFR1c/β-Klotho complex

Agonism by FGF21, FGF19, or analogs: binding induces formation of the FGFR1c–KLB–FGF ligand complex, activation of FGFR1c tyrosine kinase, and downstream signaling (mainly MAPK/ERK pathway) leading to metabolic regulatory effects[2][6][7]. - Modulation of complex assembly/stability may potentiate or inhibit signaling[1].