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

The FGFR1c–Klotho receptor complex is a heteromeric signaling unit composed of the fibroblast growth factor receptor 1 isoform c (FGFR1c) and a member of the Klotho family, specifically alpha-Klotho (KL) or beta-Klotho (KLB) [nih.gov, natap.org]. This complex is essential for the high-affinity binding and signaling of endocrine fibroblast growth factors (FGFs), such as FGF23 and FGF21, which lack the ability to bind heparin and thus require Klotho as an obligatory co-receptor [frontiersin.org, pnas.org]. The FGFR1c–alpha-Klotho complex primarily functions in the kidney to regulate phosphate reabsorption and vitamin D synthesis in response to FGF23 [nih.gov]. In contrast, the FGFR1c–beta-Klotho complex is predominantly expressed in adipose tissue and the brain, where it mediates the metabolic effects of FGF21, including the stimulation of glucose uptake and thermogenesis [nih.gov, oup.com]. Dysregulation of these receptor pathways is implicated in a variety of conditions, ranging from mineral metabolism disorders like X-linked hypophosphatemia to metabolic diseases such as nonalcoholic steatohepatitis (NASH) and obesity [frontiersin.org, nih.gov]. Consequently, the complex is a significant therapeutic target, with several FGF21 mimetics and bispecific agonist antibodies currently under clinical investigation [nih.gov]. These drugs aim to activate the receptor complex to improve insulin sensitivity and reduce hepatic fat in metabolic patients [nih.gov]. Safety considerations for targeting this complex include gastrointestinal distress and potential effects on bone mineral density [frontiersin.org].

Other names

FGFR1c-alpha-Klotho complexFGFR1c-beta-Klotho complexFGF23 receptorFGF21 receptorFGFR1c-KLFGFR1c-KLBFGFR1c-Klotho heteromer

Agonism of the FGFR1c–Klotho complex to mimic endocrine FGF signaling for metabolic or mineral regulation.