Dynamics and Distribution of Klothoβ (KLB) and Fibroblast Growth Factor Receptor-1 (FGFR1) in Living Cells Reveal the Fibroblast Growth Factor-21 (FGF21)-induced Receptor Complex

Abstract

Background: FGFR1c and KLB form an ill-defined FGF21 signaling complex. Results: FGFR1c competes with galectin for binding to KLB. KLB and FGFR1c interact in a 1:1 heterocomplex, and subsequent addition of FGF21 induces FGFR1c dimers. Conclusion: KLB and FGFR1c activity and dynamics suggest that the galectin lattice modulates FGF21 signaling. Significance: The galectin lattice is a novel target to potentiate therapeutic effects of FGF21.

Unliganded Fibroblast Growth Factor Receptor 1 Forms Density-independent Dimers

“…There has been a previous attempt to study behaviors of C-terminally tagged full-length FGFR1c and KLB in the context of plasma membrane using a fluorescent imaging-based method ("the number and brightness analysis") in living HeLa cells (53). This study by Ming et al (53) has observed that fulllength FGFR1c molecules exist as dimers in the absence of ligands, consistent with our conclusion.…”

“…By combining SNAP and ACP tags with TR-FRET technology, we demonstrate here that, like EGFR, full-length FGFR1 can efficiently form ligand-independent oligomers, most likely dimers, on the cell surface. This confirms the previously proposed but rather controversial idea that FGFR1 forms preformed dimers in the absence of ligand (48,53). Structurefunction analysis supports the role for TMD and TKD, rather than ECD, in ligand-independent FGFR1 dimerization.…”

“…The study also found that KLB existed as monomers in the absence of ligand addition and, oddly, that FGF21 addition induced dimerization of KLB only when FGFR1 was absent (but presumably in the presence of endogenously expressed FGFRs). Taking together, Ming et al (53) suggested that FGF21 affects KLB in two independent ways; on one hand, FGF21 induces KLB dimerization without FGFR1, and on the other, FGF21 induces formation of an active 2:1 FGFR1⅐KLB signaling complex. Taking all the existing data together, we favor a model in which KLB and FGFR1c form a 2:1 FGFR1:KLB heterotrimeric complex or 2:2 FGFR1:KLB heterotetrameric complex in the absence of FGF21, depending on the abundance of KLB.…”

Fibroblast growth factor-21, energy balance and obesity

“…Cellular responsiveness to FGF21, either from the circulation or from autocrine/paracrine action, is determined by the presence in the cell membrane of FGF receptors (FGFRs) and, especially, of the co-receptor β-Klotho. FGF21 has a low affinity for FGFRs (FGFR1-4), which are ubiquitously distributed, and requires the formation of the ternary complex, FGF21-FGFR-β-Klotho (1:2:1), to exert its actions (Ming et al, 2012). Among FGFR subtypes, FGFR1 appears to play a predominant role (Adams et al, 2012;Kuroso et al, 2007;Yang et al, 2012).…”

Modulation of energy balance by fibroblast growth factor 21

“…It is synthetized mainly in liver [31] but also in white [32] and brown [18] adipose tissue, skeletal muscle [33], heart [34], and β cells [12]. Action of FGF21 is through cell membrane receptor FGFR1c and β-Klotho interaction ( Figure 1) [35][36][37]. Intracellular signaling is then activated through phosphorylation of FGFR substrate 2 α (FRS2 α), extracellular response kinase 1/2 (ERK1/2), and Akt (protein kinase B) pathways [38,39].…”