The FGF21 Receptor Signaling Complex

Scientific evidence is quickly growing that establishes FGF21 as a cytokine that signals both locally and systemically to induce metabolic effects. The focus of this chapter is the receptor/co-receptor signaling complex formed by endocrine FGF21. We provide an introduction to the major components of the complex including the Klotho family of co-receptors, fibroblast growth factor receptors (FGFRs), and the fibroblast growth factor ligands, placing each in the context of its own family members while emphasizing structural features that drive interaction. We subsequently focus specifically on FGF21 signaling through FGFR1c and KLB, describing what is known about each protein's structure and how this drives protein interaction and formation of the signaling complex at the plasma membrane. We subsequently explore the stoichiometry of FGFR1c and KLB at the plasma membrane before and after the addition of FGF21 ligand, comparing how unique features of the interaction could potentially affect signaling intensity. Finally, we discuss how formation of the signaling complex is potentially regulated by other regulatory interactions, including galectins, the extracellular matrix, and co-expression of FGFR5.