title: The FGF21 Receptor Signaling Complex: Klothoβ, FGFR1c, and Other Regulatory Interactions.
abstract: 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.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada. Electronic address: dawn.kilkenny@utoronto.ca.
authors.forename: D M
authors.initials: DM
authors.lastname: Kilkenny
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada; Toronto General Research Institute, University Health Network, Toronto, ON, Canada. Electronic address: jon.rocheleau@utoronto.ca.
authors.forename: J V
authors.initials: JV
authors.lastname: Rocheleau
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D005346:Fibroblast Growth Factors / Q000378:metabolism; D015870:Gene Expression; D014644:Genetic Variation; D006801:Humans; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D055503:Protein Multimerization; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C538995:KLB protein, human; C418622:Klb protein, mouse; D008565:Membrane Proteins; D017468:Receptors, Fibroblast Growth Factor; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D000090265:Klotho Proteins
keywords: FGF; FGF21; FGFR; FGFR1; FGFR5; Heterodimer; Homodimer; KLB; Klotho-beta; Matrix