Cubilin, a high affinity receptor for fibroblast growth factor 8, is required for cell survival in the developing vertebrate head

J Biol Chem. 2013 Jun 7;288(23):16655-16670. doi: 10.1074/jbc.M113.451070. Epub 2013 Apr 16.

Abstract

Cubilin (Cubn) is a multiligand endocytic receptor critical for the intestinal absorption of vitamin B12 and renal protein reabsorption. During mouse development, Cubn is expressed in both embryonic and extra-embryonic tissues, and Cubn gene inactivation results in early embryo lethality most likely due to the impairment of the function of extra-embryonic Cubn. Here, we focus on the developmental role of Cubn expressed in the embryonic head. We report that Cubn is a novel, interspecies-conserved Fgf receptor. Epiblast-specific inactivation of Cubn in the mouse embryo as well as Cubn silencing in the anterior head of frog or the cephalic neural crest of chick embryos show that Cubn is required during early somite stages to convey survival signals in the developing vertebrate head. Surface plasmon resonance analysis reveals that fibroblast growth factor 8 (Fgf8), a key mediator of cell survival, migration, proliferation, and patterning in the developing head, is a high affinity ligand for Cubn. Cell uptake studies show that binding to Cubn is necessary for the phosphorylation of the Fgf signaling mediators MAPK and Smad1. Although Cubn may not form stable ternary complexes with Fgf receptors (FgfRs), it acts together with and/or is necessary for optimal FgfR activity. We propose that plasma membrane binding of Fgf8, and most likely of the Fgf8 family members Fgf17 and Fgf18, to Cubn improves Fgf ligand endocytosis and availability to FgfRs, thus modulating Fgf signaling activity.

Keywords: Cell Death; Cubilin; Development; Fibroblast Growth Factor (FGF); Megalin; Molecular Cell Biology; Mouse; Xenopus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / physiology
  • Endocytosis / physiology
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblast Growth Factor 8 / genetics
  • Fibroblast Growth Factor 8 / metabolism*
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Gene Silencing
  • Head / embryology*
  • Ligands
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mice, Transgenic
  • Neural Crest / cytology
  • Neural Crest / embryology*
  • Protein Binding
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism*

Substances

  • Fgf17 protein, mouse
  • Fgf8 protein, mouse
  • Ligands
  • Receptors, Cell Surface
  • Receptors, Fibroblast Growth Factor
  • intrinsic factor-cobalamin receptor
  • Fibroblast Growth Factor 8
  • Fibroblast Growth Factors
  • Extracellular Signal-Regulated MAP Kinases