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J Biol Chem June 7, 2013; 288 (23): 16655-16670.
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Cubilin, a high affinity receptor for fibroblast growth factor 8, is required for cell survival in the developing vertebrate head.

Cases O , Perea-Gomez A , Aguiar DP , Nykjaer A , Amsellem S , Chandellier J , Umbhauer M , Cereghini S , Madsen M , Collignon J , Verroust P , Riou JF , Creuzet SE , Kozyraki R .

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.

PubMed ID: 23592779
PMC ID: PMC3675600
Article link: J Biol Chem

Species referenced: Xenopus
Genes referenced: actl6a casp3.2 cubn fgf8 foxg1 mapk1 otx2 smad1
Morpholinos: cubn MO1 cubn MO2 fgf8 MO1

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References [+] :
Amsellem, Cubilin is essential for albumin reabsorption in the renal proximal tubule. 2010, Pubmed