FGFR3 biology and skeletal disease

Abstract

Fibroblast Growth Factor Receptor 3 (FGFR3) is one of four high-affinity receptors for canonical FGF ligands. It acts in many tissues and plays a special role in skeletal development, especially post-embryonic bone growth, where it inhibits chondrocyte proliferation and differentiation. Gain of function mutations cause the most common forms of dwarfism in humans, and they are also detected in cancer. Triggered by ligand binding or in some cases mutation, FGFR3 activation involves dimerization of receptor monomers, phosphorylation of specific tyrosine residues in the receptor's kinase domain and in the tightly linked scaffold protein Fibroblast Receptor Factor Substrate 2 (FRS2). Signaling molecules recruited to these phosphorylation sites propagate signals through cascades that are subject to modulation. Signal output is also regulated by the fate of the receptor and the interval between its activation and degradation. Trafficking pathways have been identified for both lysosomal and proteasomal degradation, as well as, an alternative fate that involves intramembrane cleavage that produces an intracellular domain fragment capable of nuclear transport and potential function.

Keywords: Achondroplasia; FGFR3; RTK; bone growth; growth plate.