Nuclear Fibroblast Growth Factor Receptor Signaling in Skeletal Development and Disease.

Abstract

Fibroblast growth factor receptor (FGFR) signaling regulates proliferation and differentiation during development and homeostasis. While membrane-bound FGFRs play a central role in these processes, the function of nuclear FGFRs is also critical. Here, we highlight mechanisms for nuclear FGFR translocation and the effects of nuclear FGFRs on skeletal development and disease. Full-length FGFRs, internalized by endocytosis, enter the nucleus through β-importin-dependent mechanisms that recognize the nuclear localization signal within FGFs. Alternatively, soluble FGFR intracellular fragments undergo nuclear translocation following their proteolytic release from the membrane. FGFRs enter the nucleus during the cellular transition between proliferation and differentiation. Once nuclear, FGFRs interact with chromatin remodelers to alter the epigenetic state and transcription of their target genes. Dysregulation of nuclear FGFR is linked to the etiology of congenital skeletal disorders and neoplastic transformation. Revealing the activities of nuclear FGFR will advance our understanding of 20 congenital skeletal disorders caused by FGFR mutations, as well as FGFR-related cancers.