Nuclear Fibroblast Growth Factor Receptor Signaling in Skeletal Development and Disease
Creighton T Tuzon1, Diana Rigueur1, Amy E Merrill2,3
1Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, 90033, USA.
Purpose Of Review:
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.
Recent Findings:
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.
Insights
Nuclear fibroblast growth factor receptors (FGFRs) regulate gene transcription and are crucial for skeletal development. Understanding their translocation and function offers insights into skeletal disorders and cancers.
Area of Science:
- Cell biology
- Molecular biology
- Developmental biology
Background:
- Fibroblast growth factor receptors (FGFRs) are key regulators of cell proliferation and differentiation.
- While membrane-bound FGFRs are well-studied, the role of nuclear FGFRs is increasingly recognized.
Purpose of the Study:
- To review mechanisms of nuclear FGFR translocation.
- To highlight the impact of nuclear FGFRs on skeletal development and disease.
Main Methods:
- Review of existing literature on FGFR nuclear translocation.
- Analysis of the functional consequences of nuclear FGFRs on gene expression and epigenetic modifications.
Main Results:
- FGFRs translocate to the nucleus via endocytosis or proteolytic release.
- Nuclear FGFRs interact with chromatin remodelers, influencing gene transcription.
- Dysregulation of nuclear FGFRs is implicated in congenital skeletal disorders and cancers.
Conclusions:
- Nuclear FGFRs play a critical role in skeletal development and homeostasis.
- Understanding nuclear FGFR functions is vital for advancing treatments for FGFR-related skeletal diseases and cancers.
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