Fibroblast growth factor receptor 1

SH2 domains in complex with FGFR1 kinase

Fibroblast Growth Factor Receptor 1 (FGFR1) is a protein that in humans is encoded by the FGFR1 gene. It is a member of the fibroblast growth factor receptor family, which is characterized by its unique biological functions and clinical significance. FGFR1 plays a crucial role in various cellular processes, including cell division, growth, and differentiation, making it essential for normal development and tissue repair.

Structure

FGFR1 is a transmembrane tyrosine kinase receptor. It consists of three main parts: an extracellular domain, a single hydrophobic transmembrane segment, and a cytoplasmic tyrosine kinase domain. The extracellular domain is responsible for binding to fibroblast growth factors (FGFs), leading to receptor dimerization and activation of the tyrosine kinase domain. This activation triggers a cascade of downstream signaling pathways.

Function

The primary function of FGFR1 is to bind to its ligands, the FGFs, which are a family of growth factors involved in a wide array of processes such as angiogenesis, wound healing, and embryonic development. Upon binding to FGFs, FGFR1 undergoes dimerization and autophosphorylation, which activates its kinase domain. This activation leads to the phosphorylation of specific tyrosine residues on the receptor itself and on downstream signaling molecules, initiating multiple signaling pathways, including the MAPK pathway and the PI3K/AKT pathway. These pathways are crucial for mediating the effects of FGFs on cell proliferation, survival, migration, and differentiation.

Clinical Significance

Mutations in the FGFR1 gene have been associated with various developmental disorders and diseases. For example, point mutations, deletions, and translocations involving the FGFR1 gene have been linked to conditions such as Pfeiffer syndrome, Kallmann syndrome, and other craniosynostosis syndromes, which affect bone development and morphology. Furthermore, aberrant activation of FGFR1, due to overexpression or mutation, has been implicated in the pathogenesis of several types of cancer, including breast, lung, and prostate cancers. As a result, FGFR1 is considered a potential therapeutic target, and several FGFR inhibitors are currently under investigation in clinical trials for cancer treatment.

Genetics

The FGFR1 gene is located on chromosome 8p11.23-p11.22. It spans approximately 60 kb and consists of 18 exons. Various isoforms of the FGFR1 protein are produced through alternative splicing, which contributes to its diverse functions in different tissues and developmental stages.

Therapeutic Implications

Given the role of FGFR1 in disease, targeting the FGFR1 signaling pathway offers a promising therapeutic strategy. FGFR inhibitors, which can be small molecule tyrosine kinase inhibitors or monoclonal antibodies, are designed to block the activity of FGFR1, thereby inhibiting the proliferation and survival of cancer cells. These inhibitors are being evaluated in clinical trials for their efficacy and safety in treating cancers with FGFR1 abnormalities.