FGFR4 - fibroblast growth factor receptor 4 | Elisa - Clia - Antibody - Protein

Background

Fibroblast Growth Factor Receptor 4 (FGFR4) is one of the four members of the FGFR family, which includes FGFR1, FGFR2, FGFR3, and FGFR4. FGFR4 plays a crucial role in cell growth, survival, differentiation, and angiogenesis, making it an essential component in various physiological and pathological processes. The FGFR4 gene is located on chromosome 5q35.2 and encodes a protein that is integral to transmembrane signaling. FGFR4 expression is observed in many tissues, including the liver, lung, muscle, and kidney, highlighting its diverse functional significance.

Aberrations in FGFR4 signaling have been implicated in various diseases, including cancers and metabolic disorders. Understanding the structural and functional aspects of FGFR4 is crucial for developing targeted therapies for these conditions.

Protein Structure

FGFR4, like other FGFRs, is a transmembrane protein comprising several distinct domains:

1. Extracellular Domain: The extracellular region of FGFR4 contains three immunoglobulin-like (Ig-like) domains (D1, D2, and D3). These domains are crucial for ligand binding and interaction with heparan sulfate proteoglycans, which enhance ligand affinity and specificity. The D2 and D3 domains are directly involved in FGF binding, while the D1 domain and the acidic box (a short acidic region between D1 and D2) modulate receptor activation and ligand binding.
2. Transmembrane Domain: This single hydrophobic alpha-helix anchors the receptor in the cell membrane, playing a role in maintaining the structural integrity of the receptor and facilitating signal transduction across the membrane.
3. Intracellular Domain: The intracellular region contains a split tyrosine kinase domain. Upon ligand binding and receptor dimerization, this kinase domain undergoes autophosphorylation, which activates various downstream signaling pathways. This domain is crucial for mediating cellular responses to FGF stimulation.

Classification and Subtypes

FGFR4 is part of the FGFR family, which is characterized by its ability to bind FGFs and mediate signal transduction through tyrosine kinase activity. Unlike FGFR1, FGFR2, and FGFR3, which have multiple isoforms due to alternative splicing, FGFR4 has fewer known isoforms. However, its primary isoform exhibits unique properties that distinguish it from other FGFRs.

Function and Biological Significance

FGFR4 mediates numerous biological processes through its interaction with various FGFs. Key functions and biological significance of FGFR4 include:

1. Cell Growth and Differentiation: FGFR4 is involved in regulating cell proliferation and differentiation. It plays a significant role in muscle development and regeneration, as well as in the maintenance of tissue homeostasis.
2. Metabolism: FGFR4 is crucial in regulating bile acid metabolism in the liver. It modulates cholesterol metabolism by influencing the expression of key enzymes involved in bile acid synthesis, thereby maintaining metabolic homeostasis.
3. Angiogenesis: FGFR4 contributes to angiogenesis, the process of new blood vessel formation, which is vital for wound healing and tissue regeneration. It promotes endothelial cell proliferation and migration, essential steps in the angiogenic process.
4. Cancer: FGFR4 signaling is implicated in various cancers, including hepatocellular carcinoma, breast cancer, and rhabdomyosarcoma. Overexpression or mutations in FGFR4 can lead to enhanced cell proliferation, survival, and metastasis, contributing to tumor progression. FGFR4 has emerged as a potential therapeutic target in oncology, with various inhibitors being developed to block its activity in cancer cells.

Clinical Issues

Aberrations in FGFR4 signaling are associated with several clinical conditions:

1. Cancer: Mutations in FGFR4, such as the FGFR4 G388R polymorphism, have been linked to increased cancer risk and poor prognosis in various cancers, including breast, prostate, and colorectal cancer. This mutation leads to enhanced receptor stability and prolonged signaling, promoting tumor growth and metastasis. FGFR4-targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, are under investigation in clinical trials for treating FGFR4-driven cancers.
2. Metabolic Disorders: FGFR4 plays a significant role in liver metabolism. Dysregulation of FGFR4 signaling can lead to metabolic disorders, including dyslipidemia and fatty liver disease. Understanding FGFR4's role in metabolism could lead to novel therapeutic strategies for managing these conditions.
3. Fibrosis: FGFR4 is involved in tissue fibrosis, a pathological process characterized by excessive deposition of extracellular matrix components. Dysregulated FGFR4 signaling can contribute to fibrotic diseases, including liver fibrosis and cardiac fibrosis. Targeting FGFR4 signaling pathways may offer therapeutic benefits in treating fibrotic diseases.

Summary

FGFR4 is a critical receptor in the FGFR family, essential for mediating various physiological processes, including cell growth, differentiation, metabolism, and angiogenesis. Its structure, comprising distinct extracellular, transmembrane, and intracellular domains, allows it to interact with FGFs and activate downstream signaling pathways.

Clinically, FGFR4 is significant due to its association with various diseases, including cancers and metabolic disorders. Understanding the molecular mechanisms of FGFR4 signaling and its pathological alterations provides insights into potential therapeutic strategies. FGFR4-targeted therapies hold promise for treating conditions resulting from its dysregulation, highlighting the receptor's importance in both health and disease. As research progresses, targeting FGFR4 in clinical settings may offer new avenues for treating cancer and metabolic disorders.