FGFR2 - fibroblast growth factor receptor 2 | Elisa - Clia - Antibody - Protein

Background

Fibroblast Growth Factor Receptor 2 (FGFR2) is one of the four known receptors in the fibroblast growth factor receptor family, which are crucial for the regulation of cell growth, differentiation, and development. The FGFR2 gene is located on chromosome 10q26 and encodes a receptor tyrosine kinase that is activated by fibroblast growth factors (FGFs). FGFR2 plays a vital role in various developmental processes, including limb and craniofacial development, and is implicated in several pathological conditions, such as cancer and congenital disorders.

FGFR2 is expressed in a wide range of tissues, including the brain, skin, bones, and various epithelial tissues. Its expression patterns suggest that it has both broad and specific roles in cellular processes. The receptor's importance is underscored by the diverse effects of its signaling pathways, which influence cellular proliferation, differentiation, migration, and apoptosis.

Protein Structure

FGFR2 is a transmembrane protein composed of several distinct domains:

1. Extracellular Domain: The extracellular region of FGFR2 consists of three immunoglobulin-like (Ig-like) domains (D1, D2, and D3). These domains are responsible for binding to FGFs and heparan sulfate proteoglycans, which are essential for the receptor's activation. The D2-D3 region is particularly crucial for ligand binding specificity.
2. Acid Box: Between the D1 and D2 Ig-like domains, there is a short acidic region known as the "acid box," which is involved in modulating ligand binding and receptor dimerization.
3. Transmembrane Domain: FGFR2 has a single hydrophobic transmembrane helix that anchors the receptor in the cell membrane.
4. Intracellular Domain: The intracellular region contains a split tyrosine kinase domain, which is responsible for autophosphorylation and the activation of downstream signaling pathways upon ligand binding and receptor dimerization.

Classification and Subtypes

FGFR2 belongs to the FGFR family, which includes FGFR1, FGFR2, FGFR3, and FGFR4. FGFR2 itself has two main isoforms resulting from alternative splicing: FGFR2b (or KGFR) and FGFR2c. These isoforms differ in their ligand-binding specificities and tissue distribution:

• FGFR2b: Primarily expressed in epithelial cells and binds to FGFs 1, 3, 7, 10, and 22.
• FGFR2c: Predominantly expressed in mesenchymal cells and binds to FGFs 1, 2, 4, 6, 9, 18, and 20.

These isoforms play distinct roles in development and tissue maintenance, reflecting the versatility and complexity of FGFR2 signaling.

Function and Biological Significance

FGFR2 mediates a variety of cellular processes through its interaction with FGFs and subsequent activation of intracellular signaling cascades. Some of its key functions include:

1. Developmental Regulation: FGFR2 is essential for normal development, particularly in the formation of limbs, craniofacial structures, and various organs. It regulates the proliferation and differentiation of progenitor cells during embryogenesis.
2. Cell Growth and Differentiation: By activating the MAPK, PI3K/AKT, and PLCγ pathways, FGFR2 influences cell growth, survival, and differentiation. These pathways are crucial for maintaining tissue homeostasis and responding to external signals.
3. Wound Healing: FGFR2 plays a role in tissue repair and regeneration, particularly in the skin and other epithelial tissues. It promotes the proliferation and migration of keratinocytes during wound healing.
4. Bone Development: FGFR2 is involved in osteogenesis and chondrogenesis, regulating the proliferation and differentiation of osteoblasts and chondrocytes.

Clinical Issues

Mutations and aberrant signaling of FGFR2 are associated with various clinical conditions:

1. Craniosynostosis Syndromes: Mutations in FGFR2 can lead to craniosynostosis, a condition characterized by the premature fusion of skull bones, resulting in abnormal skull shape and potential developmental delays. Syndromes such as Apert, Crouzon, and Pfeiffer are linked to FGFR2 mutations.
2. Cancer: FGFR2 is implicated in several cancers, including breast, gastric, and endometrial cancers. Overexpression, amplification, or mutations in FGFR2 can lead to uncontrolled cell proliferation and tumorigenesis. FGFR2-targeted therapies, such as tyrosine kinase inhibitors and monoclonal antibodies, are being explored for cancer treatment.
3. Skeletal Disorders: FGFR2 mutations are also associated with skeletal dysplasias, affecting bone growth and development. These conditions can lead to dwarfism and other skeletal abnormalities.
4. Therapeutic Targets: Due to its role in cancer and other diseases, FGFR2 is a target for therapeutic intervention. Inhibitors and antibodies targeting FGFR2 are being developed and tested in clinical trials to treat FGFR2-driven malignancies and other pathological conditions.

Summary

FGFR2 is a critical receptor in the FGFR family, playing vital roles in development, tissue maintenance, and disease. Its structure, characterized by distinct extracellular, transmembrane, and intracellular domains, enables it to mediate diverse cellular functions through interactions with FGFs. The receptor's isoforms, FGFR2b and FGFR2c, further expand its functional versatility by binding different FGFs and exhibiting varied tissue distributions.

Clinically, FGFR2 is significant due to its association with developmental disorders like craniosynostosis, various cancers, and skeletal dysplasias. Understanding the molecular mechanisms of FGFR2 signaling and its pathological alterations provides insights into potential therapeutic strategies. As research progresses, FGFR2-targeted therapies hold promise for treating conditions resulting from its dysregulation, highlighting the receptor's importance in both health and disease.