The Introduction of Fibroblast Growth Factor Receptors

Some antibodies:

  1. R1MAB1(FGFR1 antibody)

An anti-fibroblast growth factor receptor-1 (FGFR1) antibody is a human antibody which can be potentially used for the treatment of diabetes.

  1. CBL539 (FGFR2 antibody)

This antibody is a rat monoclonal antibody that binds specifically to mouse FGFR2, and it can neutralize the bioactivity of mouse FGFR2.

  1. R3Mab (FGFR3 antibody)

Recombinant Human Antibody (R3Mab) is capable of binding FGFR3 expressed in HEK 293 cells as the combination of a heavy chain (HC) containing VH from anti-FGFR3 mAb and CH1-3 region of human IgG1 and a light chain (LC) encoding VL from anti-FGFR3 proteins mAb and CL of human kappa light chain. Exists as a disulfide linked dimer of the HC and LC hetero-dimer under non-reducing condition. This antibody inhibit not only WT FGFR3, but also various mutants of the receptor.

  1. U4-3(FGFR4 antibody)

The antibody is used to bind the FGFR4 and the medical use thereof, in particular for the diagnosis prevention or treatment of diseases associated with FGFR expression, over-expression or hyperactivity.

What is FGFR?

 

Figure1. FGFR2b

Fibroblast growth factor receptors (FGFRs) are members of the immunoglobulin gene superfamily, whose extracellular segments have three or two immunoglobulin-like functional regions. FGFRs are also a family of proteins. Four kinds of independent gene-coded FGFRs have been found that are FGFR1, FGFR2, FGFR3 and FGFR4 which widely distribute on the surface of target cells of fibroblast growth factor (FGF), such as vascular endothelial cells, fibroblasts, T and B lymphocytes. The biological activity of FGF is achieved by acting on FGFRs. It is known that the FGF gene family has many biological activities, such as stimulating angiogenesis, promoting embryonic tissue development and differentiation, participating in wound healing and tissue regeneration, neurotrophic and endocrine regulation.

The relationship between structure and function of FGFRs

FGFRs are transmembrane proteins belonging to receptor tyrosine kinases, which are composed of three main components: extracellular, transmembrane and intracellular segments. The extracellular segment of FGFRs is generally made up of three immunoglobulin-like functional regions, signal peptide structure and acid box. There are two tyrosine kinase active regions in the intracellular segment of FGFRs. When the extracellular segment of FGFRs binds to ligands, the receptors form dimers, which activate the tyrosine kinase in the intracellular segment, catalyze the phosphorylation of their own tyrosine residues, and also phosphorylate the tyrosine residues in the target protein of FGFRs. The activity of receptor tyrosine kinase is very crucial for the signal transduction pathways required for mitosis, transformation and differentiation of cells. It is the signal transduction pathways initiated by tyrosine phosphorylation that lead to changes in gene transcription in the nucleus and ultimately to biological reactions.

FGFRs have three unique characteristics:

  • Overlapping recognition and multi-specificity. That is, one receptor can bind to several kinds of FGFin similar affinity, and one kind of FGF can bind to several kinds of FGFRs in similar forms;
  • The binding of FGFand its receptor depends on heparin sulfate proteoglycan on the cell surface;
  • Many kinds of cell-binding and secretory receptors can be produced from the same gene.
  1. Structure and function of FGFR1

Various types of FGFR1 can be formed due to different forms of splicing of the precursor of mRNA. Receptor cross-linking test showed that FGFR1 with two or three immunoglobulin-like functional regions in the extracellular segment was the main type of FGFR1. The affinity of the two types of FGFR1 was similar to that of aFGF and bFGF. The first immunoglobulin-like functional region (Ig1) can be deleted, and the affinity of Ig1-deleted FGFR1 with aFGF and bFGF is not affected.

  1. Structure and function of FGFR2

FGFR2 with two or three immunoglobulin-like functional regions is the main type of FGFR2. These two types have similar affinity to aFGF and bFGF. Another truncated FGFR2 was found in the study of keratinocyte growth factor (KGF) receptors. Its first immunoglobulin-like functional region and acid box were simultaneously deleted. This is the first FGFR without acid box. Two kinds of FGFR2 with different carboxyl end were found in human cancer cDNA library by DNA sequencing analysis. In most cells, there are 27 amino acids at the carboxyl end of FGFR2 and only 12 amino acids at the carboxyl end of variant FGFR2. Although its function is still unclear, previous studies have shown that mutations in the carboxyl end of receptor tyrosine can increase the potential of protein transformation.

  1. Structure and FGFR3 and FGFR4

Up to now, the cloned FGFR3 and FGFR4 belong to receptors containing three immunoglobulin-like functional regions.

FGFRs and cell signaling

Intercellular communication is an important link in the genesis, development and survival of cells and multicellular organs. Most cell signals are mediated by polypeptides secreted by cells. These polypeptides regulate cell growth, differentiation and maintain the stability of the metabolic environment. Studies have found that polypeptide growth factors and cytokines function significantly in regulating cell growth and differentiation, and they play their biological functions through receptors on the cell surface. FGFRs are the basis for FGF to exert its biological activity. The tyrosine kinase activity of FGFRs is the key link in the signal transduction pathway required for cell mitosis, transformation and differentiation. When FGF binds to FGFR, tyrosine kinase in the cell segment of fibroblast growth factor receptors is activated, and tyrosine residues of receptors themselves are phosphorylated and can be subjected to it. Tyrosine residues on body target proteins are converted to phosphorylation, which initiates signaling cascades.

After the binding of growth factors and receptors, almost all of them form receptor dimers, which may vary because they’r induced by different growth factors.

Regulation of the expression of FGFRs

Some studies have shown that tissue-specific splicing of FGFR and tissue-specific expression of different FGFR genes can make different tissue cells express different FGFRs, which can selectively respond to different members of the fibroblast family, so as to regulate cell growth and differentiation.

The relationship between FGFRs and diseases

The changes of gene and expression of FGFRs realtes to the occurrence of many diseases.

  1. FGFRs and breast cancer

Researchers have detected the expression of FGFR1 in normal breast epithelial cells and breast cancer cells, and found that the expression of FGFR1 in breast cancer cells is much higher than that in normal breast cells. It was found that breast epithelial cells could express four kinds of FGFRs, namely, FGFR1, FGFR2, FGFR3 and FGFR4, but the expression levels of FGFR2 and FGFR4 were high. In this cell, a variant FGFR3 located in the nucleus was found. The FGFR3 consisted of only intracellular tyrosine kinase regions.

  1. FGFRsand Achondroplasia

Researchers have found that the etiology of Achondroplasia (ACH) is related to the point mutation of FGFR3 gene. In 19 patients, G mutation at position 1138 of the transmembrane region of FGFR3 accounted for L5 cases of A mutation and 4 cases of G mutation to C mutation. The ACH caused by the point mutation of this receptor gene can be inherited.

  1. FGFRs and ophthalmic diseases

Biological effects mediated by the binding of FGF and its receptors have been paid more and more attention in ophthalmic diseases. Eye is the most widely originated organ of embryonic tissue. FGF can be produced by various cells, such as corneal endothelial cells, lens epithelial cells, melanocytes, glial cells, pigment epithelial cells and retinal cells. Moreover, soluble high affinity FGFR1 exists in the vitreous humor of the eyes. It is speculated that regulating the biological effects of FGF binding to membrane receptors is important. Many ophthalmic diseases are caused by disorders in the regulation of growth factors and their receptors. It has been reported that proliferative vitreoretinopathy is a complication of ocular trauma, rhegmatogenous retinal detachment and vitreoretinal surgery. Fibroblasts, glial cells and retinal pigment epithelial cells that form proliferative vitreoretinopathy have the expression of FGFR.

In addition, FGFRs play an important role in the occurrence of fibrotic diseases and angiogenesis of tumors.

With the further study of FGFRs, the pathogenesis of some diseases will be revealed. Therapeutic methods and drugs related to FGFRs will emerge as the times require.