Activation of FGFRs (fibroblast growth factor receptors) has an essential role in regulating cell survival, proliferation, migration and differentiation. Dysregulation of the FGFR signaling pathway has been associated with human cancer. FGFRs represent an important target for cancer therapeutics because a growing body of evidence indicates that they can act in an oncogenic fashion to promote multiple steps of cancer progression, including induction of mitogenic and survival signals.
At present, four distinct FGFR cDNAs have been identified and classified as FGFR 1-4. Their high degree of homology and the presence of a ligand-dependent tyrosine kinase activity distinguishes FGFRs as a distinct subfamily among the receptor tyrosine kinases. The four different FGF receptors are closely related and, as a family, possess a number of uniquely characteristic structural features which set them apart from other tyrosine kinase receptors: (a) An extracellular, ligand-binding region of the FGF receptors consisting of three immunoglobulin (Ig) -like domains; (b) A single transmembrane domain, followed by a relatively long juxtamembrane region (approxim ately 80 residues); (c) A split tyrosine kinase domain in the cytoplasmic region, where a kinase insert (13 amino acids long) separates the two portions of the tyrosine kinase domain; (d) A COOH-terminal tail that contains tyrosines which may be phosphorylated upon ligand binding.
FGFR1, FGFR2, FGFR3, and FGFR4 have distinct distributions in many tissues of the chicken embryo. Although mRNAs from these receptors are often found in the same tissues, they generally tend to localize in different cell types within these tissues. It has been shown that FGFR-1 is the most abundant of the three receptors and is found in most tissues, with the highest levels being found in cardiac, skeletal, and some types of smooth muscle. FGFR-1 has also been shown to bind both FGF-1 and FGF-2 with similar affinities and is known to be expressed in the developing CNS and in embryonic mesenchyme. In situ studies show FGFR1 expression in the mesenchyme of developing mouse limb bud and FGFR2 expression localized to the limb bud ectoderm. The distribution of the mRNAs for FGFR2 are restricted to a more limited number of tissues than FGFR1. FGFR2 has been localized by northern blot analysis to human fetal brain, skin, and bones and by in situ hybridization to epithelial cells of embryonic skin and other organs in embryonic mice. FGFR3, which is closely related to FGFR2, was localized by northern blot analysis to human fetal brain, skin, bones, intestine, and lung. FGFR4 was shown to be expressed at high levels in the adrenal and lung and at lower levels in human fetal kidney, intestine, pancreas, striated muscle, spleen, and liver by northern blot analysis. No FGFR4 expression was found in embryonic brain, heart, or skin.
Fibroblast growth factor signaling pathway
The fibroblast growth factor (FGF) signaling pathway plays critical roles in many aspects of neural development. The FGF ligand family is composed of a family of 22 polypeptides recognized by four distinct high-affinity receptor tyrosine kinases, FGFRs. FGF signaling is initiated by FGF binding to the FGFR extracellular ligand-binding domain, which is mediated by FGF oligomerization with heparin sulfate proteoglycans. Ligand-receptor binding facilitates receptor homo- or hetero-dimerization and subsequent autophosphorylation of the intracellular tyrosine kinase domains. The mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K)/Akt, and phospholipase Cγ (PLCγ) pathways are the major downstream signaling pathways of FGFR activation leading to gene expression responsible for controlling a variety of cellular processes such as proliferation, survival, differentiation, and migration. A variety of different FGFs are expressed focally in the developing mouse forebrain35, and Fgfr1, -2, and -3 are expressed by VZ cells . Previous experiments have defined roles for FGF signaling in the development of the forebrain including the formation of axon tracts and the commissures and the specification and patterning of dorsal cortex areas through regulation of cell proliferation, differentiation, and survival.
Heitman, Nicholas. Pathogenic fibroblast growth factor receptor 2 signaling adversely affects diverse cellular processes during embryonic and post-natal development of the mouse cerebral cortex. Icahn School of Medicine at Mount Sinai, 2013.