Abstract
FGFR (fibroblast growth factor receptor) signaling controls fundamental processes in embryonic, fetal and adult human life. The magnitude, duration, and location of FGFR signaling must be strictly controlled in order to induce the correct biological response. Uncontrolled receptor signaling has been shown to lead to a variety of diseases, such as skeletal disorders and cancer. Here we review the numerous cellular mechanisms that regulate and turn off FGFR signaling, once the receptor is activated. These mechanisms include endocytosis and endocytic sorting, phosphatase activity, negative regulatory proteins and negative feedback phosphorylation events. The mechanisms act together simultaneously or sequentially, controlling the same or different steps in FGFR signaling. Although more work is needed to fully understand the regulation of FGFR signaling, it is clear that the cells in our body have evolved an extensive repertoire of mechanisms that together keep FGFR signaling tightly controlled and prevent excess FGFR signaling.
Highlights
It has been shown that expression of a mutant form of FGFR1, which is unable to bind to NEDD-4 leading to reduced endocytosis and sustained signaling, results in disrupted anterior neuronal patterning in zebrafish [44]
FGFR3 is subject to context-dependent regulation by the phosphatases, PTPN1 and PTPN2, and loss of either PTP resulted in ligand-independent activation of FGFR3 [87]
Another molecule that acts as an antagonist of FGFR signaling is SEF, a conserved inhibitor of the MAPK pathway [116]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. FGFs probably originated from a beta-trefoil FGF-like domain present in a choanoflagellate metazoan ancestor [5,6] Eighteen of these FGFs function as high affinity ligands for the four FGFRs and multiple splice variants of three of them (FGFR1-3). The FGF/FGFR families have evolved through gene amplification and differentiation as a regulatory signaling system crucially important for a sophisticated organization of tissues in multi-cellular organisms [1,12,13].
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