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Abstract
Fibroblast growth factor receptors (FGFRs) in response to fibroblast growth factors (FGFs) transmit signals across the cell membrane, regulating important cellular processes, like differentiation, division, motility, and death. The aberrant activity of FGFRs is often observed in various diseases, especially in cancer. The uncontrolled FGFRs’ function may result from their overproduction, activating mutations, or generation of FGFRs’ fusion proteins. Besides their typical subcellular localization on the cell surface, FGFRs are often found inside the cells, in the nucleus and mitochondria. The intracellular pool of FGFRs utilizes different mechanisms to facilitate cancer cell survival and expansion. In this review, we summarize the current stage of knowledge about the role of FGFRs in oncogenic processes. We focused on the mechanisms of FGFRs’ cellular trafficking—internalization, nuclear translocation, and mitochondrial targeting, as well as their role in carcinogenesis. The subcellular sorting of FGFRs constitutes an attractive target for anti-cancer therapies. The blocking of FGFRs’ nuclear and mitochondrial translocation can lead to the inhibition of cancer invasion. Moreover, the endocytosis of FGFRs can serve as a tool for the efficient and highly selective delivery of drugs into cancer cells overproducing these receptors. Here, we provide up to date examples how the cellular sorting of FGFRs can be hijacked for selective cancer treatment.
Highlights
Receptor tyrosine kinases (RTKs) constitute a large family of integral plasma membrane proteins that, by binding to appropriate ligands, transmit signals across the cell membrane
The cytoplasmic part of FGFRL1 is composed of a short tail that has no kinase activity, it is still capable of recruiting signaling proteins, like SHP1 [26]
The phosphorylated tyrosine residues serve as docking sites for the downstream signaling proteins—phospholipase C-gamma (PLCγ) and the signal transducer for the downstream signaling proteins—phospholipase C-gamma (PLCγ) and the signal transducer and activator of transcription (STAT) [21,22,49,50,51], whereas the adaptor protein FRS2 binds to the and activator of transcription (STAT) [21,22,49,50,51], whereas the adaptor protein FRS2 binds to the juxtamembrane domain of Fibroblast growth factor receptors (FGFRs) [52]
Summary
Receptor tyrosine kinases (RTKs) constitute a large family of integral plasma membrane proteins that, by binding to appropriate ligands, transmit signals across the cell membrane. RTKs are composed of an extracellular region responsible for ligand binding, a single transmembrane α-helix that embeds these receptors in the cellular membranes, and an intracellular region with a tyrosine kinase domain responsible for signal propagation [2]. RTK-determined cell fate depends on the strength and duration of the signal propagation [4]. Because of their critical function for cell homeostasis, the activity of RTKs is under tight control at various levels [5]. We focus on the subcellular trafficking of FGFRs and its implications in cancer treatment
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