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.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) constitute signaling circuits that transmit signals across the plasma membrane, regulating pivotal cellular processes like differentiation, migration, proliferation, and apoptosis. The malfunction of FGFs/FGFRs signaling axis is observed in numerous developmental and metabolic disorders, and in various tumors. The large diversity of FGFs/FGFRs functions is attributed to a great complexity in the regulation of FGFs/FGFRs-dependent signaling cascades. The function of FGFRs is modulated at several levels, including gene expression, alternative splicing, posttranslational modifications, and protein trafficking. One of the emerging ways to adjust FGFRs activity is through formation of complexes with other integral proteins of the cell membrane. These proteins may act as coreceptors, modulating binding of FGFs to FGFRs and defining specificity of elicited cellular response. FGFRs may interact with other cell surface receptors, like G-protein-coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs). The cross-talk between various receptors modulates the strength and specificity of intracellular signaling and cell fate. At the cell surface FGFRs can assemble into large complexes involving various cell adhesion molecules (CAMs). The interplay between FGFRs and CAMs affects cell–cell interaction and motility and is especially important for development of the central nervous system. This review summarizes current stage of knowledge about the regulation of FGFRs by the plasma membrane-embedded partner proteins and highlights the importance of FGFRs-containing membrane complexes in pathological conditions, including cancer.

Fibroblast growth factor receptors (FGFRs) are integral membrane proteins that transmit signals through the plasma membrane. FGFRs signaling needs to be precisely adjusted as aberrant FGFRs function is associated with development of human cancers or severe metabolic diseases. The subcellular localization, trafficking and function of FGFRs rely on the formation of multiprotein complexes. In this study we revealed galectins, lectin family members implicated in cancer development and progression, as novel FGFR1 binding proteins. We demonstrated that galectin-1 and galectin-3 directly bind to the sugar chains of the glycosylated extracellular part of FGFR1. Although both galectins compete for the same binding sites on FGFR1, these proteins elicit different impact on FGFR1 function and cellular trafficking. Galectin-1 mimics fibroblast growth factor as it efficiently activates FGFR1 and receptor-downstream signaling pathways that result in cell proliferation and apoptotic evasion. In contrast, galectin-3 induces extensive clustering of FGFR1 on the cell surface that inhibits constitutive internalization of FGFR1. Our data point on the interplay between extracellular galectins and FGFRs in the regulation of cell fate.

Fibroblast growth factor receptor 1 (FGFR1) is a plasma membrane protein that transmits signals from the extracellular environment, regulating cell homeostasis and function. Dysregulation of FGFR1 leads to the development of human cancers and noncancerous diseases. Numerous tumors overproduce FGFR1, making this receptor a perspective target for cancer therapies. Antibody-drug conjugates (ADCs) are highly potent and selective anticancer agents. ADCs are composed of antibodies (targeting factors) fused to highly cytotoxic drugs (warheads). The efficiency of ADC strategy largely depends on the internalization of cytotoxic conjugate into cancer cells. Here, we have studied an interplay between affinity of anti-FGFR1 antibodies and efficiency of their cellular uptake. We have developed a unique set of engineered anti-FGFR1 antibodies that bind the same epitope in the extracellular part of FGFR1, but with different affinities. We have demonstrated that these antibodies are effectively taken up by cancer cells in the FGFR1-dependent manner. Interestingly, we have found that efficiency, defined as rate and level of antibody internalization, largely depends on the affinity of engineered antibodies towards FGFR1, as high affinity antibody displays fastest internalization kinetics. Our data may facilitate design of therapeutically relevant targeting molecules for selective treatment of FGFR1 overproducing cancers.

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