Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Abstract

Increasing evidence indicates that success of targeted therapies in the treatment of cancer is context-dependent and is influenced by a complex crosstalk between signaling pathways and between cell types in the tumor. The Fibroblast Growth Factor (FGF)/FGF receptor (FGFR) signaling axis highlights the importance of such context-dependent signaling in cancer. Aberrant FGFR signaling has been characterized in almost all cancer types, most commonly non-small cell lung cancer (NSCLC), breast cancer, glioblastoma, prostate cancer and gastrointestinal cancer. This occurs primarily through amplification and over-expression of FGFR1 and FGFR2 resulting in ligand-independent activation. Mutations and translocations of FGFR1-4 are also identified in cancer. Canonical FGF-FGFR signaling is tightly regulated by ligand-receptor combinations as well as direct interactions with the FGFR coreceptors heparan sulfate proteoglycans (HSPGs) and Klotho. Noncanonical FGFR signaling partners have been implicated in differential regulation of FGFR signaling. FGFR directly interacts with cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins, contributing to invasive and migratory properties of cancer cells, whereas interactions with other receptor tyrosine kinases (RTKs) regulate angiogenic, resistance to therapy, and metastatic potential of cancer cells. The diversity in FGFR signaling partners supports a role for FGFR signaling in cancer, independent of genetic aberration.

Spatially Resolved Phosphoproteomics Reveals Fibroblast Growth Factor Receptor Recycling-driven Regulation of Autophagy and Survival

“…There are four FGFRs, with FGFR1-3 having splice-variants denoted as b and c isoforms, and 21 FGF ligands, with each FGFR/FGF pair regulating signalling specificity in a context-dependent manner during development, in maintaining adult homeostasis, and in several diseases such as cancer 24,25 . One stark example of such functional selectivity is given by FGFR2b which is expressed on epithelial cells [24][25][26] . Stimulation of FGFR2b with FGF7 induced receptor degradation in contrast to stimulation with FGF10 which resulted in recycling of FGFR2b via the REs 13,22,27 .…”

“…The FGFR family is a useful model for studying the contribution of trafficking to signalling outputs 23 . There are four FGFRs, with FGFR1-3 having splice-variants denoted as b and c isoforms, and 21 FGF ligands, with each FGFR/FGF pair regulating signalling specificity in a context-dependent manner during development, in maintaining adult homeostasis, and in several diseases such as cancer 24,25 . One stark example of such functional selectivity is given by FGFR2b which is expressed on epithelial cells [24][25][26] .…”

“…These two different trafficking routes of FGFR2b were associated with different phosphorylation dynamics within the signalling cascade and an increase in cell proliferation and proliferation/migration, respectively 13,22 . Therefore, the duration and location of FGFR signalling must be strictly regulated to modulate the appropriate cellular outputs 23,25 .…”

Roles of the FGF-FGFR Signaling System in Cancer Development and Inflammation

“…Various aspects of FGF-FGFR signaling and downstream partners in several types of cancer such as breast cancer [ 9 , 10 ], pancreatic cancer [ 11 ], GIST and soft tissue sarcomas [ 12 ] are discussed. In addition, more general mechanisms of FGF-FGFR signaling in cancer including negative regulation of signaling [ 13 ], noncanonical FGF/FGFR binding partners in cancer [ 14 ] and role of oncogenic fusion proteins in centrosome and cilia formation [ 15 ] are presented. An important part of the Special Issue is dedicated to the therapeutic potential of targeting of FGF/FGFRs [ 16 , 17 ] and downstream signaling partners [ 9 , 18 ] in cancer and inflammatory diseases.…”

“…FGFR signaling can also be regulated by so-called noncanonical binding partners such as adhesion molecules and extracellular matrix components. The role of these noncanonical partners in FGFR signaling in cancer is reviewed by Ferguson et al [ 14 ]. Direct interaction between FGFRs and cell adhesion molecules or extracellular matrix proteins can induce highly invasive, metastatic phenotypes of given cancer cells.…”