Fibroblast growth factor receptors, developmental corruption and malignant disease

Abstract

Fibroblast growth factors (FGF) are a family of ligands that bind to four different types of cell surface receptor entitled, FGFR1, FGFR2, FGFR3 and FGFR4. These receptors differ in their ligand binding affinity and tissue distribution. The prototypical receptor structure is that of an extracellular region comprising three immunoglobulin (Ig)-like domains, a hydrophobic transmembrane segment and a split intracellular tyrosine kinase domain. Alternative gene splicing affecting the extracellular third Ig loop also creates different receptor isoforms entitled FGFRIIIb and FGFRIIIc. Somatic fibroblast growth factor receptor (FGFR) mutations are implicated in different types of cancer and germline FGFR mutations occur in developmental syndromes particularly those in which craniosynostosis is a feature. The mutations found in both conditions are often identical. Many somatic FGFR mutations in cancer are gain-of-function mutations of established preclinical oncogenic potential. Gene amplification can also occur with 19-22% of squamous cell lung cancers for example having amplification of FGFR1. Ontologic comparators can be informative such as aberrant spermatogenesis being implicated in both spermatocytic seminomas and Apert syndrome. The former arises from somatic FGFR3 mutations and Apert syndrome arises from germline FGFR2 mutations. Finally, therapeutics directed at inhibiting the FGF/FGFR interaction are a promising subject for clinical trials.

Unliganded Fibroblast Growth Factor Receptor 1 Forms Density-independent Dimers

“…In addition, some FGFR splice isoforms (1c, 2c, 3c, and 4) interact with membrane-bound coreceptor proteins, Klotho or ␤Klotho (KLB), to form receptor complexes for the endocrine FGFs, FGF19, -21, and -23, to regulate bile acid, energy, and phosphate metabolism, respectively (3,(7)(8)(9)(10)(11). Notably, gain-and loss-of-function mutations in FGFRs are implicated in a variety of pathological conditions in humans (12)(13)(14)(15). Thus, FGFRs are attractive targets for therapeutic interventions for various pathological conditions (3,12,16,17).…”

“…5A). Analogous mutations were also found in FGFR2 and -3 in various human genetic syndromes and in human tumor samples (14,41,42). To compare the signaling properties of wild type (WT) and mutant FGFR1c constructs, we expressed each of them as a SNAP-tagged protein.…”

The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling

“…FGFR2 isoform switching via alternative splicing has been observed in multiple contexts, including normal epithelialmesenchymal transition (Warzecha and Carstens, 2012), embryonic development (Eswarakumar et al, 2002;Rice et al, 2003;Takeuchi et al, 2005;Liu et al, 2011), human birth defects (Hajihosseini et al, 2001;Teebi et al, 2002;Ibrahimi et al, 2005), cancer and various pathologies (Katoh, 2008(Katoh, , 2009Holzmann et al, 2012;Kelleher et al, 2013). Whether PQBP1 regulates fgfr2 alternative splicing in these normal and disease situations will be worth investigating.…”

Identification of Oncogenic and Drug-Sensitizing Mutations in the Extracellular Domain of FGFR2

“…FGFR2 point mutations have been well described in studies of different diseases, such as craniosynotosis syndrome, gastric cancer, and endometrial carcinomas (6,(25)(26)(27). Furthermore, recent studies suggest that FGFR2 might define a molecular subset in other cancers as well, including NSCLC (8,10,19).…”

“…FGF ligand binding results in FGFR dimerization, followed by receptor autophosphorylation and activation of downstream signaling, playing key roles in multiple biologic processes such as tissue repair, angiogenesis, and embryonic development (5). Aside from their normal physiological roles, aberrant FGFR signaling has been implicated in a variety of diseases, including cancers (6). The FGFR signaling pathway can be activated in various ways.…”