The fibroblast growth factor receptor 3 (FGFR3) gene (Figure 1) encodes one member of the FGF receptor tyrosine kinase family, which includes four kinases: FGFR1, FGFR2, FGFR3, and FGFR4. FGFR tyrosine kinases belong to the immunoglobulin superfamily and act as receptors for the various fibroblast growth factors (FGFs). FGFR3 consists of three extracellular immunoglobulin-like domains, a transmembrane domain, and an intracellular split kinase domain with two contiguous active regions (Ahmad, Iwata, and Leung 2012; Dienstmann et al. 2014; Goetz and Mohammadi 2013; Kelleher et al. 2013; di Martino, Tomlinson, and Knowles 2012; Touat et al. 2015). Canonical models of FGF-FGFR signaling hold that binding of FGF ligands, in coordination with heparin sulphate, to the extracellular domains promotes receptor dimerization and autophosphorylation of the tyrosine kinase domains, thereby activating these enzymes (Adar et al. 2002; d'Avis et al. 1998; Goetz and Mohammadi 2013; Kelleher et al. 2013; Schlessinger et al. 2000; Tomlinson et al. 2007; Touat et al. 2015; Turner and Grose 2010). However, recent biophysical evidence suggests that full length FGFRs, in particular FGFR3, can dimerize in the absence of ligand at physiological concentrations and that FGFR3 responds with different levels of activation to different FGF ligands (Sarabipour and Hristova 2016).
After activation, FGFRs are involved in downstream signaling via the MAP kinase, JAK/STAT, and PI3K/AKT pathways (Figure 2). They play crucial roles in development, differentiation, cell survival, and cell migration (Ahmad, Iwata, and Leung 2012; Dienstmann et al. 2014; Kelleher et al. 2013). FGFR3 has been shown in cancers to be dysregulated by amplification, missense mutation, fusion, or translocation, with most carcinogenic mutations having an activating effect on FGFR3 (di Martino, Tomlinson, and Knowles 2012). FGFR3 gene aberrations have been reported in urothelial, breast, head and neck, lung, brain, gastric, pancreatic, colorectal, kidney, endometrial, ovarian, and cervical cancers (Dienstmann et al. 2014; Helsten et al. 2016; Kelleher et al. 2013; Parker et al. 2014; Touat et al. 2015) and are known to be highly prevalent in bladder cancers (di Martino, Tomlinson, and Knowles 2012).
Many oncogenic FGFR3 missense mutations are activating, potentially through mechanisms that promote constitutive dimerization of FGFR3 or by conformational activation of the TK domain (Lievans, Roncador, and Liboi 2006; di Martino, Tomlinson, and Knowles 2012; Tomlinson et al. 2007; Touat et al. 2015; Webster et al. 1996). However, more recent biophysical work demonstrates that cysteine mutations in the extracellular and transmembrane domains, formerly thought to act by promoting constitutive dimerization, only result in modest dimer stabilization in absence of ligand and instead lead to structural changes of the dimers (Piccolo, Placone, and Hristova 2014). FGFR3 fusions have also been implicated in dimerization, as they introduce dimerization domains that may promote constitutive dimerization (Parker et al. 2014). FGFR3 amplification and FGFR3 overexpression may result in enhanced ligand-free dimerization and signaling due to locally enhanced FGFR3 concentrations in the membrane and/or enhanced signaling due to concomitant FGF ligand overexpression (di Martino, Tomlinson, and Knowles 2012; Sarabipour and Hristova 2016). Recent work suggests that FGFR3 adopts several active dimer conformations and that activating mutations may act by locking FGFR3 into the most active of these conformations even in the absence of ligand (Sarabipour and Hristova 2016).
Figure 1. Diagram of the FGFR3 protein domains and corresponding FGFR3 coding exons. SP = signal peptide; Ig = immunoglobulin-like domain; AB = acid box; TM = transmembrane domain; TK = tyrosine kinase domain. For comprehensive information of the FGFR3 gene and FGFR3 protein, see reviews in Ahmad, Iwata, and Leung 2012; Dienstmann et al. 2014; Goetz and Mohammadi 2013; di Martino, Tomlinson, and Knowles 2012; Touat et al. 2015;Turner and Grose 2010.
Figure 2. Fibroblast growth factor receptors (FGFRs) consist of extracellular Ig-like domains, a transmembrane domain, and a bipartite tyrosine kinase (TK) domain. The Ig I domain is postulated to be involved in auto-inhibition, while the Ig II and Ig III domains are involved in fibroblast growth factor (FGF) ligand binding. Multiple isoforms of the receptor are generated by alternative splicing, which affects the Ig III domain. Canonical models state that FGF binding to the FGFR induces receptor dimerization and trans-phosphorylation of the TK domain, thereby activating the kinase function. The activated kinase binds to a number of adaptor proteins and also phosphorylates downstream substrates, thereby inducing signaling via a number of pathways, including the MAP kinase pathway, the JAK/STAT pathway, and the PI3K/AKT pathway. These pathways alter a number of cellular processes that can lead to alterations in gene transcription, metabolic regulation, and cell growth, survival, proliferation, and differentiation. TK inhibitors that act on FGFR3 bind to the intracellular TK domain, while therapeutic antibodies targeting FGFR3 act on the extracellular domains. For comprehensive information of the FGFR activated pathways and FGFR signaling in cancer, see reviews in Ahmad, Iwata, and Leung 2012; Dienstmann et al. 2014; Goetz and Mohammadi 2013; Kelleher et al. 2013; di Martino, Tomlinson, and Knowles 2012; Touat et al. 2015;Turner and Grose 2010.
Suggested Citation: Lovly, C., P. Hammerman. 2016. FGFR3. My Cancer Genome https://www.mycancergenome.org/content/disease/breast-cancer/fgfr3/?tab=0 (Updated January 28).
Last Updated: January 28, 2016