The DNA was cloned in 1991 (Partanen et al., 1991).
18.9 Kb; 18 exons.

3.1 Kb mRNA; alternative splicing gives rise to 18 transcripts with evidence of 11 transcripts at protein level.

The canonical sequence possesses 802 amino acids, 120 kDa, contains a signal peptide 1-17 amino acids, an extracellular domain with 3 Ig-like loops, a transmembrane domain with 26 amino acids and an intracellular domain with tyrosine kinase activity.
Transcripts lacking the intracellular domain and transmembrane domain are secreted.

FGFR4 is expressed in a tissue-specific manner during embryogenesis and displays unique affinity for certain FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, FGF16, FGF17, FGF18 and FGF19). FGFR4 function is not essential during embryogenesis and adult life (Weinstein et al., 1998), though it may be involved in several metabolic pathways (Gutierrez et al., 2006; Yu et al., 2000).
Evidence of FGFR4 expression has been described at: adrenal cortex, adrenal gland, bile duct, cervix, cornea, corneal endothelial cell, corneal epithelial cell, heart, hepatocyte, intestine, islets of langerhans, kidney, lamina propria, liver, lung, lymph node, mammary gland, muscle, muscularis mucosa, ovary, pituitary gland, renal tubular epithelium, retina, skin, spleen, stomach, sublingual gland, ureter, urothelium and uterus (www.hprd.org).

Plasma membrane, but also some FGF-FGFR complexed are endocytosed and develop its function directly in the cytosol or nucleus.
FGFR4 isoform 2 may be secreted.

FGF receptor with tyrosine-protein kinase activity acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration.
Binding of fibroblast growth factors produces receptor dimerization, autophosphorilation and signal transduction. FGFR4 binds mainly FGF19.
There are evidences that FGFR4 function may not necessarily require FGF ligand: i) heparin in the absence of FGF produced the activation of FGFR4 (Gao and Goldfarb, 1995), ii) FGFR4 was found to function in a complex with N-CAM independently of FGF (Cavallaro et al., 2001), and iii) the detection of N-linked glycosylation on an overexpressed extracellular domain of human FGFR4 suggested that the function of this receptor might also be regulated by glycosylation, similar to what occurs with other FGFRs (Tuominen et al., 2001).
A key regulator of the FGFR4 pathway is its co-receptor klotho-beta (KLB), a 130 kDa transmembrane protein that exhibits a more restricted expression profile in adipose, liver and pancreas tissues. KLB and FGFR4 are both expressed at high levels in mature hepatocytes, where KLB stabilizes FGF19-FGFR4 binding to regulate production of cholesterol 7a-hydroxylase (CYP7A1) and hepatocyte proliferation (Kurosu et al., 2007; Lin et al., 2007; Wu et al., 2010).
It has also been identified that FGFR4 is part of a complex with MT1-MMP, where MT1-MMP and FGFR4 are regulated in an opposite direction depending on the tumor progression and the presence of FGFR4 SNP Gly388Arg (Hotary et al., 2000; Lehti et al., 2000; Okada et al., 1995; Sugiyama et al., 2010). This SNP changes Gly388Arg in the predicted FGFR4 transmembrane domain, resulting in enhanced stability of the activated receptor (Ingvarsen et al., 2008). Both FGFR4-R388 and FGFR4-G388 form a complex with MT1-MMP and induced MT1-MMP tyrosil phosphorylation, but they had opposite effects on MT1-MMP levels. FGFR4-R388 stabilizes MT1-MMP, whereas FGFR4-G388 down-regulates MT1-MMP. The Y573F point mutation blocks MT1-MMP tyrosyl phosphorylation increasing cell-membrane MT1-MMP (Ingvarsen et al., 2008).

Other fibroblast growth factor receptors (FGFR1, FGFR2 and FGFR3).
Homology with other tyrosin-protein kinase family members through its tyrosin-protein kinase domain.

In the FGFR4 gene transcript from a mammary carcinoma cell line, a G-to-A transition was discovered that resulted in the substitution of glycine by arginine at position 388 in the transmembrane domain of the receptor (Bange et al., 2002). The arg388 allele was also found in cell lines derived from a variety of other tumor types as well as in the germline of cancer patients and healthy individuals. Analysis of 3 geographically separated groups indicated that it occurs in approximately 50% of humans. Moreover, the FGFR4 arg388 allele was associated with early metastasis and advanced tumor-node metastasis stage in 82 colon cancer patients.
The results support that FGFR4 arg388 allele represents an innocuous determinant in healthy individuals but predisposes cancer patients for significantly accelerated disease progression.

FGFR4 was significantly overexpressed in rhabdomyosarcoma tumors of high metastatic potential. Higher FGFR4 expression was associated to a lower rate of survival (Taylor et al., 2009).
Six missense mutations were observed in the FGFR4 tyrosine kinase domain among 7 of 94 (7.5%) primary rhabdomyosarcomas, and none of these substitutions were found in normal controls. Comparison with the available genomic data suggested that the mutations were somatic. Four of the mutations affected residues Asn535 and Val550 and were predicted to be activating mutations that would alter conformational dynamics during phosphorylation in the case of Asn535 substitutions and ATP binding in the case of Val550 substitutions.
Using human and mouse rhabdomyosarcoma cell lines, it was found that two of these mutations, Asn535Lys (N535K) and Val550Glu (V550E), increased autophosphorylation, Stat3 signaling, cell growth, tumor proliferation and metastatic potential when injected into nude mice (Taylor et al., 2009). These mutants differentiated mouse NIH3T3 cells to an enhanced metastatic phenotype.
Ruhe et al. discovered the Y367C mutation in the FGFR4 gene by a comprehensive analysis of the tyrosine kinase gene family in cancer cell lines (Ruhe et al., 2007). This mutation occurred in the MDA-MB453 breast cancer cell line.
Cloning and ectopic expression of the FGFR4 Y367C mutant in HEK293 cells revealed high pERK levels and enhanced cell proliferation (Roidl et al., 2010).
Based on these findings, it has been proposed that FGFR4 may be a driver gene of tumour growth.