Alternative titles; symbols
HGNC Approved Gene Symbol: FGFR4
Cytogenetic location: 5q35.2 Genomic coordinates (GRCh38): 5:177,086,915-177,098,144 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.2 | {Cancer progression/metastasis} | 3 |
Partanen et al. (1991) reported the cDNA cloning and analysis of a novel member of the fibroblast growth factor receptor (FGFR) gene family expressed in K562 erythroleukemia cells. Its deduced amino acid sequence was 55% identical with the previously characterized FGFRs, FLG (FGFR1; 136350) and BEK (176943), and had the structural characteristics of an FGFR family member including 3 immunoglobulin-like domains in its extracellular part. The expression pattern of FGFR4 was found to be distinct from that of FLG and BEK and also distinct from that of FGFR3 (134934), which they (Keegan et al., 1991) had also cloned from K562 erythroleukemia cells.
To elucidate further the physiologic relevance of protein-tyrosine kinases and to search for additional members of the gene family as possible factors in carcinogenesis, Holtrich et al. (1991) amplified mRNA from lung tissue by the polymerase chain reaction (PCR) using PTK-specific primers followed by sequencing of the clones. They identified a novel protein-tyrosine kinase, which they called TKF (tyrosine kinase related to fibroblast growth factor receptor). Among a wide variety of cells and tissues tested, including human lymphocytes and macrophages, TKF was found to be expressed only in lung and in some tumors of lung origin as well as in malignancies not derived from lung tissues. Sequence comparison has demonstrated that TKF is identical to FGFR4 (Scott, 1999).
Vainikka et al. (1992) described structural and functional peculiarities that are specific to FGFR4 within the FGFR family. Kostrzewa and Muller (1998) found that the FGFR4 gene spans approximately 11.3 kb and is composed of 18 exons ranging in size from 17 to 600 bp. Exon 1 is untranslated and preceded by structural elements characteristic of a TATA-free promoter. Short tandem repeat polymorphisms were identified in introns 2 and 16 of FGFR4.
By analysis of somatic cell hybrids and by in situ hybridization, Armstrong et al. (1992) mapped the FGFR4 gene to 5q33-qter, an area involved in leukemias and lymphomas. In a radiation hybrid mapping of 18 genes on distal 5q, Warrington et al. (1992) found that the FGFR4 gene lies distal to DRD1 with high probability. Assuming that the mapping of DRD1 is correct, FGFR4 would be located in the segment 5q35.1-qter. Using an interspecific backcross mapping panel, Avraham et al. (1994) mapped the Fgfr4 gene to mouse chromosome 13 in a region of homology of synteny with distal human 5q.
Jung et al. (1999) studied the initiation of mammalian liver development from endoderm by fibroblast growth factors. The hepatogenic response was restricted to endoderm tissue, which selectively coexpresses FGFR1 and FGFR4.
Cinque et al. (2015) investigated the role of autophagy during bone growth, which is mediated by chondrocyte rate of proliferation, hypertrophic differentiation, and extracellular matrix (ECM) deposition in growth plates. They showed that autophagy is induced in growth plate chondrocytes during postnatal development and regulates the secretion of type II collagen (Col2), the major component of cartilage ECM. Mice lacking the autophagy related gene-7 (ATG7; 608760) in chondrocytes experience endoplasmic reticulum storage of type II procollagen (see 120140) and defective formation of the Col2 fibrillary network in the ECM. Surprisingly, postnatal induction of chondrocyte autophagy is mediated by the growth factor FGF18 (603726) through FGFR4 and JNK (601158)-dependent activation of the autophagy initiation complex VPS34 (602609)-beclin-1 (604378). Autophagy is completely suppressed in growth plates from Fgf18 -/- embryos, while Fgf18 +/- heterozygous and Fgfr4 -/- mice fail to induce autophagy during postnatal development and show decreased Col2 levels in the growth plate. Strikingly, the Fgf18 +/- and Fgfr4 -/- phenotypes could be rescued in vivo by pharmacologic activation of autophagy, pointing to autophagy as a novel effector of FGF signaling in bone. The data of Cinque et al. (2015) demonstrated that autophagy is a developmentally regulated process necessary for bone growth, and identified FGF signaling as a crucial regulator of autophagy in chondrocytes.
In the FGFR4 gene transcript from a mammary carcinoma cell line, Bange et al. (2002) discovered a G-to-A transition that resulted in the substitution of glycine by arginine at position 388 in the transmembrane domain of the receptor. 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. Investigation of the clinical data of 84 breast cancer patients revealed that homo- or heterozygous carriers of the arg388 allele had a significantly reduced disease-free survival time (P = 0.01) within a median follow-up of 62 months. Moreover, the FGFR4 arg388 allele was associated with early metastasis and advanced tumor-node metastasis stage in 82 colon cancer patients. Consistent with this finding, the mammary tumor cell line expressing FGFR4 arg388 exhibited increased motility relative to cells expressing the FGFR4 gly388 isotype. The results supported the conclusion that the FGFR4 arg388 allele represents a determinant that is innocuous in healthy individuals but predisposes cancer patients for significantly accelerated disease progression.
Taylor et al. (2009) noted that FGFR4 is expressed in myoblasts during normal development, in regenerating muscle following injury, and in rhabdomyosarcomas, but not in normal mature skeletal muscle. They found that FGFR4 was significantly overexpressed in rhabdomyosarcoma tumors of high metastatic potential, and higher FGFR4 expression was associated with a lower rate of survival. Taylor et al. (2009) identified 6 missense mutations 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, Taylor et al. (2009) found that 2 of these mutations, asn535 to lys (N535K) and val550 to glu (V550E), increased autophosphorylation, Stat3 (102582) signaling, cell growth, tumor proliferation, and metastatic potential when injected into nude mice. These mutants also transformed mouse NIH3T3 cells and led to enhanced metastatic phenotype.
Kogan et al. (2018) generated transgenic knockin mice homozygous for the minor A allele of the human FGFR4 SNP rs351855. Knockin mice had significantly decreased Cd8-positive T-cell numbers, whereas Stat3-associated proliferative and suppressive function of regulatory T cells (Tregs) was enhanced, leading to a systemic decrease in the Cd8/Treg ratio. The authors demonstrated that the decreased Cd8/Treg ratio and the Stat3-enhancing gain of function caused by the minor A allele was not due to altered activity of the FGFR4 variant protein, but rather to the pleiotropic function of the variant, as the G allele disrupts the membrane-proximal STAT3-docking site in FGFR4. Disruption of Stat3 membrane recruitment in Fgfr4-knockout mice abolished the SNP-specific gain of the immunologic phenotype, supporting the results observed in knockin mice. Using knockin transgenic mouse models for breast and lung cancers, Kogan et al. (2018) found significantly elevated tumor burden and progression in mice expressing the minor A allele, indicating that the STAT3-enhancing FGFR4 variant mediates a tumor-extrinsic immune-evasive pleiotropic phenotype.
Bange et al. (2002) found a relationship between the gly388-to-arg substitution in FGFR4 and cancer progression and tumor cell motility. The arg388 allele was associated with metastasis and poor prognosis in breast cancer and in colon cancer. In a control group of 123 subjects, the frequencies of the gly/gly, gly/arg, and arg/arg genotypes were 45%, 49%, and 6%, respectively.
Ulaganathan et al. (2015) noted that the FGFR4 SNP rs351855 (c.1162G-A, G388R), associated with cancer progression and poor prognosis, was found in the 1000 Genomes Project database at a minor allele frequency of 0.30 and was found in approximately 50% of patients with cancer (Bange et al., 2002). Ulaganathan et al. (2015) showed that substitution of the conserved glycine-388 residue to a charged arginine residue alters the transmembrane-spanning segment and exposes a membrane-proximal cytoplasmic STAT3 (102582)-binding site Y(390)-(P)XXQ(393). Ulaganathan et al. (2015) demonstrated that such membrane-proximal STAT3-binding motifs in the germline of type I membrane receptors enhance STAT3 tyrosine phosphorylation by recruiting STAT3 proteins to the inner cell membrane. Remarkably, such germline variants frequently colocalize with somatic mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Using Fgfr4 G385R (mouse homolog of human G388R) knockin mice and transgenic mouse models for breast and lung cancers, the authors validated the enhanced STAT3 signaling induced by the FGFR4 G388R variant in vivo. Ulaganathan et al. (2015) concluded that their findings elucidated the molecular mechanism behind the genetic association of rs351855 with accelerated cancer progression and suggested that germline variants of cell surface molecules that recruit STAT3 to the inner cell membrane confer a significant risk for cancer prognosis and disease progression.
Armstrong, E., Partanen, J., Cannizzaro, L., Huebner, K., Alitalo, K. Localization of the fibroblast growth factor receptor-4 gene to chromosome region 5q33-qter. Genes Chromosomes Cancer 4: 94-98, 1992. [PubMed: 1377018] [Full Text: https://doi.org/10.1002/gcc.2870040116]
Avraham, K. B., Givol, D., Avivi, A., Yayon, A., Copeland, N. G., Jenkins, N. A. Mapping of murine fibroblast growth factor receptors refines regions of homology between mouse and human chromosomes. Genomics 21: 656-658, 1994. [PubMed: 7959747] [Full Text: https://doi.org/10.1006/geno.1994.1330]
Bange, J., Prechtl, D., Cheburkin, Y., Specht, K., Harbeck, N., Schmitt, M., Knyazeva, T., Muller, S., Gartner, S., Sures, I., Wang, H., Imyanitov, E., Haring, H.-U., Knayzev, P., Iacobelli, S., Hofler, H., Ullrich, A. Cancer progression and tumor cell motility are associated with the FGFR4 Arg388 allele. Cancer Res. 62: 840-847, 2002. [PubMed: 11830541]
Cinque, L., Forrester, A., Bartolomeo, R., Svelto, M., Venditti, R., Montefusco, S., Polishchuk, E., Nusco, E., Rossi, A., Medina, D. L., Polishchuk, R., De Matteis, M. A., Settembre, C. FGF signalling regulates bone growth through autophagy. Nature 528: 272-275, 2015. [PubMed: 26595272] [Full Text: https://doi.org/10.1038/nature16063]
Holtrich, U., Brauninger, A., Strebhardt, K., Rubsamen-Waigmann, H. Two additional protein-tyrosine kinases expressed in human lung: fourth member of the fibroblast growth factor receptor family and an intracellular protein-tyrosine kinase. Proc. Nat. Acad. Sci. 88: 10411-10415, 1991. [PubMed: 1720539] [Full Text: https://doi.org/10.1073/pnas.88.23.10411]
Jung, J., Zheng, M., Goldfarb, M., Zaret, K. S. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 284: 1998-2003, 1999. [PubMed: 10373120] [Full Text: https://doi.org/10.1126/science.284.5422.1998]
Keegan, K., Johnson, D. E., Williams, L. T., Hayman, M. J. Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3. Proc. Nat. Acad. Sci. 88: 1095-1099, 1991. [PubMed: 1847508] [Full Text: https://doi.org/10.1073/pnas.88.4.1095]
Kogan, D., Grabner, A., Yanucil, C., Faul, C., Ulaganathan, V. K. STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion. J. Clin. Invest. 128: 1867-1872, 2018. [PubMed: 29438108] [Full Text: https://doi.org/10.1172/JCI96708]
Kostrzewa, M., Muller, U. Genomic structure and complete sequence of the human FGFR4 gene. Mammalian Genome 9: 131-135, 1998. [PubMed: 9457674] [Full Text: https://doi.org/10.1007/s003359900703]
Partanen, J., Makela, T. P., Eerola, E., Korhonen, J., Hirvonen, H., Claesson-Welsh, L., Alitalo, K. FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. EMBO J. 10: 1347-1354, 1991. [PubMed: 1709094] [Full Text: https://doi.org/10.1002/j.1460-2075.1991.tb07654.x]
Scott, A. F. Personal Communication. Baltimore, Md. 10/12/1999.
Taylor, J. G., VI, Cheuk, A. T., Tsang, P. S., Chung, J.-Y., Song, Y. K., Desai, K., Yu, Y., Chen, Q.-R., Shah, K., Youngblood, V., Fang, J., Kim, S. Y., and 13 others. Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. J. Clin. Invest. 119: 3395-3407, 2009. [PubMed: 19809159] [Full Text: https://doi.org/10.1172/JCI39703]
Ulaganathan, V. K., Sperl, B., Rapp, U. R., Ullrich, A. Germline variant FGFR4 p.G388R exposes a membrane-proximal STAT3 binding site. Nature 528: 570-574, 2015. [PubMed: 26675719] [Full Text: https://doi.org/10.1038/nature16449]
Vainikka, S., Partanen, J., Bellosta, P., Coulier, F., Basilico, C., Jaye, M., Alitalo, K. Fibroblast growth factor receptor-4 shows novel features in genomic structure, ligand binding and signal transduction. EMBO J. 11: 4273-4280, 1992. Note: Erratum: EMBO J. 12: 810 only, 1993. [PubMed: 1385111] [Full Text: https://doi.org/10.1002/j.1460-2075.1992.tb05526.x]
Warrington, J. A., Bailey, S. K., Armstrong, E., Aprelikova, O., Alitalo, K., Dolganov, G. M., Wilcox, A. S., Sikela, J. M., Wolfe, S. F., Lovett, M., Wasmuth, J. J. A radiation hybrid map of 18 growth factor, growth factor receptor, hormone receptor, or neurotransmitter receptor genes on the distal region of the long arm of chromosome 5. Genomics 13: 803-808, 1992. [PubMed: 1322355] [Full Text: https://doi.org/10.1016/0888-7543(92)90156-m]