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Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor
1Department of Biology, Israel Institute of Technology, Technion City, Haifa.
Abstract:
A cDNA predicted to encode a transmembrane tyrosine kinase receptor with sequence features characteristic of known fibroblast growth factor (FGF) receptors was isolated from an expression library constructed from the human mammary epithelial cell line B5/589. This cDNA, designated cl44, encodes a product of 803 amino acid residues and was readily distinguishable from known FGF receptors. During the course of our studies, Partanen et al. (Partanen, J., Makela, T. P., Eerola, E., Korhonen, J., Hirvonen, H., Claesson, W. L., and Alitalo, K. (1991) EMBO J. 10, 1347-1354) isolated a new FGF receptor, designated FGFR4, from the human leukemia cell line, K562. Its amino acid sequence is identical to that of cl44 with the exception of 1 residue. The 5'-untranslated sequences of the two cDNAs diverged far upstream of the initiation codon. A myoblast line, L6E9, which lacks FGF receptors, was utilized to express high levels of FGFR4. We found, in contrast to Partenen et al., who reported only binding of acidic FGF, that FGFR4 bound both acidic and basic FGF with dissociation constants of 10-15 and 120 pM, respectively. No detectable binding of keratinocyte growth factor was observed. In studies aimed to determine whether FGF receptors contribute to the development of human tumors, we screened RNAs prepared from cell lines derived from a variety of solid tumors. High levels of the cl44 transcript were detected in 8 of 14 and 6 of 9 human mammary and kidney carcinomas, respectively, but only infrequently in other types of tumors. In contrast, FGFR1 was found to be frequently expressed in kidney, but not in breast tumor cells, suggesting a possible role for FGFR4 in human mammary cancer.
Insights
Researchers identified a new fibroblast growth factor (FGF) receptor, FGFR4, which binds both acidic and basic FGF. FGFR4 shows high expression in mammary and kidney carcinomas, suggesting a role in human mammary cancer development.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Fibroblast growth factor (FGF) receptors are crucial transmembrane tyrosine kinases involved in cell signaling.
- Previous research identified several FGF receptors, but their roles in specific cancers remained unclear.
Purpose of the Study:
- To isolate and characterize a novel FGF receptor from human mammary epithelial cells.
- To investigate the binding properties of the new receptor.
- To determine the expression patterns of this receptor in various human tumors.
Main Methods:
- cDNA library construction and screening from human mammary epithelial cell line B5/589.
- Expression of the isolated cDNA (cl44) in L6E9 myoblast cells lacking endogenous FGF receptors.
- Ligand binding assays to determine affinity for acidic FGF, basic FGF, and keratinocyte growth factor.
- RNA screening of cell lines from various solid tumors to assess cl44 transcript levels.
Main Results:
- Isolation of cl44 cDNA encoding an 803-amino acid transmembrane tyrosine kinase receptor, distinct from known FGF receptors.
- Demonstrated that the receptor, later identified as FGFR4, binds both acidic FGF (Kd 10-15 pM) and basic FGF (Kd 120 pM), but not keratinocyte growth factor.
- High levels of cl44 transcript were detected in human mammary (8/14) and kidney (6/9) carcinomas.
- FGFR1 was frequently expressed in kidney tumors but not breast tumors, contrasting with cl44 expression.
Conclusions:
- The novel FGF receptor, FGFR4, exhibits distinct ligand-binding properties.
- FGFR4 is highly expressed in human mammary and kidney carcinomas.
- FGFR4 may play a significant role in the development of human mammary cancer.