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.
Highlights
A cDNA predicted to encodea transmembrane tyro- multi-functional polypeptide mitogens that play a role in a sine kinase receptor with sequence features charactwerid-e array of biological processes such as embryonal develistic of known fibroblast growth factor (FGF) receptoorpsment, tissue repair, neuronal cell survival, cardiovascular was isolated from a n expression library constructed from the human mammary epithelicaelll lineB5/589
In contrast to Parteneent al., who reported only binding of acidic FGF, that FGFR4 bound both acidic and basic FGF with dissociation constants of 10-15 and
High affinity FGF receptors have been recently cloned from different species including human andavian (1418),and theoverall picture that emerges from a large number of studies reveals that FGF receptors are members of a multigene family
Summary
A cDNA predicted to encodea transmembrane tyro- multi-functional polypeptide mitogens that play a role in a sine kinase receptor with sequence features charactwerid-e array of biological processes such as embryonal develistic of known fibroblast growth factor (FGF) receptoorpsment, tissue repair, neuronal cell survival, cardiovascular was isolated from a n expression library constructed from the human mammary epithelicaelll lineB5/589. The transfected cultures were marker-selected with G418, and resistant colonies were isolated, expanded, and analyzed for the expression of each receptor using binding analysis with '251-labeledaFGF bFGF, or KGF. Expression of e144 and FGFRl Transcript in Normal and Tumor Cell Lines-Receptor tyrosine kinases and their ligands have been implicated in tehteiology of cancer, because of theirfrequentalterationand overexpression inhuman tumors (for review see Ref. 51).
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