Abstract
The fibroblast growth factor (FGF) family consists of seven members whose activities are thought to be mediated by multiple receptors. Here we describe the cDNA cloning, expression, and characterization of a cysteine-rich FGF receptor (CFR) that is distinct from previously identified FGF receptors. The deduced amino acid sequence for CFR suggests that it is an integral membrane protein containing a large extracellular domain comprising 16 cysteine-rich repeated units and an intracellular domain of 13 amino acids. No reported sequences exhibit significant homologies to either the repeated extracellular motif or to the entire CFR amino acid sequence. Several CFR transcripts are present in embryonic chick tissue, suggesting that CFR undergoes alternate mRNA splicing or that related genes are present. Chinese hamster ovary cells transfected with the CFR cDNA express a 150-kDa polypeptide that binds FGF-1, FGF-2, and FGF-4 but does not bind several non-FGF family members. The high degree of evolutionary conservation among vertebrate CFRs and its ability to bind three different FGFs with high affinity suggest that this unique receptor plays an important role in FGF biology.
Full text
PDF









Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Acland P., Dixon M., Peters G., Dickson C. Subcellular fate of the int-2 oncoprotein is determined by choice of initiation codon. Nature. 1990 Feb 15;343(6259):662–665. doi: 10.1038/343662a0. [DOI] [PubMed] [Google Scholar]
- Baird A., Klagsbrun M. The fibroblast growth factor family. Cancer Cells. 1991 Jun;3(6):239–243. [PubMed] [Google Scholar]
- Baird A., Ling N. Fibroblast growth factors are present in the extracellular matrix produced by endothelial cells in vitro: implications for a role of heparinase-like enzymes in the neovascular response. Biochem Biophys Res Commun. 1987 Jan 30;142(2):428–435. doi: 10.1016/0006-291x(87)90292-0. [DOI] [PubMed] [Google Scholar]
- Bairoch A., Boeckmann B. The SWISS-PROT protein sequence data bank. Nucleic Acids Res. 1991 Apr 25;19 (Suppl):2247–2249. doi: 10.1093/nar/19.suppl.2247. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baldin V., Roman A. M., Bosc-Bierne I., Amalric F., Bouche G. Translocation of bFGF to the nucleus is G1 phase cell cycle specific in bovine aortic endothelial cells. EMBO J. 1990 May;9(5):1511–1517. doi: 10.1002/j.1460-2075.1990.tb08269.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Berkner K., Busby S., Davie E., Hart C., Insley M., Kisiel W., Kumar A., Murray M., O'Hara P., Woodbury R. Isolation and expression of cDNAs encoding human factor VII. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):531–541. doi: 10.1101/sqb.1986.051.01.065. [DOI] [PubMed] [Google Scholar]
- Bernard O., Li M., Reid H. H. Expression of two different forms of fibroblast growth factor receptor 1 in different mouse tissues and cell lines. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7625–7629. doi: 10.1073/pnas.88.17.7625. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bilofsky H. S., Burks C., Fickett J. W., Goad W. B., Lewitter F. I., Rindone W. P., Swindell C. D., Tung C. S. The GenBank genetic sequence databank. Nucleic Acids Res. 1986 Jan 10;14(1):1–4. doi: 10.1093/nar/14.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bouche G., Gas N., Prats H., Baldin V., Tauber J. P., Teissié J., Amalric F. Basic fibroblast growth factor enters the nucleolus and stimulates the transcription of ribosomal genes in ABAE cells undergoing G0----G1 transition. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6770–6774. doi: 10.1073/pnas.84.19.6770. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Burgess W. H., Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem. 1989;58:575–606. doi: 10.1146/annurev.bi.58.070189.003043. [DOI] [PubMed] [Google Scholar]
- Burgess W. H., Shaheen A. M., Ravera M., Jaye M., Donohue P. J., Winkles J. A. Possible dissociation of the heparin-binding and mitogenic activities of heparin-binding (acidic fibroblast) growth factor-1 from its receptor-binding activities by site-directed mutagenesis of a single lysine residue. J Cell Biol. 1990 Nov;111(5 Pt 1):2129–2138. doi: 10.1083/jcb.111.5.2129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Burrus L. W., Olwin B. B. Isolation of a receptor for acidic and basic fibroblast growth factor from embryonic chick. J Biol Chem. 1989 Nov 5;264(31):18647–18653. [PubMed] [Google Scholar]
- Busby S., Kumar A., Joseph M., Halfpap L., Insley M., Berkner K., Kurachi K., Woodbury R. Expression of active human factor IX in transfected cells. Nature. 1985 Jul 18;316(6025):271–273. doi: 10.1038/316271a0. [DOI] [PubMed] [Google Scholar]
- Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
- D'Amore P. A. Modes of FGF release in vivo and in vitro. Cancer Metastasis Rev. 1990 Nov;9(3):227–238. doi: 10.1007/BF00046362. [DOI] [PubMed] [Google Scholar]
- DiMario J., Buffinger N., Yamada S., Strohman R. C. Fibroblast growth factor in the extracellular matrix of dystrophic (mdx) mouse muscle. Science. 1989 May 12;244(4905):688–690. doi: 10.1126/science.2717945. [DOI] [PubMed] [Google Scholar]
- Dionne C. A., Crumley G., Bellot F., Kaplow J. M., Searfoss G., Ruta M., Burgess W. H., Jaye M., Schlessinger J. Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors. EMBO J. 1990 Sep;9(9):2685–2692. doi: 10.1002/j.1460-2075.1990.tb07454.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Feramisco J. R., Glass D. B., Krebs E. G. Optimal spatial requirements for the location of basic residues in peptide substrates for the cyclic AMP-dependent protein kinase. J Biol Chem. 1980 May 10;255(9):4240–4245. [PubMed] [Google Scholar]
- Florkiewicz R. Z., Sommer A. Human basic fibroblast growth factor gene encodes four polypeptides: three initiate translation from non-AUG codons. Proc Natl Acad Sci U S A. 1989 Jun;86(11):3978–3981. doi: 10.1073/pnas.86.11.3978. [DOI] [PMC free article] [PubMed] [Google Scholar]
- George D. G., Barker W. C., Hunt L. T. The protein identification resource (PIR). Nucleic Acids Res. 1986 Jan 10;14(1):11–15. doi: 10.1093/nar/14.1.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gonzalez A. M., Buscaglia M., Ong M., Baird A. Distribution of basic fibroblast growth factor in the 18-day rat fetus: localization in the basement membranes of diverse tissues. J Cell Biol. 1990 Mar;110(3):753–765. doi: 10.1083/jcb.110.3.753. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gribskov M., Lüthy R., Eisenberg D. Profile analysis. Methods Enzymol. 1990;183:146–159. doi: 10.1016/0076-6879(90)83011-w. [DOI] [PubMed] [Google Scholar]
- Gribskov M., McLachlan A. D., Eisenberg D. Profile analysis: detection of distantly related proteins. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4355–4358. doi: 10.1073/pnas.84.13.4355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hamm G. H., Cameron G. N. The EMBL data library. Nucleic Acids Res. 1986 Jan 10;14(1):5–9. doi: 10.1093/nar/14.1.5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Holtrich U., Bräuninger A., Strebhardt K., Rübsamen-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 Natl Acad Sci U S A. 1991 Dec 1;88(23):10411–10415. doi: 10.1073/pnas.88.23.10411. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Iida S., Yoshida T., Naito K., Sakamoto H., Katoh O., Hirohashi S., Sato T., Onda M., Sugimura T., Terada M. Human hst-2 (FGF-6) oncogene: cDNA cloning and characterization. Oncogene. 1992 Feb;7(2):303–309. [PubMed] [Google Scholar]
- Imamura T., Engleka K., Zhan X., Tokita Y., Forough R., Roeder D., Jackson A., Maier J. A., Hla T., Maciag T. Recovery of mitogenic activity of a growth factor mutant with a nuclear translocation sequence. Science. 1990 Sep 28;249(4976):1567–1570. doi: 10.1126/science.1699274. [DOI] [PubMed] [Google Scholar]
- Johnson D. E., Lee P. L., Lu J., Williams L. T. Diverse forms of a receptor for acidic and basic fibroblast growth factors. Mol Cell Biol. 1990 Sep;10(9):4728–4736. doi: 10.1128/mcb.10.9.4728. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kiefer M. C., Stephans J. C., Crawford K., Okino K., Barr P. J. Ligand-affinity cloning and structure of a cell surface heparan sulfate proteoglycan that binds basic fibroblast growth factor. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6985–6989. doi: 10.1073/pnas.87.18.6985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Klagsbrun M., D'Amore P. A. Regulators of angiogenesis. Annu Rev Physiol. 1991;53:217–239. doi: 10.1146/annurev.ph.53.030191.001245. [DOI] [PubMed] [Google Scholar]
- Kozak M. The scanning model for translation: an update. J Cell Biol. 1989 Feb;108(2):229–241. doi: 10.1083/jcb.108.2.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kyte J., Doolittle R. F. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982 May 5;157(1):105–132. doi: 10.1016/0022-2836(82)90515-0. [DOI] [PubMed] [Google Scholar]
- Lee P. L., Johnson D. E., Cousens L. S., Fried V. A., Williams L. T. Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor. Science. 1989 Jul 7;245(4913):57–60. doi: 10.1126/science.2544996. [DOI] [PubMed] [Google Scholar]
- Mansukhani A., Moscatelli D., Talarico D., Levytska V., Basilico C. A murine fibroblast growth factor (FGF) receptor expressed in CHO cells is activated by basic FGF and Kaposi FGF. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4378–4382. doi: 10.1073/pnas.87.11.4378. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marck C. 'DNA Strider': a 'C' program for the fast analysis of DNA and protein sequences on the Apple Macintosh family of computers. Nucleic Acids Res. 1988 Mar 11;16(5):1829–1836. doi: 10.1093/nar/16.5.1829. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mignatti P., Rifkin D. B. Release of basic fibroblast growth factor, an angiogenic factor devoid of secretory signal sequence: a trivial phenomenon or a novel secretion mechanism? J Cell Biochem. 1991 Nov;47(3):201–207. doi: 10.1002/jcb.240470303. [DOI] [PubMed] [Google Scholar]
- Miki T., Fleming T. P., Bottaro D. P., Rubin J. S., Ron D., Aaronson S. A. Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop. Science. 1991 Jan 4;251(4989):72–75. doi: 10.1126/science.1846048. [DOI] [PubMed] [Google Scholar]
- Moscatelli D. High and low affinity binding sites for basic fibroblast growth factor on cultured cells: absence of a role for low affinity binding in the stimulation of plasminogen activator production by bovine capillary endothelial cells. J Cell Physiol. 1987 Apr;131(1):123–130. doi: 10.1002/jcp.1041310118. [DOI] [PubMed] [Google Scholar]
- Olwin B. B., Hauschka S. D. Fibroblast growth factor receptor levels decrease during chick embryogenesis. J Cell Biol. 1990 Feb;110(2):503–509. doi: 10.1083/jcb.110.2.503. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Olwin B. B., Hauschka S. D. Identification of the fibroblast growth factor receptor of Swiss 3T3 cells and mouse skeletal muscle myoblasts. Biochemistry. 1986 Jun 17;25(12):3487–3492. doi: 10.1021/bi00360a001. [DOI] [PubMed] [Google Scholar]
- Olwin B. B., Rapraeger A. Repression of myogenic differentiation by aFGF, bFGF, and K-FGF is dependent on cellular heparan sulfate. J Cell Biol. 1992 Aug;118(3):631–639. doi: 10.1083/jcb.118.3.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Partanen J., Mäkelä 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. 1991 Jun;10(6):1347–1354. doi: 10.1002/j.1460-2075.1991.tb07654.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pasquale E. B. A distinctive family of embryonic protein-tyrosine kinase receptors. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5812–5816. doi: 10.1073/pnas.87.15.5812. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pasquale E. B., Singer S. J. Identification of a developmentally regulated protein-tyrosine kinase by using anti-phosphotyrosine antibodies to screen a cDNA expression library. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5449–5453. doi: 10.1073/pnas.86.14.5449. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pearson W. R., Lipman D. J. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2444–2448. doi: 10.1073/pnas.85.8.2444. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Prats H., Kaghad M., Prats A. C., Klagsbrun M., Lélias J. M., Liauzun P., Chalon P., Tauber J. P., Amalric F., Smith J. A. High molecular mass forms of basic fibroblast growth factor are initiated by alternative CUG codons. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1836–1840. doi: 10.1073/pnas.86.6.1836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Presta M., Maier J. A., Ragnotti G. The mitogenic signaling pathway but not the plasminogen activator-inducing pathway of basic fibroblast growth factor is mediated through protein kinase C in fetal bovine aortic endothelial cells. J Cell Biol. 1989 Oct;109(4 Pt 1):1877–1884. doi: 10.1083/jcb.109.4.1877. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Presta M., Rifkin D. B. Immunoreactive basic fibroblast growth factor-like proteins in chromaffin granules. J Neurochem. 1991 Mar;56(3):1087–1088. doi: 10.1111/j.1471-4159.1991.tb02034.x. [DOI] [PubMed] [Google Scholar]
- Proudfoot N. J., Brownlee G. G. 3' non-coding region sequences in eukaryotic messenger RNA. Nature. 1976 Sep 16;263(5574):211–214. doi: 10.1038/263211a0. [DOI] [PubMed] [Google Scholar]
- Quarto N., Finger F. P., Rifkin D. B. The NH2-terminal extension of high molecular weight bFGF is a nuclear targeting signal. J Cell Physiol. 1991 May;147(2):311–318. doi: 10.1002/jcp.1041470217. [DOI] [PubMed] [Google Scholar]
- Rapraeger A. C., Krufka A., Olwin B. B. Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation. Science. 1991 Jun 21;252(5013):1705–1708. doi: 10.1126/science.1646484. [DOI] [PubMed] [Google Scholar]
- Rapraeger A., Jalkanen M., Endo E., Koda J., Bernfield M. The cell surface proteoglycan from mouse mammary epithelial cells bears chondroitin sulfate and heparan sulfate glycosaminoglycans. J Biol Chem. 1985 Sep 15;260(20):11046–11052. [PubMed] [Google Scholar]
- Renko M., Quarto N., Morimoto T., Rifkin D. B. Nuclear and cytoplasmic localization of different basic fibroblast growth factor species. J Cell Physiol. 1990 Jul;144(1):108–114. doi: 10.1002/jcp.1041440114. [DOI] [PubMed] [Google Scholar]
- Represa J., León Y., Miner C., Giraldez F. The int-2 proto-oncogene is responsible for induction of the inner ear. Nature. 1991 Oct 10;353(6344):561–563. doi: 10.1038/353561a0. [DOI] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saunders S., Jalkanen M., O'Farrell S., Bernfield M. Molecular cloning of syndecan, an integral membrane proteoglycan. J Cell Biol. 1989 Apr;108(4):1547–1556. doi: 10.1083/jcb.108.4.1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stark K. L., McMahon J. A., McMahon A. P. FGFR-4, a new member of the fibroblast growth factor receptor family, expressed in the definitive endoderm and skeletal muscle lineages of the mouse. Development. 1991 Oct;113(2):641–651. doi: 10.1242/dev.113.2.641. [DOI] [PubMed] [Google Scholar]
- Steinbuch M., Audran R. The isolation of IgG from mammalian sera with the aid of caprylic acid. Arch Biochem Biophys. 1969 Nov;134(2):279–284. doi: 10.1016/0003-9861(69)90285-9. [DOI] [PubMed] [Google Scholar]
- Tessler S., Neufeld G. Basic fibroblast growth factor accumulates in the nuclei of various bFGF-producing cell types. J Cell Physiol. 1990 Nov;145(2):310–317. doi: 10.1002/jcp.1041450216. [DOI] [PubMed] [Google Scholar]
- Van Doren K., Hanahan D., Gluzman Y. Infection of eucaryotic cells by helper-independent recombinant adenoviruses: early region 1 is not obligatory for integration of viral DNA. J Virol. 1984 May;50(2):606–614. doi: 10.1128/jvi.50.2.606-614.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Woodgett J. R., Gould K. L., Hunter T. Substrate specificity of protein kinase C. Use of synthetic peptides corresponding to physiological sites as probes for substrate recognition requirements. Eur J Biochem. 1986 Nov 17;161(1):177–184. doi: 10.1111/j.1432-1033.1986.tb10139.x. [DOI] [PubMed] [Google Scholar]
- Yayon A., Klagsbrun M., Esko J. D., Leder P., Ornitz D. M. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell. 1991 Feb 22;64(4):841–848. doi: 10.1016/0092-8674(91)90512-w. [DOI] [PubMed] [Google Scholar]
- Yoshida T., Miyagawa K., Sakamoto H., Sugimura T., Terada M. Identification and characterization of fibroblast growth factor-related transforming gene hst-1. Methods Enzymol. 1991;198:124–138. doi: 10.1016/0076-6879(91)98014-w. [DOI] [PubMed] [Google Scholar]