Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-06-23
2000-06-27
Ulm, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530350, C07K 14705
Patent
active
060807180
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Transmembrane receptors are proteins which are localized in the plasma membrane of eukaryotic cells. These receptors have an extracellular domain, a transmembrane domain and an intracellular domain. Transmembrane receptors mediate molecular signaling functions by, for example, binding specifically with an external signaling molecule (referred to as a ligand) which activates the receptor. Activation results typically in the triggering of an intracellular catalytic function which is carried out by, or mediated through, the intracellular domain of the transmembrane receptor.
There are various families of transmembrane receptors that show overall similarity in sequence. The highest conservation of sequence is in the intracellular catalytic domain. Characteristic amino acid position can be used to define classes of receptors or to distinguish related family members. Sequences are much more divergent in the extracellular domain.
A variety of methods have been developed for the identification and isolation of transmembrane receptors. This is frequently a straightforward matter since receptors often share a common sequence in their catalytic domain. However, the identification of the ligands which bind to, and activate, the transmembrane receptors is a much more difficult undertaking. Brute force approaches for the identification of ligands for known receptors are rarely successful. Brute force approaches usually depend on a growth for nerve growth factor; or glucose homeostasis for the insulin receptor) or they depend on finding a source of the ligand and using affinity to purify it. In general, however, a source of the ligand is not known, nor is there an obvious or easily assayed biological activity. Therefore, there are many receptors, referred to as "orphan receptors", for which no corresponding ligand has been identified. Further, although several ligands may be known for a specific receptor, it is important to determine the remaining ligands for that receptor to fully understand its role in the growth and maintenance of the vertebrate body. A systematic approach to the identification of receptor ligands would be of great value for the identification of ligands having useful pharmacological activities.
SUMMARY OF THE INVENTION
The present invention relates to compositions and methods which are useful in connection with the identification of transmembrane receptors and their corresponding ligands. Preferred transmembrane receptors include tyrosine kinase receptors, cytokine receptors and tyrosine phosphatase receptors. Such receptors mediate cell signaling through the interaction of specific binding pairs (e.g., receptor/ligand pairs). The present invention is based on the finding that an unknown component in a receptor-mediated signaling pathway, which results ultimately in an intracellular catalytic event, can be identified by combining other known components within a cellular background within which the catalytic event ordinarily will not take place at significant levels. A cDNA expression library is then used to transform such cells. If the cDNA insert encodes the missing component of the transmembrane receptor-mediated signaling pathway, the catalytic event will be triggered. Detection of the otherwise absent catalytic activity is indicative of a cDNA insert encoding the missing component.
The invention also provides two novel ligands for the FGF receptor. Both the isolated DNA sequences of these ligands (FRL-2 is SEQ ID NO:1 and FRL-1 is SEQ ID NO:3), as well as the isolated polypeptides (SEQ ID NO:2 and SEQ ID NO:4, respectively) encoded by these DNA sequences are described. Other nucleic acids of this invention include nucleotide sequences, both DNA and RNA, that comprise a portion of or all of sequences complementary to the DNA sequences described above. The genes FRL-2 and FRL-1 were formerly designated XT1 (or ALP) and EG2 (or CLP), respectively, in U.S. patent application Ser. No. 08/279,217.
This invention also encompasses agonists (mimics) and antagonists (inhibit
REFERENCES:
patent: 5238916 (1993-08-01), Goldfarb et al.
patent: 5256643 (1993-10-01), Persico et al.
patent: 5264557 (1993-11-01), Salomon et al.
Hanks, Steven K., "Eukaryotic Protein Kinases," Current Opinion in Structural Biology, 1:369-383 (1991).
Fett, James W. et al., "Isolation and Characterization of Angiogenin, an Angiogenic Protein from Human Carcinoma Cells," Biochemistry, 24(20):5480-5486 (1985).
Maes, P. et al., "The Complete Amino Acid Sequence of Bovine Milk Angiogenin," FEBS Letters, 241(1,2):41-45 (1988).
Haugg and Schein, "The DNA Sequences of the Human and Hamster Secretory Ribonucleases Determined with the Polymerase Chain Reaction (PCR)," Nucleic Acids Research, 20(3):612 (1992).
Ciccodicola, Alfredo et al., "Molecular Characterization of a Gene of the `EGF Family` Expressed in Undifferentiated Human NTERA2 Teratocarcinoma Cells," The EMBO Journal, 8(7):1987-1991 (1989).
Dono, Rosanna et al., "The Murine Cripto Gene: Expression During Mesoderm Induction and Early Heart Morphogenesis," Development, 118:1157-1168 (1993).
Basilico and Moscatelli, "The FGF Family of Growth Factors and Oncogenes," Adv. Cancer Res., 59:115-165 (1992).
Cheng and Flanagan, "Identification and Cloning of ELF-1, a Developmentally Expressed Ligand for the Mek 4 and Sek Receptor Tyrosine Kinases," Cell, 79:157-168 (1994).
Flanagan and Leder, "The kit Ligand: A Cell Surface Molecule Altered in Steel Mutant Fibroblasts," Cell, 63:185-194 (1990).
Carlson, Marian et al., "The Secreted Form of Invertase in Saccharomyces cerevisiae Is Synthesized from mRNA Encoding a Signal Sequence," Molecular and Cellular Biology, 3(3):439-447 (1983).
Musci, Thomas J. et al., "Regulation of the Fibroblast Growth Factor Receptor in Early Xenopus Embryos," Proc. Natl. Acad Sci. USA, 87:8365-8369 (1990).
Elledge, Stephen J. et al., ".lambda.YES: A Multifunctional cDNA Expression Vector for the Isolation of Genes by Complementation of Yeast and Escherichia coli Mutations," Proc. Natl. Acad. Sci. USA, 88:1731-1735 (1991).
Amaya, Enrique et al., "Expression of a Dominant Negative Mutant of the FGF Receptor Disrupts Mesoderm Formation in Xenopus Embryos," Cell, 66:257-270 (1991).
Gallwitz, D. et al., "The Actin Gene in Yeast Saccharomyces Cerevisiae: 5'and 3' End Mapping, Flanking and Putative Regulatory Sequences," Nucleic Acids Research, 9:6339-6350 (1981).
Kimelman, David Et al., "The Presence of Fibroblast Growth Factor in the Frog Egg: Its Role as a Natural Mesoderm Inducer," Science, 242:1053-1056 (1988).
Isaacs, H.V. et al., "Expression of a Novel FGF in the Xenopus Embryo. A New Candidate Inducing Factor for Mesoderm Formation and Anteroposterior Specification," Development, 114:711-720.
Tannahill, D. et al., "Developmental Expression of the Xenopus int-2 (FGF-3) Gene: Activation by Mesodermal and Neural Induction," Development, 115:695-702 (1992).
Joseph, Loren J. et al., "Complete Nucleotide and Deduced Amino Acid Sequences of Human and Murine Preprocathepsin L. An Abundant Transcript Induced by Transformation of Fibroblasts," J. Clin. Invest., 81:1621-1629 (1988).
Gal and Gottesman, "Isolation and Sequence of a cDNA for Human Pro-(Cathepsin L)," Biochem. J., 253:303-306 (1988).
Kay, Brian K. et al., "Potential for Two Isoforms of the A1 Ribonucleoprotein in Xenopus laevis," Proc. Natl. Acad. Sci. USA, 87:1367-1371 (1990).
Kim and Baker, "Isolation of RRM-Type RNA-Binding Protein Genes and the Analysis of Their Relatedness by Using a Numerical Approach," Molecular and Cellular Biology, 13(1):174-183 (1993).
Wilson, R. et al., "2.2 Mb of Contiguous Nucleotide Sequence from Chromosome III of C. elegans," Nature, 368:32-38 (1994).
Hao, Qian-Lin et al., "Isolation and Sequence Analysis of a Novel Human Tyrosine Kinase Gene," Molecular and Cellular Biology, 9(4):1587-1593 (1989).
Johnson, Daniel E. et al., "Diverse Forms of a Receptor for Acidic and Basic Fibroblast Growth Factors," Molecular and Cellular Biology, 10:4728-4736 (1990).
Nieuwkoop and Faber (editors), "The Further Develop
Kinoshita Noriyuki
Kirschner Marc W.
President and Fellows of Harvard College
Ulm John
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