Oligomerized receptors which affect pathways regulated by transmembrane ligands for elk-related receptor tyrosine kinases
AssigneeMount Sinai Hospital
InventorsSacha Holland, Geraldine Mbamalu, Tony Pawson
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Abstract
A method of modulating the biological activity of a transmembrane ligand for an Elk-related receptor tyrosine kinase in a cell expressing the transmembrane ligand, comprising forming a complex between a purified and isolated oligomerized Elk-related receptor tyrosine kinase, or an isoform or an extracellular domain of the kinase, and a transmembrane ligand expressed on the cell, thereby affecting a pathway in the cell which is regulated by the transmembrane ligand.
Claims19
A method of modulating the biological activity of a transmembrane ligand for an Elk-related receptor tyrosine kinase in a cell expressing the transmembrane ligand comprising forming a complex between a purified and isolated oligomerized Elk-related receptor tyrosine kinase, or an isoform or an extracellular domain of the Elk-related receptor tyrosine kinase, and the transmembrane ligand expressed on the cell, thereby modulating the biological activity of the transmembrane ligand.
A method of affecting a pathway regulated by a transmembrane ligand for an Elk-related receptor tyrosine kinase in a cell expressing the transmembrane ligand, comprising forming a complex between a purified and isolated oligomerized Elk-related receptor tyrosine kinase, or an isoform or an extracellular domain of the Elk-related receptor tyrosine kinase, and a transmembrane ligand expressed on the cell, thereby affecting or modulating a pathway in the cell which is regulated by the transmembrane ligand.
A method for evaluating a substance for its ability to modulate the biological activity of a transmembrane ligand for an Elk-related receptor tyrosine kinase in a cell expressing the transmembrane ligand comprising the steps of:
- (a) contacting an oligomerized Elk-related receptor tyrosine kinase, or an isoform or an extracellular domain of the Elk-related receptor tyrosine kinase;
- a transmembrane ligand which binds to the Elk-related receptor tyrosine kinase to form a receptor-ligand complex, wherein the transmembrane ligand is a transmembrane ligand for an Elk-related receptor tyrosine kinase expressed on a cell;
- and, a test substance, under conditions which permit the formation of receptor-ligand complexes;
- (b) assaying for receptor-ligand complexes, free Elk-related receptor tyrosine kinase, or non-complexed transmembrane ligand, or for activation of the transmembrane ligand;
- and
- (c) comparing to a control to determine if the substance inhibits or enhances the binding of the Elk-related receptor tyrosine kinase and transmembrane ligand, and thereby modulates the biological activity of the transmembrane ligand.
A method for identifying a substance which affects or modulates a pathway regulated by a transmembrane ligand for an Elk-related receptor tyrosine kinase in a cell expressing the transmembrane ligand, comprising the steps of:
- (a) contacting an oligomerized Elk-related receptor tyrosine kinase, or an isoform or an extracellular domain of the Elk-related receptor tyrosine kinase;
- a transmembrane ligand which binds to the Elk-related receptor tyrosine kinase to form receptor-ligand complexes which activate a pathway regulated by a transmembrane ligand for an Elk-related receptor tyrosine kinase in a cell expressing the transmembrane ligand;
- and a test substance under conditions which permit the formation of receptor-ligand complexes;
- (b) assaying for receptor-ligand complexes, free Elk-related receptor tyrosine kinase, or non-complexed transmembrane ligand, or for activation of the transmembrane ligand;
- and
- (c) comparing to a control to determine if the substance inhibits or enhances the binding of the Elk related receptor tyrosine kinase and transmembrane ligand and thereby affects or modulates the pathway.
A method for evaluating a substance for its ability to inhibit or enhance the interaction of an oligomerized Elk-related receptor tyrosine kinase, or an isoform, or an extracellular domain of the Elk-related receptor tyrosine kinase, and a transmembrane ligand for an Elk-related receptor tyrosine kinase expressed on a cell comprising:
- (a) providing a reporter gene operably linked to a DNA binding site for a transcriptional activator;
- (b) providing a first hybrid protein comprising the transmembrane ligand in polypeptide linkage to a DNA binding domain of the transcriptional activator;
- (c) providing a second hybrid protein comprising an oligomerized Elk-related receptor tyrosine kinase or an isoform or an extracellular domain of the Elk-related receptor tyrosine kinase in polypeptide linkage to an activation domain of the transcriptional activator;
- under conditions where the transmembrane ligand and oligomerized Elk-related receptor tyrosine kinase can bind and thereby reconstitute the transcriptional activator which induces transcription of the reporter gene;
- (d) administering a test substance;
- and
- (e) monitoring expression of the reporter gene, wherein a decrease in expression is an indication that the substance inhibits the interaction of the transmembrane ligand and oligomerized Elk-related receptor tyrosine kinase, and an increase in expression is an indication that the substance enhances the interaction of the transmembrane ligand and oligomerized Elk-related receptor tyrosine kinase.
A method for evaluating a substance for its ability to inhibit or enhance the interaction of an oligomerized Elk-related receptor tyrosine kinase, or an isoform, or an extracellular domain of the Elk-related receptor tyrosine kinase, and a transmembrane ligand for an Elk-related receptor tyrosine kinase expressed on a cell comprising:
- (a) providing a reporter gene operably linked to a DNA binding site for a transcriptional activator, (b) providing a first hybrid protein comprising an oligomerized Elk-related receptor tyrosine kinase or an isoform or an extracellular domain of the Elk-related receptor tyrosine kinase in polypeptide linkage to a DNA binding domain of the transcriptional activator;
- (c) providing a second hybrid protein comprising a transmembrane ligand in polypeptide linkage to an activation domain of the transcriptional activator;
- under conditions where the transmembrane ligand and oligomerized Elk-related receptor tyrosine kinase can bind and thereby reconstitute the transcriptional activator which induces transcription of the reporter gene;
- (d) administering a test substance;
- and
- (e) monitoring expression of the reporter gene, wherein a decrease in expression is an indication that the substance inhibits the interaction of the transmembrane ligand and oligomerized Elk-related receptor tyrosine kinase, and an increase in expression is an indication that the substance enhances the interaction of the transmembrane ligand and oligomerized Elk-related receptor tyrosine kinase.
An antibody preparation which specifically binds to a receptor-ligand complex comprising an oligomerized Elk-related receptor tyrosine kinase, or an isoform or an extracellular domain of the kinase, and a transmembrane ligand for an Elk-related receptor tyrosine kinase.
Use of a purified and isolated oligomerized Elk-related receptor tyrosine kinase, or an isoform or an extracellular domain thereof, in the preparation of a medicament for modulating the biological activity of a transmembrane ligand for an Elk-related receptor tyrosine kinase in a cell expressing the transmembrane ligand.
Use of a purified and isolated oligomerized Elk-related receptor tyrosine kinase, or an isoform or an extracellular domain thereof, in the preparation of a medicament for modulating neuronal development or regeneration in a subject.
Use of a purified and isolated oligomerized Elk-related receptor tyrosine kinase, or an isoform or an extracellular domain thereof, in the preparation of a medicament for modulating axonogenesis in a subject .
A pharmaceutical composition which comprises a purified and isolated oligomerized Elk-related receptor tyrosine kinase, or an isoform or an extracellular domain thereof, in an amount effective to stimulate or inhibit neuronal development or regeneration and a pharmaceutically acceptable carrier, diluent or excipient.
Dependencies are inferred from the claim text.