Intron fusion proteins, and methods of identifying and using same

An isolated polypeptide, comprising at least one domain of a receptor tyrosine kinase operatively linked to at least one amino acid encoded by an intron of a gene encoding the receptor tyrosine kinase,

• wherein the receptor tyrosine kinase is selected from the group consisting of DDR, EPHA, FGFR4, MET, PDGFRA, TEK and TIE;
• or
• wherein the polypeptide comprises a sequence of amino acids selected from the group consisting of SEQ ID NOS:
• 1, 3, 4-8, 10, 12, 14-17, 19, 20, 21 and 22-25.

An isolated polypeptide, comprising a shortened receptor tyrosine kinase lacking at least all or part of a kinase domain and/or all or a part of a transmembrane domain, wherein:

• the polypeptide has reduced kinase activity and/or is not membrane localized compared to the non-shortened receptor tyrosine kinase;
• the polypeptide modulates a biological activity of the receptor tyrosine kinase;
• the receptor tyrosine kinase is selected from the group consisting of DDR, EPHA1, EPHA8, FGFR2, FGFR4, MET, PDGFRA, and TIE, or the isolated polypeptide has at least 95% sequence identity with a sequence of amino acids set forth in any of SEQ ID NOS:
• 1, 3, 4-8, 10, 11, 12, 14-17, 19, 20, 21 or 22-25;
• and
• sequence identity is compared along the full length of each SEQ ID to the sequence of the full length of the isolated polypeptide.

An isolated polypeptide, comprising an intron-encoded sequence of amino acids, wherein:

• the intron is from a receptor tyrosine kinase gene selected from the group consisting of DDR1, EGFR, ERBB3, FLT1, MET, PDGFRA, TEK and TIE;
• or
• the intron-encoded sequence of any of SEQ ID NOS:
• 1-8 and 10-25;
• and
• the polypeptide lacks a receptor tyrosine kinase cytoplasmic domain.

A pharmaceutical composition, comprising a polypeptide, wherein:

• the polypeptide comprises a sequence of amino acids that has at least 95% sequence identity with a sequence of amino acids set forth in any of SEQ ID NOS:
• 1, 3, 4-8, 10, 12, 14-17, 19, 20, 21 and 22-25 and allelic variations thereof;
• sequence identity is compared along the full length of each SEQ ID to the full length of the sequence of the isolated polypeptide;
• and
• each of SEQ ID NOS:
• 1, 3, 4-8, 10, 11, 12, 14-17, 19, 20, 21 and 22-25 is a receptor tyrosine kinase isoform.

A method of drug discovery for identifying candidate molecules that modulate the activity of a cell surface receptor, comprising:

• a) selecting a set of expressed gene sequences encoding a cell surface receptor or a portion thereof;
• b) assembling the set of expressed gene sequences into an aligned set of sequences;
• and
• c) selecting at least one member sequence of the aligned set that encodes a cell surface receptor isoform, wherein the isoform lacks at least one domain or a portion thereof sufficient to modulate a biological activity of the cell surface receptor compared to a wildtype or predominant form of the cell surface receptor, thereby identifying a candidate molecule that modulates the cell surface receptor.