PMID:15611079

Citation	Kochupurakkal, BS, Harari, D, Di-Segni, A, Maik-Rachline, G, Lyass, L, Gur, G, Kerber, G, Citri, A, Lavi, S, Eilam, R, Chalifa-Caspi, V, Eshhar, Z, Pikarsky, E, Pinkas-Kramarski, R, Bacus, SS and Yarden, Y (2005) Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity. J. Biol. Chem. 280:8503-12
Abstract	Four ErbB receptors and multiple growth factors sharing an epidermal growth factor (EGF) motif underlie transmembrane signaling by the ErbB family in development and cancer. Unlike other ErbB proteins, ErbB-2 binds no known EGF-like ligand. To address the existence of a direct ligand for ErbB-2, we applied algorithms based on genomic and cDNA structures to search sequence data bases. These searches reidentified all known EGF-like growth factors including Epigen (EPG), the least characterized ligand, but failed to identify novel factors. The precursor of EPG is a widely expressed transmembrane glycoprotein that undergoes cleavage at two sites to release a soluble EGF-like domain. A recombinant EPG cannot stimulate cells singly expressing ErbB-2, but it acts as a mitogen for cells expressing ErbB-1 and co-expressing ErbB-2 in combination with the other ErbBs. Interestingly, soluble EPG is more mitogenic than EGF, although its binding affinity is 100-fold lower. Our results attribute the anomalous mitogenic power of EPG to evasion of receptor-mediated depletion of ligand molecules, as well as to inefficient receptor ubiquitylation and down-regulation. In conclusion, EPG might represent the last EGF-like growth factor and define a category of low affinity ligands, whose bioactivity differs from the more extensively studied high affinity ligands.
Links	PubMed Online version:10.1074/jbc.M413919200
Keywords	Algorithms; Amino Acid Motifs; Animals; CHO Cells; COS Cells; Cell Line, Tumor; Cell Membrane/metabolism; Cell Proliferation; Cloning, Molecular; Computational Biology; Cricetinae; DNA, Complementary/metabolism; Dose-Response Relationship, Drug; Down-Regulation; Epidermal Growth Factor/chemistry; Epidermal Growth Factor/metabolism; Epidermal Growth Factor/physiology; Exons; Glycoproteins/chemistry; Glycoproteins/metabolism; Growth Substances; Humans; Hydrogen-Ion Concentration; Immunohistochemistry; Introns; Ligands; Male; Mice; Mice, Nude; Mitogens/chemistry; Neoplasm Transplantation; Phosphorylation; Phylogeny; Polymerase Chain Reaction; Prostatic Neoplasms/metabolism; Protein Binding; Protein Structure, Tertiary; Rabbits; Receptor, erbB-2/metabolism; Signal Transduction; Time Factors; Tissue Distribution; Ubiquitin/chemistry
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:EGF	enables	GO:0005154: epidermal growth factor receptor binding	ECO:0000304: author statement supported by traceable reference used in manual assertion		F		Seeded From UniProt	complete
HUMAN:EPGN	enables	GO:0008083: growth factor activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:EPGN	enables	GO:0005154: epidermal growth factor receptor binding	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:EPGN	located_in	GO:0005887: integral component of plasma membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:EPGN	involved_in	GO:0001525: angiogenesis	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:EPGN	involved_in	GO:0008284: positive regulation of cell population proliferation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:EPGN	involved_in	GO:0043406: positive regulation of MAP kinase activity	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:EPGN	involved_in	GO:0045840: positive regulation of mitotic nuclear division	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:EPGN	involved_in	GO:0045741: positive regulation of epidermal growth factor-activated receptor activity	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:EGF	enables	GO:0008083: growth factor activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:EGF	involved_in	GO:0001525: angiogenesis	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:EGF	involved_in	GO:0045840: positive regulation of mitotic nuclear division	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:EGF	involved_in	GO:0045741: positive regulation of epidermal growth factor-activated receptor activity	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:EGF	involved_in	GO:0043406: positive regulation of MAP kinase activity	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:EGF	involved_in	GO:0042327: positive regulation of phosphorylation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:EGF	involved_in	GO:0008284: positive regulation of cell population proliferation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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