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PMID:15611079

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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

Significance

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


See also

References

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