title: Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity.
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.
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Bose S
authors.initials: BS
authors.lastname: Kochupurakkal
authors.forename: Daniel
authors.initials: D
authors.lastname: Harari
authors.forename: Ayelet
authors.initials: A
authors.lastname: Di-Segni
authors.forename: Galia
authors.initials: G
authors.lastname: Maik-Rachline
authors.forename: Ljuba
authors.initials: L
authors.lastname: Lyass
authors.forename: Gal
authors.initials: G
authors.lastname: Gur
authors.forename: Gabriele
authors.initials: G
authors.lastname: Kerber
authors.forename: Ami
authors.initials: A
authors.lastname: Citri
authors.forename: Sara
authors.initials: S
authors.lastname: Lavi
authors.forename: Raya
authors.initials: R
authors.lastname: Eilam
authors.forename: Vered
authors.initials: V
authors.lastname: Chalifa-Caspi
authors.forename: Zelig
authors.initials: Z
authors.lastname: Eshhar
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.forename: Ronit
authors.initials: R
authors.lastname: Pinkas-Kramarski
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Bacus
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D000465:Algorithms; D020816:Amino Acid Motifs; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003001:Cloning, Molecular; D019295:Computational Biology; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D066261:Epigen; D005091:Exons; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism; D006133:Growth Substances; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D007438:Introns; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008934:Mitogens / Q000737:chemistry; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011817:Rabbits; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D025801:Ubiquitin / Q000737:chemistry
chemical_list: D018076:DNA, Complementary; D004815:Epidermal Growth Factor; D066261:Epigen; D006023:Glycoproteins; D006133:Growth Substances; D008024:Ligands; D008934:Mitogens; D018719:Erb-b2 Receptor Tyrosine Kinases; D025801:Ubiquitin; C587854:EPGN protein, human; C587855:Epgn protein, mouse