title: Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility.
abstract: Release of cytokines, growth factors and other life-essential molecules from precursors by a-disintegrin-and-metalloproteases (ADAMs) is regulated with high substrate-specificity. We hypothesized that this is achieved by cleavage-regulatory intracellular-domain (ICD)-modifications of the precursors. We show here that cleavage-stimuli-induced specific ICD-modifications cause structural substrate changes that enhance ectodomain sensitivity of neuregulin-1 (NRG1; epidermal-growth-factor) or CD44 (receptor-tyrosine-kinase (RTK) co-receptor) to chymotrypsin/trypsin or soluble ADAM. This inside-out signal transfer required substrate homodimerization and was prevented by cleavage-inhibitory ICD-mutations. In chimeras, regulation could be conferred to a foreign ectodomain, suggesting a common higher-order structure. We predict that substrate-specific protease-accessibility-regulation controls release of numerous ADAM substrates.
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.|Washington University School of Medicine, Renal Division, St. Louis, MO, USA.
authors.forename: Liseth M
authors.initials: LM
authors.lastname: Parra
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Hartmann
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: Salome
authors.initials: S
authors.lastname: Schubach
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: Junzhi
authors.initials: J
authors.lastname: Ma
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Herrlich
authors.affiliation: Washington University School of Medicine, Renal Division, St. Louis, MO, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrlich
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D002678:Chimera / Q000235:genetics; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D020890:Neuregulin-1 / Q000737:chemistry / Q000235:genetics*; D010447:Peptide Hydrolases / Q000737:chemistry / Q000235:genetics; D000072417:Protein Domains / Q000235:genetics; D013379:Substrate Specificity / Q000235:genetics
chemical_list: C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D010447:Peptide Hydrolases; D051722:ADAM Proteins