Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility

Liseth M. Parra, Monika Hartmann, Salome Schubach, Junzhi Ma, Peter Herrlich, Andreas Herrlich

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish
Article number37464
JournalScientific reports
Volume6
DOIs
StatePublished - Nov 23 2016

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