Cell surface annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin
Open Access
- 15 May 2012
- journal article
- Published by American Society for Cell Biology (ASCB) in Molecular Biology of the Cell
- Vol. 23 (10), 1964-1975
- https://doi.org/10.1091/mbc.e11-08-0683
Abstract
A disintegrin and metalloproteinase (ADAM) is a family of enzymes involved in ectodomain shedding of various membrane proteins. However, the molecular mechanism underlying substrate recognition by ADAMs remains unknown. In this study, we successfully captured and analyzed cell surface transient assemblies between the transmembrane amphiregulin precursor (proAREG) and ADAM17 during an early shedding phase, which enabled the identification of cell surface annexins as components of their shedding complex. Annexin family members annexin A2 (ANXA2), A8, and A9 interacted with proAREG and ADAM17 on the cell surface. Shedding of proAREG was increased when ANXA2 was knocked down but decreased with ANXA8 and A9 knockdown, because of enhanced and impaired association with ADAM17, respectively. Knockdown of ANXA2 and A8 in primary keratinocytes altered wound-induced cell migration and ultraviolet B–induced phosphorylation of epidermal growth factor receptor (EGFR), suggesting that annexins play an essential role in the ADAM-mediated ectodomain shedding of EGFR ligands. On the basis of these data, we propose that annexins on the cell surface function as “shedding platform” proteins to determine the substrate selectivity of ADAM17, with possible therapeutic potential in ADAM-related diseases.Keywords
This publication has 50 references indexed in Scilit:
- Sequential and γ-secretase-dependent processing of the betacellulin precursor generates a palmitoylated intracellular-domain fragment that inhibits cell growthJournal of Cell Science, 2010
- Novel anticancer targets: revisiting ERBB2 and discovering ERBB3Nature Reviews Cancer, 2009
- Insufficiency of Pro-heparin-binding Epidermal Growth Factor-like Growth Factor Shedding Enhances Hypoxic Cell Death in H9c2 Cardiomyoblasts via the Activation of Caspase-3 and c-Jun N-terminal KinaseOnline Journal of Public Health Informatics, 2009
- Annexin A8 Regulates Late Endosome Organization and FunctionMolecular Biology of the Cell, 2008
- Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membraneThe Journal of cell biology, 2008
- Membrane‐anchored growth factors, the epidermal growth factor family: Beyond receptor ligandsCancer Science, 2008
- Targeting TACE-dependent EGFR ligand shedding in breast cancerJCI Insight, 2007
- Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C-shaped scaffoldThe EMBO Journal, 2006
- Protein detection using proximity-dependent DNA ligation assaysNature Biotechnology, 2002
- An Essential Role for Ectodomain Shedding in Mammalian DevelopmentScience, 1998