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¹ Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
² Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
³ Amgen, 1201 Amgen Court West, Seattle, WA 98119-3105, USA

Membrane-anchored Neuregulin ß1 sheds its ectodomain as soluble factors. Two proteases that belong to a disintegrin and metalloprotease (ADAM) family are known to cleave Neuregulin ß1. One is tumor necrosis factor- converting enzyme (TACE/ADAM17). The other is Meltrin ß (ADAM19). Against our expectation that shedding by ADAM proteases occurs at the cell surface, here we found that Meltrin ß mediates the ectodomain shedding of Neuregulin ß1 in the Golgi apparatus. Meltrin ß was localized in and around the Golgi apparatus in developing sensory neurons. Subcellular fractionation revealed that Meltrin ß generated soluble Neuregulin ß1 in Golgi-enriched fractions while TACE-cleaved Neuregulin ß1 was recovered in lighter fractions. To examine whether Meltrin ß-mediated ectodomain shedding occurs in the Golgi apparatus in living cells, we took advantage of different diffusion properties of cleavage products from those of membrane-anchored precursor proteins. Fluorescence correlation spectroscopy (FCS) is the most sensitive method to determine millisubmillisecond diffusion in vivo. Protease-active Meltrin ß caused a shift in autocorrelation function in FCS of green fluorescent protein (GFP)-tagged Neuregulin ß1 in the Golgi apparatus, suggesting a conversion of Neuregulin ß1 molecules from membrane-anchored to soluble forms in that organelle. The Golgi apparatus is a site of processing Neuregulin ß1 by Meltrin ß.

^* Correspondence: E-mail: iwada{at}fmu.ac.jp; asehara{at}frontier.kyoto-u.ac.jp

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