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Cleavage within Reelin repeat 3 regulates the duration and range of the signaling activity of Reelin protein.
J Biol Chem ; 289(18): 12922-30, 2014 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-24644294
ABSTRACT
Reelin is a secreted glycoprotein that plays essential roles in the brain. Reelin is specifically cleaved at two distinct sites, called N-t and C-t, with the former being the major one. N-t cleavage can occur both in the extracellular space and in the endosomes, although the physiological importance of endosomal N-t cleavage has not been investigated. In this study, we first determined the exact N-t cleavage site catalyzed by a protease secreted by cerebral cortical neurons. Cleavage occurred between Pro-1244 and Ala-1245 within Reelin repeat 3. A Reelin mutant in which Pro-1244 was replaced with aspartate (Reelin-PD) was resistant to a protease secreted by cultured cerebral cortical neurons, and its biological activity stayed active longer than that of wild-type Reelin. Interestingly, Reelin-PD remained in the intracellular compartments longer than wild-type Reelin and persistently activated downstream signaling. Therefore, N-t cleavage of Reelin is required for halting the signaling machinery in the extracellular space as well as within endosomes of target neurons. We established a monoclonal antibody specific to uncleaved Reelin protein and found that it is localized in the vicinity of Reelin-producing cells, whereas the N-terminal fragment diffuses, or is transported, to distant regions. These data demonstrate that N-t cleavage of Reelin plays critical roles in regulating the duration and range of Reelin functions both in the extracellular milieu and in the intracellular compartments.
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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Prolina / Serina Endopeptidases / Transdução de Sinais / Moléculas de Adesão Celular Neuronais / Proteínas da Matriz Extracelular / Ácido Aspártico / Mutação / Proteínas do Tecido Nervoso Limite: Animais / Feminino / Humanos / Masculino Idioma: Inglês Revista: J Biol Chem Ano de publicação: 2014 Tipo de documento: Artigo País de afiliação: Japão