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Doctoral Thesis
DOI
10.11606/T.42.2009.tde-09022010-113024
Document
Author
Full name
Lilian Cristina Russo
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2009
Supervisor
Committee
Ferro, Emer Suavinho (President)
Oliveira, Vitor Marcelo Silveira Bueno Brandão de
Rioli, Vanessa
Tersariol, Ivarne Luis dos Santos
Torrão, Andréa da Silva
Title in Portuguese
Análise molecular da secreção não convencional da endo-oligopeptidase EC3.4.24.15 (EP24.15)
Keywords in Portuguese
Biologia
Biologia celular
Transporte através da membrana
Transporte biológico
Abstract in Portuguese
A thimet oligopeptidase (EP24.15) foi originariamente descrita como uma enzima metabolizadora de neuropeptídeos que não possui um peptídeo sinal para entrada na via secretória clássica, mas é secretada pelas células através de um mecanismo não-convencional. Nesse trabalho, identificamos uma nova interação cálcio-dependente entre EP24.15 e calmodulina I (CaM), que é importante para a secreção estimulada, mas não constitutiva, da EP24.15. A superexpressão da CaM em células HEK293 aumenta a secreção estimulada da EP24.15, podendo ser inibida pelo inibidor da CaM. O inibidor específico da PKA reduz a secreção estimulada de EP24.15. Nossos dados sugerem que a interação entre EP24.15 e calmodulina é regulada e relevante para a secreção estimulada da EP24.15 em células HEK293. Surpreendentemente, experimentos com slices (fatias) de cérebros de ratos sugerem que, fisiologicamente, a EP24.15 é secretada predominantemente de forma constitutiva, embora o tratamento com A23187 e forskolin sejam capazes de aumentar modestamente a secreção dessa enzima nessas preparações.
Title in English
Molecular analysis of the unconventional endo-oligopeptidase EC3.4.24.15 (EP24.15) secretion.
Keywords in English
Biological transport
Biology
Cellular biology
Transport through the membrane
Abstract in English
Thimet oligopeptidase (EC3.4.24.15; EP24.15) was originally described as a neuropeptide-metabolising enzyme that lacks a typical signal-peptide sequence for entry into the secretory pathway and is secreted by cells via an unconventional and unknown mechanism. Here, we identify a novel calcium-dependent interaction between EP24.15 and calmodulin I (CaM) that is important for the stimulated, but not constitutive, secretion of EP24.15. Overexpression of CaM in HEK293 cells increase the stimulated secretion of EP24.15, which can be inhibited by the CaM inhibitor. The specific inhibition of PKA with reduced the A23187-stimulated secretion of EP24.15. Our data suggest that the interaction between EP24.15 and calmodulin is regulated within cells and is important for the stimulated secretion of EP24.15 from HEK293 cells. Surprising, the rats brain slices experiments showed that, physiological, EP24.15 has a constitutive secretion, although the A23187 and forskolin treatment are able to increase a little this enzyme secretion in these preparations.
 
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Publishing Date
2010-03-15
 
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