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Role of furin in granular acidification in the endocrine pancreas: identification of the V-ATPase subunit Ac45 as a candidate substrate

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Abstract
Furin is a proprotein convertase which activates a variety of regulatory proteins in the constitutive exocytic and endocytic pathway. The effect of genetic ablation of fur was studied in the endocrine pancreas to define its physiological function in the regulated secretory pathway. Pdx1-Cre/loxP furin KO mice show decreased secretion of insulin and impaired processing of known PC2 substrates like proPC2 and proinsulin Ill. Both secretion and PC2 activity depend on granule acidification, which was demonstrated to be significantly decreased in furin-deficient beta cells by using the acidotrophic agent 3-(2,4-dinitroanilino)-3'amino-N-methyidipropylamine (DAMP). Ac45, an accessory subunit of the proton pump V-ATPase, was investigated as a candidate substrate. Ac45 is highly expressed in islets of Langerhans and furin was able to cleave Ac45 ex vivo. Furthermore, the exact cleavage site was determined. In addition, reduced regulated secretion and proinsulin II processing could be obtained in the insulinoma cell line beta TC3 by downregulation of either furin or Ac45. Together, these data establish an important role for furin in regulated secretion, particularly in intragranular acidification most likely due to impaired processing of Ac45.
Keywords
endoprotease, PC2, insulin, islets of Langerhans, proton pump, proprotein convertase, VACUOLAR H+-ATPASE, PROPROTEIN CONVERTASE FURIN, BETA-CELLS, SECRETORY PATHWAY, ACCESSORY SUBUNIT, INTRACELLULAR TRAFFICKING, CARBOXYPEPTIDASE-E, INSULIN, PROINSULIN

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MLA
Louagie, Els et al. “Role of Furin in Granular Acidification in the Endocrine Pancreas: Identification of the V-ATPase Subunit Ac45 as a Candidate Substrate.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 105.34 (2008): 12319–12324. Print.
APA
Louagie, E., Taylor, N. A., Flamez, D., Roebroek, A. J., Bright, N. A., Meulemans, S., Quintens, R., et al. (2008). Role of furin in granular acidification in the endocrine pancreas: identification of the V-ATPase subunit Ac45 as a candidate substrate. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 105(34), 12319–12324.
Chicago author-date
Louagie, Els, Neil A Taylor, Daisy Flamez, Anton JM Roebroek, Nicholas A Bright, Sandra Meulemans, Roel Quintens, et al. 2008. “Role of Furin in Granular Acidification in the Endocrine Pancreas: Identification of the V-ATPase Subunit Ac45 as a Candidate Substrate.” Proceedings of the National Academy of Sciences of the United States of America 105 (34): 12319–12324.
Chicago author-date (all authors)
Louagie, Els, Neil A Taylor, Daisy Flamez, Anton JM Roebroek, Nicholas A Bright, Sandra Meulemans, Roel Quintens, Pedro L Herrera, Frans Schuit, Wim JM van de Ven, and John WM Creemers. 2008. “Role of Furin in Granular Acidification in the Endocrine Pancreas: Identification of the V-ATPase Subunit Ac45 as a Candidate Substrate.” Proceedings of the National Academy of Sciences of the United States of America 105 (34): 12319–12324.
Vancouver
1.
Louagie E, Taylor NA, Flamez D, Roebroek AJ, Bright NA, Meulemans S, et al. Role of furin in granular acidification in the endocrine pancreas: identification of the V-ATPase subunit Ac45 as a candidate substrate. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2008;105(34):12319–24.
IEEE
[1]
E. Louagie et al., “Role of furin in granular acidification in the endocrine pancreas: identification of the V-ATPase subunit Ac45 as a candidate substrate,” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 105, no. 34, pp. 12319–12324, 2008.
@article{847048,
  abstract     = {{Furin is a proprotein convertase which activates a variety of regulatory proteins in the constitutive exocytic and endocytic pathway. The effect of genetic ablation of fur was studied in the endocrine pancreas to define its physiological function in the regulated secretory pathway. Pdx1-Cre/loxP furin KO mice show decreased secretion of insulin and impaired processing of known PC2 substrates like proPC2 and proinsulin Ill. Both secretion and PC2 activity depend on granule acidification, which was demonstrated to be significantly decreased in furin-deficient beta cells by using the acidotrophic agent 3-(2,4-dinitroanilino)-3'amino-N-methyidipropylamine (DAMP). Ac45, an accessory subunit of the proton pump V-ATPase, was investigated as a candidate substrate. Ac45 is highly expressed in islets of Langerhans and furin was able to cleave Ac45 ex vivo. Furthermore, the exact cleavage site was determined. In addition, reduced regulated secretion and proinsulin II processing could be obtained in the insulinoma cell line beta TC3 by downregulation of either furin or Ac45. Together, these data establish an important role for furin in regulated secretion, particularly in intragranular acidification most likely due to impaired processing of Ac45.}},
  author       = {{Louagie, Els and Taylor, Neil A and Flamez, Daisy and Roebroek, Anton JM and Bright, Nicholas A and Meulemans, Sandra and Quintens, Roel and Herrera, Pedro L and Schuit, Frans and van de Ven, Wim JM and Creemers, John WM}},
  issn         = {{0027-8424}},
  journal      = {{PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}},
  keywords     = {{endoprotease,PC2,insulin,islets of Langerhans,proton pump,proprotein convertase,VACUOLAR H+-ATPASE,PROPROTEIN CONVERTASE FURIN,BETA-CELLS,SECRETORY PATHWAY,ACCESSORY SUBUNIT,INTRACELLULAR TRAFFICKING,CARBOXYPEPTIDASE-E,INSULIN,PROINSULIN}},
  language     = {{eng}},
  number       = {{34}},
  pages        = {{12319--12324}},
  title        = {{Role of furin in granular acidification in the endocrine pancreas: identification of the V-ATPase subunit Ac45 as a candidate substrate}},
  url          = {{http://dx.doi.org/10.1073/pnas.0800340105}},
  volume       = {{105}},
  year         = {{2008}},
}

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