The<i>a</i>3 isoform of V-ATPase regulates insulin secretion from pancreatic β-cells

Sun‐Wada, Ge‐Hong; Toyomura, Takao; Murata, Yoshiko; Yamamoto, Akira; Futai, Masamitsu; Wada, Yoh

doi:10.1242/jcs.03234

Cited by 200 publications

(189 citation statements)

References 57 publications

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“…Fourth, the yeast ortholog of furin, Kex2p, has been shown to have a role in the regulation of activity of the V-ATPase (19). Fifth, a KO mouse model for the a3 isoform of subunit a of the V-ATPase, which is highly expressed in the same neuroendocrine tissues as Ac45, also displays impaired exocytosis of insulin (34). Sixth, Ac45 contains a conserved furin cleavage site, which can be cleaved by furin ex vivo (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Louagie

Taylor

Flamez

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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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 II. Both secretion and PC2 activity depend on granule acidification, which was demonstrated to be significantly decreased in furin-deficient ␤ cells by using the acidotrophic agent 3-(2,4-dinitroanilino)-3 amino-N-methyldipropylamine (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 ␤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.endoprotease ͉ insulin ͉ islets of Langerhans ͉ proton pump ͉ proprotein convertase

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Section: Discussionmentioning

confidence: 99%

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

Louagie

Taylor

Flamez

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The images were processed for presentation with Adobe Photoshop CS4, Illustrator CS4 and GoLive software on Macintosh computers. For electron microscopy, embryos were fixed with 2% glutaraldehyde and 2% PFA in 0.1 M potassium phosphate (pH 7.2), and then processed according to standard procedures 59,60 . Electron microscopy was performed at the Hanaichi Ultra-Structure Research Institute (Okazaki, Japan).…”

Section: Methodsmentioning

confidence: 99%

Delivery of endosomes to lysosomes via microautophagy in the visceral endoderm of mouse embryos

et al. 2012

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The differentiation and patterning of murine early embryos are sustained by the visceral endoderm, an epithelial layer of polarised cells that has critical roles in multiple signalling pathways and nutrient uptake. Both nutritional and signalling functions rely upon the endocytosis of various molecules from the cell surface via the endocytic pathway. However, endocytic membrane dynamics in this embryonic tissue remain poorly understood. Here we show that the functions of rab7, a small GTP-binding protein regulating the late endocytic pathway, are essential for embryonic patterning during gastrulation. The endosomes of visceral endoderm cells are delivered via a unique microautophagy-like process to the apical vacuole, a large compartment exhibiting lysosomal characteristics. Loss of rab7 function results in severe inhibition of this endocytic pathway. our results indicate that the microautophagic process and flow of the endocytic membrane have essential roles in early embryonic development.

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“…a1 localizes to synaptic vesicles (12), whereas a2 is present in endosomal compartments and the Golgi (13,14). a3 localizes to lysosomes in pre-osteoclasts (13) and insulin-containing secretory vesicles in pancreatic ␤ cells (15). Both a3 and a4 target VATPases to the plasma membranes of specialized cell types.…”

mentioning

confidence: 99%

The Function of Vacuolar ATPase (V-ATPase) a Subunit Isoforms in Invasiveness of MCF10a and MCF10CA1a Human Breast Cancer Cells

Capecci

Forgac

2013

Journal of Biological Chemistry

130

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Background:The V-ATPase has been suggested to function in tumor cell invasion. Results: Invasion by MCF10CA1a cells is inhibited by knockdown of the a3 isoform, whereas a3 overexpression increases invasion and plasma membrane localization of V-ATPases in MCF10a cells. Conclusion: Invasion and plasma membrane V-ATPase localization can be controlled by expression of a3. Significance: a3 is a possible therapeutic target to limit metastasis.

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Thea3 isoform of V-ATPase regulates insulin secretion from pancreatic β-cells

Cited by 200 publications

References 57 publications

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

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

Delivery of endosomes to lysosomes via microautophagy in the visceral endoderm of mouse embryos

The Function of Vacuolar ATPase (V-ATPase) a Subunit Isoforms in Invasiveness of MCF10a and MCF10CA1a Human Breast Cancer Cells

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