Granuphilin Modulates the Exocytosis of Secretory Granules through Interaction with Syntaxin 1a

Torii, Seiji; Zhao, Shengli; Yi, Zhaohong; Takeuchi, Toshiyuki; Izumi, Tetsuro

doi:10.1128/mcb.22.15.5518-5526.2002

Cited by 90 publications

(139 citation statements)

References 32 publications

(40 reference statements)

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“…One member of this protein family, Slp4/Granuphilin, is expressed in pancreatic ␤-cells and controls insulin exocytosis (Coppola et al, 2002;Torii et al, 2002). However, Slp4 appears to inhibit rather than favor exocytosis, suggesting that other Rab27 binding proteins may also participate in the regulation of insulin release.…”

Section: Resultsmentioning

confidence: 99%

“…Overexpression of Slp4/Granuphilin in pancreatic ␤-cells results in a profound inhibition of insulin secretion (Coppola et al, 2002;Torii et al, 2002), suggesting that the protein functions as a negative modulator of exocytosis. In agreement with this hypothesis a decrease in Slp4/Granuphilin expression is associated with enhancement in the secretory response of pancreatic ␤-cells (Waselle, Coppola, and Regazzi, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Involvement of the Rab27 Binding Protein Slac2c/MyRIP in Insulin Exocytosis

Waselle

Coppola

Fukuda

et al. 2003

MBoC

152

159

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Involvement of the Rab27 Binding Protein Slac2c/MyRIP in Insulin Exocytosis

Waselle

Coppola

Fukuda

et al. 2003

MBoC

152

159

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“…4). In the case of vesicle-associated membrane protein (VAMP)-2, synaptotagmin-like protein 4 (Sytl4), and Rab3b, who interact upon Ca 2ϩ increase, this has been observed before (26,27 expression of Sytl4 reduces the number of docked vesicles to the plasma membrane, which is suggested to effect insulin secretion (19,28). Decreased mRNA and protein expression of VAMP2 and various other secretory proteins have also been associated with impaired protein secretion in diabetic patients (29) and animal models for diabetes (30).…”

Section: Resultsmentioning

confidence: 99%

Quantitative proteomic analysis of single pancreatic islets

Waanders

Chwalek

Monetti

et al. 2009

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

200

213

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Technological developments make mass spectrometry (MS)-based proteomics a central pillar of biochemical research. MS has been very successful in cell culture systems, where sample amounts are not limiting. To extend its capabilities to extremely small, physiologically distinct cell types isolated from tissue, we developed a high sensitivity chromatographic system that measures nanogram protein mixtures for 8 h with very high resolution. This technology is based on splitting gradient effluents into a capture capillary and provides an inherent technical replicate. In a single analysis, this allowed us to characterize kidney glomeruli isolated by laser capture microdissection to a depth of more than 2,400 proteins. From pooled pancreatic islets of Langerhans, another type of ''miniorgan,'' we obtained an in-depth proteome of 6,873 proteins, many of them involved in diabetes. We quantitatively compared the proteome of single islets, containing 2,000 -4,000 cells, treated with high or low glucose levels, and covered most of the characteristic functions of beta cells. Our ultrasensitive analysis recapitulated known hyperglycemic changes but we also find components up-regulated such as the mitochondrial stress regulator Park7. Direct proteomic analysis of functionally distinct cellular structures opens up perspectives in physiology and pathology.hyperglycemia ͉ liquid chromatography-mass spectrometry ͉ quantitative proteomics ͉ replay technology

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“…13 Slp4-a links SGs to the plasma membrane (PM) through SG-associated Rab proteins (principally Rab27A), PM-associated syntaxins (1a, 2, or 3) and soluble Munc18 isoforms. [15][16][17][18][19] Syntaxins exist in open and closed conformations that determine their participation in SNARE complex formation and membrane fusion. Slp4-a binds the closed conformation of syntaxin, 16,19 which selectively interacts with Munc18 proteins to hold SGs in a fusion-incompetent state at the PM.…”

Section: Introductionmentioning

confidence: 99%

The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis

Bierings

Hellen

Kiskin

et al. 2012

Blood

166

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Weibel-Palade body (WPB) exocytosis underlies hormone-evoked VWF secretion from endothelial cells (ECs). We identify new endogenous components of the WPB: Rab3B, Rab3D, and the Rab27A/ Rab3 effector Slp4-a (granuphilin), and determine their role in WPB exocytosis. We show that Rab3B, Rab3D, and Rab27A contribute to Slp4-a localization to WPBs. siRNA knockdown of Slp4-a, MyRIP, Rab3B, Rab3D, Rab27A, or Rab3B/ Rab27A, or overexpression of EGFPSlp4-a or EGFP-MyRIP showed that Slp4-a is a positive and MyRIP a negative regulator of WPB exocytosis and that Rab27A alone mediates these effects. We found that ECs maintain a constant amount of cellular Rab27A irrespective of the WPB pool size and that Rab27A (and Rab3s) cycle between WPBs and a cytosolic pool. The dynamic redistribution of Rab proteins markedly decreased the Rab27A concentration on individual WPBs with increasing WPB number per cell. Despite this, the probability of WPB release was independent of WPB pool size showing that WPB exocytosis is not determined simply by the absolute amount of Rab27A and its effectors on WPBs. Instead, we propose that the probability of release is determined by the fractional occupancy of WPB-Rab27A by Slp4-a and MyRIP, with the balance favoring exocytosis. (Blood. 2012;120(13):2757-2767) IntroductionHormone-evoked VWF secretion from endothelial cells (ECs) is mediated by exocytosis of specialized secretory granules (SGs) called Weibel-Palade bodies (WPBs). 1 WPB exocytosis is triggered by increases in intracellular free Ca 2ϩ or cAMP concentrations, and involves a number of molecular components, including the Nethylmaleimide-sensitive factor, VAMP3, SNAP23, syntaxin 4, RalA, the annexin A2/S100A10 complex, and phospholipase D. [2][3][4][5][6][7] In addition, Rab proteins also regulate WPB exocytosis. A subset of Rab proteins, including Rab3A-3D, Rab27A/B, and Rab37, is associated with SGs in different cell types where they regulate SG biogenesis, trafficking, and exocytosis. 8 Secretory cells often express a mixture of these "secretory" Rabs, which may have overlapping or distinct functions. Human ECs are reported to express mRNA for Rab3A, Rab3D, and Rab37,3,9,10 Rab3B protein, 11 and Rab27A mRNA and protein. 12,13 To date, Rab27A is the only endogenous EC Rab protein that has been detected on WPBs. Through its effector MyRIP and Myosin Va, Rab27A is proposed to negatively regulate WPB exocytosis. 13,14 Rab27A can interact with different effector molecules, and many secretory cells express a mixture of these effectors. 8 In these cases, SG exocytosis probably depends on the balance of Rab27A interactions with the complement of Rab effectors in the cell.In addition to MyRIP, ECs contain mRNA for the Rab27A effector Slp4-a (granuphilin). 13 Slp4-a links SGs to the plasma membrane (PM) through SG-associated Rab proteins (principally Rab27A), PM-associated syntaxins (1a, 2, or 3) and soluble Munc18 isoforms. [15][16][17][18][19] Syntaxins exist in open and closed conformations that determine their participation in SNARE complex f...

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Granuphilin Modulates the Exocytosis of Secretory Granules through Interaction with Syntaxin 1a

Cited by 90 publications

References 32 publications

Involvement of the Rab27 Binding Protein Slac2c/MyRIP in Insulin Exocytosis

Involvement of the Rab27 Binding Protein Slac2c/MyRIP in Insulin Exocytosis

Quantitative proteomic analysis of single pancreatic islets

The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis

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