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

Bierings, R; Hellen, N; Kiskin, N; Knipe, L; Fonseca, AV; Patel, B; Meli, A; Rose, M; Hannah, MJ; Carter, T (2012) The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis. Blood, 120 (13). pp. 2757-2767. ISSN 0006-4971 https://doi.org/10.1182/blood-2012-05-429936
SGUL Authors: Carter, Thomas David

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Abstract

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 EGFP-Slp4-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.

Item Type: Article
Additional Information: © 2012 by The American Society of Hematology. Published version made available with permission of publisher.
Keywords: Blotting, Western, Cells, Cultured, Endothelium, Vascular, Exocytosis, Fluorescent Antibody Technique, Hormones, Humans, Immunoenzyme Techniques, RNA, Messenger, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Vesicular Transport Proteins, Weibel-Palade Bodies, rab GTP-Binding Proteins, rab3 GTP-Binding Proteins, von Willebrand Factor, Endothelium, Vascular, Cells, Cultured, Weibel-Palade Bodies, Humans, Hormones, rab GTP-Binding Proteins, rab3 GTP-Binding Proteins, von Willebrand Factor, Vesicular Transport Proteins, RNA, Small Interfering, RNA, Messenger, Fluorescent Antibody Technique, Blotting, Western, Immunoenzyme Techniques, Reverse Transcriptase Polymerase Chain Reaction, Exocytosis, Real-Time Polymerase Chain Reaction, Science & Technology, Life Sciences & Biomedicine, Hematology, HEMATOLOGY, VON-WILLEBRAND-FACTOR, CORE VESICLE EXOCYTOSIS, ENDOTHELIAL-CELLS, SECRETORY GRANULES, NUCLEOTIDE EXCHANGE, REGULATED SECRETION, FACTOR RELEASE, PC12 CELLS, MYOSIN VA, IN-VIVO, Immunology, 1102 Cardiovascular Medicine And Haematology, 1103 Clinical Sciences, 1114 Paediatrics And Reproductive Medicine
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Blood
ISSN: 0006-4971
Language: eng
Dates:
DateEvent
16 August 2012Published
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
MC_U117573808Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
U117570589Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
U117573808Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 22898601
Web of Science ID: WOS:000311615800031
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107673
Publisher's version: https://doi.org/10.1182/blood-2012-05-429936

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