Journal article
Secretion of Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1/sFlt1) Requires Arf1, Arf6, and Rab11 GTPases
PLoS One, Vol.7(9), pp.e44572-e44572
09/04/2012
DOI: 10.1371/journal.pone.0044572
PMCID: PMC3433446
PMID: 22962618
Abstract
The soluble form of vascular endothelial growth factor receptor 1 (sVEGFR-1/sFlt1) is generated by alternative splicing of the FLT1 gene. Secretion of sFlt1 from endothelial cells plays an important role in blood vessel sprouting and morphogenesis. However, excess sFlt1 secretion is associated with diseases such as preeclampsia and chronic kidney disease. To date, the secretory transport process involved in the secretion of sFlt1 is poorly understood. In the present study, we investigated the itinerary of sFlt1 trafficking along the secretory pathway. To understand the timecourse of sFlt1 secretion, endothelial cells stably expressing sFlt1 were metabolically radiolabeled with [\n35\nS]-methionine and cysteine. Our results indicate that after initial synthesis the levels of secreted [\n35\nS]-sFlt1 in the extracellular medium peaks at 8 hours. Treatment with brefeldin A (BFA), a drug which blocks trafficking between the endoplasmic reticulum (ER) and the Golgi complex, inhibited extracellular release of sFlt1 suggesting that ER to Golgi and intra-Golgi trafficking of sFlt1 are essential for its secretion. Furthermore, we show that ectopic expression of dominant-negative mutant forms of Arf1, Arf6, and Rab11 as well as siRNA-mediated knockdown of these GTPases block secretion of sFlt1 during normoxic and hypoxic conditions suggesting role for these small GTPases. This work is the first to report role of regulatory proteins involved in sFlt1 trafficking along the secretory pathway and may provide insights and new molecular targets for the modulation of sFlt-1 release during physiological and pathological conditions.
Details
- Title: Subtitle
- Secretion of Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1/sFlt1) Requires Arf1, Arf6, and Rab11 GTPases
- Creators
- Jae-Joon JungAjit TiwariShivangi M InamdarChristie P ThomasApollina GoelAmit Choudhury
- Resource Type
- Journal article
- Publication Details
- PLoS One, Vol.7(9), pp.e44572-e44572
- DOI
- 10.1371/journal.pone.0044572
- PMID
- 22962618
- PMCID
- PMC3433446
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library of Science; San Francisco, USA
- Alternative title
- Role of Arf1, Arf6, and Rab11 in sFlt1 Secretion
- Language
- English
- Date published
- 09/04/2012
- Academic Unit
- Stead Family Department of Pediatrics; Radiation Oncology; Obstetrics and Gynecology; Internal Medicine
- Record Identifier
- 9983986083702771
Metrics
25 Record Views