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The Rho/Rac Guanine Nucleotide Exchange Factor Vav1 Regulates Hif-1α and Glut-1 Expression and Glucose Uptake in the Brain

1
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
2
Department of Biology, University of Maryland, College Park, MD 20742, USA
3
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(4), 1341; https://doi.org/10.3390/ijms21041341
Received: 26 December 2019 / Revised: 14 February 2020 / Accepted: 14 February 2020 / Published: 17 February 2020
(This article belongs to the Section Molecular Endocrinology and Metabolism)
Vav1 is a Rho/Rac (Ras-related C3 botulinum toxin substrate) guanine nucleotide exchange factor expressed in hematopoietic and endothelial cells that are involved in a wide range of cellular functions. It is also stabilized under hypoxic conditions when it regulates the accumulation of the transcription factor HIF (Hypoxia Inducible Factor)-1α, which activates the transcription of target genes to orchestrate a cellular response to low oxygen. One of the genes induced by HIF-1α is GLUT (Glucose Transporter)-1, which is the major glucose transporter expressed in vessels that supply energy to the brain. Here, we identify a role for Vav1 in providing glucose to the brain. We found that Vav1 deficiency downregulates HIF-1α and GLUT-1 levels in endothelial cells, including blood-brain barrier cells. This downregulation of GLUT-1, in turn, reduced glucose uptake to endothelial cells both in vitro and in vivo, and reduced glucose levels in the brain. Furthermore, endothelial cell-specific Vav1 knock-out in mice, which caused glucose uptake deficiency, also led to a learning delay in fear conditioning experiments. Our results suggest that Vav1 promotes learning by activating HIF-1α and GLUT-1 and thereby distributing glucose to the brain. We further demonstrate the importance of glucose transport by endothelial cells in brain functioning and reveal a potential new axis for targeting GLUT-1 deficiency syndromes and other related brain diseases. View Full-Text
Keywords: Vav1; HIF-1α; GLUT-1; learning deficiency; hypoxia Vav1; HIF-1α; GLUT-1; learning deficiency; hypoxia
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Hong, J.; Kim, Y.; Yanpallewar, S.; Lin, P.C. The Rho/Rac Guanine Nucleotide Exchange Factor Vav1 Regulates Hif-1α and Glut-1 Expression and Glucose Uptake in the Brain. Int. J. Mol. Sci. 2020, 21, 1341.

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