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Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 111(45)
- Publication Year :
- 2014
-
Abstract
- The with no lysine (K) (WNK) family of enzymes is best known for control of blood pressure through regulation of the function and membrane localization of ion cotransporters. In mice, global as well as endothelial-specific WNK1 gene disruption results in embryonic lethality due to angiogenic and cardiovascular defects. WNK1(-/-) embryos can be rescued by endothelial-specific expression of a constitutively active form of the WNK1 substrate protein kinase OSR1 (oxidative stress responsive 1). Using human umbilical vein endothelial cells (HUVECs), we explored mechanisms underlying the requirement of WNK1-OSR1 signaling for vascular development. WNK1 is required for cord formation in HUVECs, but the actions of the two major WNK1 effectors, OSR1 and its close relative SPAK (STE20/SPS1-related proline-, alanine-rich kinase), are distinct. SPAK is important for endothelial cell proliferation, whereas OSR1 is required for HUVEC chemotaxis and invasion. We also identified the zinc-finger transcription factor Slug in WNK1-mediated control of endothelial functions. Our study identifies a separation of functions for the WNK1-activated protein kinases OSR1 and SPAK in mediating proliferation, invasion, and gene expression in endothelial cells and an unanticipated link between WNK1 and Slug that is important for angiogenesis.
- Subjects :
- Angiogenesis
Neovascularization, Physiologic
Biology
Protein Serine-Threonine Kinases
Minor Histocompatibility Antigens
Mice
WNK Lysine-Deficient Protein Kinase 1
Human Umbilical Vein Endothelial Cells
Animals
Humans
Protein kinase A
Cell Proliferation
Regulation of gene expression
Mice, Knockout
Multidisciplinary
Kinase
Intracellular Signaling Peptides and Proteins
Biological Sciences
WNK1
Cell biology
Endothelial stem cell
Gene Expression Regulation
Cancer research
Snail Family Transcription Factors
Signal transduction
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 111
- Issue :
- 45
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....725facd3454b9699217b7803e8861363