title: Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK.
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.
authors.affiliation: Departments of Pharmacology and.
authors.forename: Hashem A
authors.initials: HA
authors.lastname: Dbouk
authors.affiliation: Departments of Pharmacology and.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Weil
authors.affiliation: Departments of Pharmacology and.
authors.forename: G K Sachith
authors.initials: GK
authors.lastname: Perera
authors.affiliation: Surgery.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Dellinger
authors.affiliation: Departments of Pharmacology and Simmons Comprehensive Cancer Center, and.
authors.forename: Gray
authors.initials: G
authors.lastname: Pearson
authors.affiliation: Departments of Pharmacology and Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.affiliation: Departments of Pharmacology and melanie.cobb@utsouthwestern.edu.
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Cobb
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D018919:Neovascularization, Physiologic / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C118135:OXSR1 protein, human; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C498744:Wnk1 protein, mouse
keywords: EMT; Slug; angiogenesis; endothelium; migration