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FLASH GENE
Symbol WNK1 contributors: mct/npt/pgu - updated : 20-10-2016
HGNC name WNK lysine deficient protein kinase 1
HGNC id 14540
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • catalytic domain near the N terminus, including the unique sequence variation around catalytically important lysine residues that characterize the WNK subfamily (N-terminal region is required for protein complex formation with TBC1D4)
  • serine/threonine protein kinase
  • a catalytic domain containing a cysteine in place of a lysine in catalytic subdomain II, the WNK sequence signature within the subdomains I and II
  • several phosphorylation sites
  • PY motifs, which bind the E3 ubiquitin ligase NEDD4L
  • regulatory C-terminal including a highly conserved acidic motif and two coil-coil domains, and C-terminal WNK1 fragments can be phosphorylated by OXSR1, suggesting that OXSR1 catalyzes feedback phosphorylation of WNK1
    • conjugated GlycoP , PhosphoP
    mono polymer tetramer
    HOMOLOGY
    interspecies homolog to Drosophila calphatin
    Homologene
    FAMILY
  • protein kinase superfamily
  • Ser/Thr protein kinase family
  • WNK subfamily
    • CATEGORY enzyme , signaling
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytoskeleton,microtubule,mitotic spindle
    text
  • colocalized in cortical neurons with LINGO1
  • during cell division, WNK1 localizes to mitotic spindles
    • basic FUNCTION
  • may be involved in osmotic control
  • may be able to influence ion homeostasis through its effects on synaptotagmin function
  • mediating with STK39, and OXSR1 the hypotonic stress signaling pathway to the transporters and may provide insights into the mechanisms by which WNK1 regulates ion balance
  • with WNK2, WNK3, WNK4, have vital roles in the control of salt homeostasis and blood pressure
  • when activated, subsequently phosphorylate and activate the related protein kinases STK39 and OXSR1
  • signaling molecule involved in regulation of LINGO1 mediated inhibition of neurite extension
  • controls sodium and chloride ion transport by inhibiting the activity of WNK4
  • may also play a role in actin cytoskeletal reorganization
  • regulate many ion transport proteins by altering membrane trafficking by activating SGK1 to inhibit Nedd4-mediated internalization of the epithelial Na+ channel
  • involved in the regulation of SLC2A11, which secures glucose transport in noninsulin target cells
  • may exert its mitotic function through its enzymatic activity, protein-protein associations, or likely both
  • potential mitotic kinase regulating both the formation of mitotic spindles and the completion of abscission
  • WNK1 activation of the OSR1 signaling cascade is likely an essential pathway that regulates angiogenesis and cardiac formation during development
  • functions as a chloride sensor through direct binding of a regulatory chloride ion to the active site, which inhibits autophosphorylation
  • mediates aldosterone-dependent activity of the WNK/SPAK/OSR1 pathway
  • WNK1 is a negative regulator of integrin-mediated adhesion, whereas it acts as a positive regulator of migration via the kinases OXSR1 and STK39 and the ion co-transporter SLC12A2
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    text salt, K+, pH, water homeostasis
    PATHWAY
    metabolism
    signaling
    signalling pathway that plays a key role in controlling the phosphorylation and activity of SLC12A3
    a component
  • WNK1-STK39/OXSR1 signalling pathway
  • forms a complex with the Rab-GAP TBC1D4 that is involved in regulating the amount of glucose transporter SLC2A1 expressed at the cell surface
    • INTERACTION
    DNA
    RNA
    small molecule cofactor,
  • Mg2+
    • protein
  • WNK1 autoinhibitory domain inhibited the catalytic activity of other WNKs (potential mechanisms for interconnected regulation of WNK family members)
  • activating STK39 and OXSR1 (phosphorylates and regulates the STE20-related kinases, Ste20-related proline-alanine-rich kinase (STK39) and oxidative stress response 1 (OXSR1))
  • interacts with WNK3 and WNK4 to regulate SLC12A3 in both human kidney cells and Xenopus oocytes
  • binds to synaptotagmin 2 and Munc18c, two proteins involved in the fusion of secretory membrane vesicles
  • through interaction with TBC1D4, a Rab GTPase-activating protein (GAP) involved in regulated exocytosis of glucose transporters, promotes SLC2A1 surface expression
  • interacting with OXSR1 (WNK1 and OXSR1 are tightly bound to each other in cells)
  • WNK1 affects ion transport in part through activation of OSR1 and STK39
  • KLHL2 interacts with and ubiquitinates WNK1 and WNK4 kinases
  • WNK1 enhances BK channel function by reducing ERK1/2 signaling-mediated lysosomal degradation of the channel
  • separation of functions for the WNK1-activated protein kinases OSR1 and STK39 in mediating proliferation, invasion, and gene expression in endothelial cells and an unanticipated link between WNK1 and SNAI2 that is important for angiogenesis
  • WNK1 and WNK4 are the targets for the KLHL3-CUL3 complex and modulate the activity of SLC12A5 by means of intermediary Ste20-type kinases known as STK39 or OSR1
  • WNK1-regulated changes in SLC12A5 phosphorylation contribute to the developmental excitatory-to-inhibitory GABA sequence
  • proline-rich exons are modular cassettes that convert WNK1 into a NEDD4L substrate, thereby linking aldosterone and other NEDD4L-suppressing antinatriuretic hormones to SLC12A3 phosphorylation status
    • cell & other
    REGULATION
    activated by hypertonic stress in kidney epithelial cells and in breast and colon cancer cell lines
    Other inactivated by autoinhibition and autophosphorylation
    ASSOCIATED DISORDERS
    corresponding disease(s) PHA2C , HSAN2A
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    could lead to hypertension
    Susceptibility to essential hypertension
    Variant & Polymorphism SNP associated with essential hypertension
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • 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)
  • endothelial-specific deletion of Wnk1 in mice results in embryonic lethality, with angiogenesis and cardiac defects beginning at embryonic day &
    • 8764;10.5