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FLASH GENE
Symbol WNK1 contributors: mct/npt/pgu - updated : 20-10-2020
HGNC name WNK lysine deficient protein kinase 1
HGNC id 14540
Corresponding disease
HSAN2A hereditary sensory and autonomic neuropathy, type IIA
PHA2C pseudohypoaldosterenism, type 2 C
Location 12p13.33      Physical location : 862.088 - 1.020.617
Synonym name
  • kinase deficient protein
  • With-No-K, (lysine)1
  • protein kinase, lysine deficient 1
  • prostate-derived sterile 20-like kinase
  • erythrocyte 65 kDa protein
  • serine/threonine-protein kinase WNK1
    • Synonym symbol(s) KDP, PRKWNK1, KIAA0344, HSAN2, HSN2, p65, PSK
    EC.number 2.7.11.1
    DNA
    TYPE anonymous DNA segment
    STRUCTURE 158.85 kb     28 Exon(s)
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    text has multiple alternatively spliced isoforms (PMID: 20061383)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    28 - 10461 251 2382 ubiquitously 2015 26241057
    long isoform
    26 - 9717 - 2134 kidney-specific isoform, predominantly expressed in distal tubules of the kidney 2015 26241057
  • also called WNK1S
  • lacking the kinase domain
  • 2 alternatively spliced exons embedded within a proline-rich region of WNK1 that contain PY motifs, which bind the E3 ubiquitin ligase NEDD4L
    • 28 - 11208 - 2634 - 2015 26241057
    28 - 11232 - 2642 - 2015 26241057
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Nervousspinal cordsensory ganglia  highly Homo sapiens
    Reproductivemale systemtestis  highly
    Respiratorylung   highly
    Urinarykidneytubulecollecting duct  
    urinarykidneynephrondistal convoluted tubule  
    Visualeyelens    Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    Nervousperipherous    Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousastrocyte Homo sapiens
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    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
  • UBR5 is a regulator of WNK1 protein stability that leads to lysosomal degradation of WNK1 protein
    • 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