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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_018979 28 - 10461 NP_061852 251 2382 ubiquitously 2015 26241057 long isoform NM_014823 26 - 9717 NP_055638 - 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 NM_213655 28 - 11208 NP_998820 - 2634 - 2015 26241057 NM_001184985 28 - 11232 NP_001171914 - 2642 - 2015 26241057

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Nervous spinal cord sensory ganglia     highly Homo sapiens Reproductive male system testis     highly Respiratory lung       highly Urinary kidney tubule collecting duct     urinary kidney nephron distal convoluted tubule     Visual eye lens       Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal     Nervous peripherous       Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Nervous astrocyte Homo sapiens Nervous neuron 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

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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