Serine/threonine-protein kinase WNK1 (WNK1)
The protein contains 2382 amino acids for an estimated molecular weight of 250794 Da.
Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival, and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Activates SCNN1A, SCNN1B, SCNN1D and SGK1. Controls sodium and chloride ion transport by inhibiting the activity of WNK4, by either phosphorylating the kinase or via an interaction between WNK4 and the autoinhibitory domain of WNK1. WNK4 regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation. WNK1 may also play a role in actin cytoskeletal reorganization. Phosphorylates NEDD4L. Acts as a scaffold to inhibit SLC4A4, SLC26A6 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition (By similarity).', 'Dominant-negative regulator of the longer isoform 1. Does not have kinase activity, does not directly inhibit WNK4 and has no direct effect on sodium and chloride ion transport. Downregulates sodium-chloride cotransporter activity indirectly by inhibiting isoform 1, it associates with isoform 1 and attenuates its kinase activity. In kidney, may play an important role regulating sodium and potassium balance. (updated: Dec. 11, 2019)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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Biological Process
Cellular response to calcium ion
Cellular response to chemokine
Chemokine (C-C motif) ligand 21 signaling pathway
Intracellular signal transduction
Ion homeostasis
Ion transport
Lymphocyte migration into lymph node
Negative regulation of cell-cell adhesion mediated by integrin
Negative regulation of GTPase activity
Negative regulation of heterotypic cell-cell adhesion
Negative regulation of leukocyte cell-cell adhesion
Negative regulation of pancreatic juice secretion
Negative regulation of phosphatase activity
Negative regulation of sodium ion transport
Neuron development
Peptidyl-serine phosphorylation
Peptidyl-threonine phosphorylation
Positive regulation of canonical Wnt signaling pathway
Positive regulation of ion transmembrane transporter activity
Positive regulation of potassium ion import across plasma membrane
Positive regulation of sodium ion transmembrane transporter activity
Positive regulation of systemic arterial blood pressure
Positive regulation of T cell chemotaxis
Protein autophosphorylation
Protein phosphorylation
Regulation of cation transmembrane transport
Regulation of cellular process
Regulation of sodium ion transport
Signal transduction
Signal transduction by trans-phosphorylation
T cell receptor signaling pathway
Molecular Function
ATP binding
Chloride channel inhibitor activity
Magnesium ion binding
Phosphatase binding
Potassium channel inhibitor activity
Protein kinase activator activity
Protein kinase activity
Protein kinase binding
Protein kinase inhibitor activity
Protein serine kinase activity
Protein serine/threonine kinase activity
Protein serine/threonine kinase inhibitor activity
Protein threonine kinase activity
The reference OMIM entry for this protein is 201300
Neuropathy, hereditary sensory and autonomic, type iia; hsan2a
Hsan iia
Neuropathy, hereditary sensory, type iia; hsn2a
Hsn iia
Acroosteolysis, neurogenic
Acroosteolysis, giaccai type
Neuropathy, hereditary sensory radicular, autosomal re
A number sign (#) is used with this entry because hereditary sensory and autonomic neuropathy type IIA (HSAN2A) can be caused by mutation in the HSN2 isoform of the WNK1 gene (WNK1/HSN2; see 605232). HSAN2B (613115) is caused by mutation in the FAM134B gene (613114). For a discussion of genetic heterogeneity of HSAN, see HSAN1 (162400).
CLINICAL FEATURES
Giaccai (1952) reported 'neurogenic acroosteolysis' in 4 children born of an Arab man who married 2 first cousins. By the first wife, 1 of the children was affected, and by the second wife, 3 of 5 children were affected. Since the spinal cord was normal at autopsy, Giaccai (1952) concluded that the abnormality resided in peripheral sensory nerves. Heller and Robb (1955) described a French Canadian family in which 5 members had the full form of hereditary sensory neuropathy and 3 had an incomplete form, suggesting autosomal dominant inheritance. No amyloid was found on dorsal root ganglion biopsy. Heller and Robb (1955) suggested that the disease was the same as Morvan disease. The patient reported by Ogden et al. (1959) as having progressive sensory radicular neuropathy of Denny-Brown (HSAN1) may have had neurogenic acroosteolysis because symptoms began as early as 1 year and the parents were first cousins. Biemond (1955) described 11-year-old fraternal twins (male and female) with loss of pain sensation, diminished touch and temperature sense, and absent tendon reflexes. Postmortem examination showed deficient development in the posterior root ganglia, gasserian ganglion, posterior roots, posterior horns of the spinal gray matter, and posterior columns. The spinothalamic tracts could not be demonstrated. In a child with sensory and autonomic dysfunction, Freytag and Lindenberg (1967) found decreased posterior ascending tracts, severe reduction in the number of neurons in peripheral sensory and autonomic ganglia, and hypoplasia of the pyramidal tracts. Johnson and Spalding (1964) described a slowly progressive sensory neuropathy in 2 unrelated boys, aged 10 and 15 years, each of whom had consanguineous parents. The disorder began in early childhood and involved all modalities of sensation with no disturbance of motor or autonomic function. Involvement was predominantly distal with late involvement of the trunk, and resulted in loss of digits and Charcot joints at the ankles. Johnson and Spalding (1964) differentiated the disorder from congenital indifference to pain (147430, 243000) by the involvement of all sensory modalities, preservation of proximal sensation, including pain, loss of tendon reflexes, gradual progression, and peripheral nerve degeneration, and from autosomal dominant HSN1 by the recessive mode of inheritance, early age of onset, and ultimate involvement of the trunk. Haddow et al. (1970) described a brother and sister, offspring of nonconsanguineous parents, with a nonprogressive sensory defect leading to extensive damage of the fingers. The patients had low spinal fluid protein and had suffered from unexplained chronic diarrhea in early life. The mother was Irish and the father was French Canadian. Haddow et al. (1970) suggested that the disorder in the French Canadian family described by Hould and Verret (1967) was the same, although onset in that family was not until the middle of the first decade. Ohta et al. (1973) reported further on the family described by Hould and Verret (1967). They suggested that the families of Schoene et al. (1970), Ogryzlo (19 ... More on the omim web site
Jan. 22, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 201300 was added.