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First published online October 8, 2008
doi: 10.1242/10.1242/jcs.029223

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The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway

MRC Protein Phosphorylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK

Dario R. Alessi

MRC Protein Phosphorylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK

View larger version (66K): [in this window] [in a new window]   Fig. 1. Domain structure and covalent modifications of human WNK protein kinases. Phosphorylation sites that were identified on endogenous WNK1 isolated from control cells or sorbitol-stimulated cells (Zagorska et al., 2007) are highlighted in green and red, respectively. Further phosphorylation sites are in black and are reported on the PhosphoSitePlus website (http://www.phosphosite.org); the location of additional exons within the neuronal WNK1 splice variants is indicated. In addition, the neuronal isoforms are predicted to lack some of the N-terminal non-catalytic residues. Furthermore, the WNK1 variant that is found in brain and spinal cord reportedly lacks exons 11-12, whereas the variant found in the dorsal root ganglia and sciatic nerve cells lacks exon 11 (Shekarabi et al., 2008). Sequence alignment of the acidic segment of WNK isoforms is illustrated and reported PHAII-associated mutations of WNK4 are highlighted (E562K, D564A, Q565E, R1185C). The positions of domains and residues are drawn approximately to scale in each figure.

View larger version (83K): [in this window] [in a new window]   Fig. 2. (A) Domain structure and covalent modifications of human SPAK and OSR1 protein kinases. Residues on SPAK and OSR1 that are phosphorylated by WNK1 and WNK4 are highlighted in red. Further phosphorylation sites are in black and are reported on the PhosphoSitePlus website (http://www.phosphosite.org). (B) Crystal structure of the CCT domain of OSR1 in complex with a WNK4-derived RFxV-containing peptide. (Left panel) Sequence conservation of the protein surface of the CCT domain of OSR1 in orthologues from C. elegans to human. Grey represents non-conserved residues and red represents identical residues. The location of the primary pocket, in which the RFxV motif (peptide stick representation with yellow carbon atoms) is bound, and the surface-exposed secondary groove (of unknown function) are labelled. (Right panel) Molecular interactions of the CCT domain of OSR1 (-helices are in red and β-strands in blue) and the WNK4-derived RFQV-containing peptide. The RFQV motif (residues 1016-1019) and residue Thr1020 are labelled. The arrow indicates that phosphorylation of Thr1020 would cause a steric clash with the backbone of the CCT domain, which could inhibit binding of the RFQV motif. Note that Thr1020 is equivalent to the residue termed Thr1008 in the original structural study (Villa et al., 2007), which was wrongly numbered.

View larger version (83K): [in this window] [in a new window]   Fig. 3. (A) Domain structure and covalent modifications of the human SLC12 co-transporters NKCC1, NKCC2 and NCC. (B) Sequence alignment of the N-terminal region of NCC, NKCC1 and NKCC2, which is regulated by phosphorylation. Identical residues are highlighted in black and similar residues are in grey. Numbering above symbols indicates residue number on human NCC. h, human; m, mouse; s, shark.

View larger version (43K): [in this window] [in a new window]   Fig. 4. Proposed mechanism by which the WNK-SPAK/OSR1 signalling pathway regulates salt re-absorption and blood pressure. Although there is clear evidence that WNK1 activates NCC via SPAK and OSR1, further work is required to determine whether other WNK isoforms regulate ion co-transporters through SPAK and OSR1. It should also be noted that most studies that employ overexpression systems have reported that WNK4 negatively regulates NCC. Whether this inhibitory effect is mediated through SPAK or OSR1 has not been studied.

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