NDLI: On the substrate recognition and negative regulation of SPAK, a kinase modulating $Na^{+}-K^{+}-2Cl^{−}$ cotransport activity

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On the substrate recognition and negative regulation of SPAK, a kinase modulating $Na^{+}-K^{+}-2Cl^{−}$ cotransport activity

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Gagnon, Kenneth B. Delpire, Eric
Description	Country affiliation: United States Author Affiliation: Gagnon KB ( Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.)
Abstract	Threonines targeted by Ste20-related proline-alanine-rich kinase (SPAK) for phosphorylation have been identified in Na+-K+-2Cl(-) cotransporter type 1 (NKCC1), NKCC2, and Na+-Cl(-) cotransporter (NCC). However, what constitutes the substrate recognition of the kinase is still unknown. Using site-directed mutagenesis and functional measurement of NKCC1 activity in Xenopus laevis oocytes, we determined that SPAK recognizes two threonine residues separated by four amino acids. Addition or removal of a single residue abrogated SPAK activation of NKCC1. Although both threonines are followed by hydrophobic residues, in vivo experiments have determined that SPAK activation of the cotransporter only requires a hydrophobic residue after the first threonine. Interestingly, downstream of the second threonine residue, we have identified a conserved aspartic acid residue which is critical for NKCC1 function. Mouse SPAK activity requires phosphorylation of two specific residues by WNK [with no lysine (K)] kinases: a threonine (T243) in the catalytic domain and a serine (S383) in the regulatory domain. We found that mutating the threonine residue into a glutamic acid (T243E) combined with mutation of the serine into an aspartic acid (S383D) rendered SPAK constitutively active. Surprisingly, alanine substitution of S383 or mutation of residues surrounding this residue also resulted in a constitutively active kinase. Interestingly, deletion of amino acids 356-398 identified another serine residue in the catalytic domain (S321) as another putative target of WNK phosphorylation. We found that WNK4 is capable of stimulating the deletion mutant when S321 is present, but not when S321 is mutated into an alanine.
File Format	HTM / HTML
ISSN	03636143
e-ISSN	15221563
DOI	10.1152/ajpcell.00074.2010
Journal	American Journal of Physiology - Cell Physiology
Issue Number	3
Volume Number	299
Language	English
Publisher	American Physiological Society
Publisher Date	2010-09-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Cell Biology Protein-serine-threonine Kinases Physiology Sodium-potassium-chloride Symporters Metabolism Amino Acid Sequence Animals Hydrophobic And Hydrophilic Interactions In Vitro Techniques Mice Molecular Sequence Data Mutation Oocytes Phosphorylation Protein Structure, Tertiary Biosynthesis Genetics Solute Carrier Family 12, Member 2 Xenopus Laevis Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Cell Biology Physiology

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