title: Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals.
abstract: The Ste20 family protein kinases oxidative stress-responsive 1 (OSR1) and the STE20/SPS1-related proline-, alanine-rich kinase directly regulate the solute carrier 12 family of cation-chloride cotransporters and thereby modulate a range of processes including cell volume homeostasis, blood pressure, hearing, and kidney function. OSR1 and STE20/SPS1-related proline-, alanine-rich kinase are activated by with no lysine [K] protein kinases that phosphorylate the essential activation loop regulatory site on these kinases. We found that inhibition of phosphoinositide 3-kinase (PI3K) reduced OSR1 activation by osmotic stress. Inhibition of the PI3K target pathway, the mammalian target of rapamycin complex 2 (mTORC2), by depletion of Sin1, one of its components, decreased activation of OSR1 by sorbitol and reduced activity of the OSR1 substrate, the sodium, potassium, two chloride cotransporter, in HeLa cells. OSR1 activity was also reduced with a pharmacological inhibitor of mTOR. mTORC2 phosphorylated OSR1 on S339 in vitro, and mutation of this residue eliminated OSR1 phosphorylation by mTORC2. Thus, we identify a previously unrecognized connection of the PI3K pathway through mTORC2 to a Ste20 protein kinase and ion homeostasis.
authors.affiliation: Departments of Pharmacology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041.
authors.forename: Samarpita
authors.initials: S
authors.lastname: Sengupta
authors.forename: Andrés
authors.initials: A
authors.lastname: Lorente-Rodríguez
authors.forename: Svetlana
authors.initials: S
authors.lastname: Earnest
authors.forename: Steve
authors.initials: S
authors.lastname: Stippec
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Guo
authors.forename: David C
authors.initials: DC
authors.lastname: Trudgian
authors.forename: Hamid
authors.initials: H
authors.lastname: Mirzaei
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Cobb
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency; D000704:Analysis of Variance; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D009997:Osmotic Pressure / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D013012:Sorbitol; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C493277:MAPKAP1 protein, human; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes; D009841:Oligonucleotides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D028021:Sodium-Potassium-Chloride Symporters; D013012:Sorbitol; C118135:OXSR1 protein, human; D000076225:Mechanistic Target of Rapamycin Complex 2; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human; D058570:TOR Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human
keywords: Akt; WNK1; ion transport; phosphoregulation