SIK1 is part of a cell sodium-sensing network that regulates active sodium transport through a calcium-dependent process.
In mammalian cells, active sodium transport and its derived functions (e.g., plasma membrane potential) are dictated by the activity of the Na(+),K(+)-ATPase (NK), whose regulation is essential for maintaining cell volume and composition, as well as other vital cell functions. Here we report the existence of a salt-inducible kinase-1 (SIK1) that associates constitutively with the NK regulatory complex and is responsible for increases in its catalytic activity following small elevations in intracellular sodium concentrations. Increases in intracellular sodium are paralleled by elevations in intracellular calcium through the reversible Na(+)/Ca(2+) exchanger, leading to the activation of SIK1 (Thr-322 phosphorylation) by a calcium calmodulin-dependent kinase. Activation of SIK1 results in the dephosphorylation of the NK alpha-subunit and an increase in its catalytic activity. A protein phosphatase 2A/phosphatase methylesterase-1 (PME-1) complex, which constitutively associates with the NK alpha-subunit, is activated by SIK1 through phosphorylation of PME-1 and its dissociation from the complex. These observations illustrate the existence of a distinct intracellular signaling network, with SIK1 at its core, which is triggered by a monovalent cation (Na(+)) and links sodium permeability to its active transport.
Sjöström
Mattias
M
Membrane Signaling Networks, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, S-171 76 Stockholm, Sweden.
Stenström
Karin
K
Eneling
Kristina
K
Zwiller
Jean
J
Katz
Adrian I
AI
Takemori
Hiroshi
H
Bertorello
Alejandro M
AM
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009893:Opossums; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D012964:Sodium / Q000378:metabolism* / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D021122:Protein Subunits; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium