The protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation and increases sarcoplasmic/endoplasmic reticulum calcium ATPase 2 levels.
The ubiquitously expressed protein glycogen synthase kinase-3 (GSK3) is constitutively active, however its activity is markedly diminished following phosphorylation of Ser21 of GSK3alpha and Ser9 of GSK3beta. Although several kinases are known to phosphorylate Ser21/9 of GSK3, for example Akt, relatively much less is known about the mechanisms that cause the dephosphorylation of GSK3 at Ser21/9. In the present study KCl-induced plasma membrane depolarization of SH-SY5Y cells, which increases intracellular calcium concentrations caused a transient decrease in the phosphorylation of Akt at Thr308 and Ser473, and GSK3 at Ser21/9. Overexpression of the selective protein phosphatase-1 inhibitor protein, inhibitor-2, increased basal GSK3 phosphorylation at Ser21/9 and significantly blocked the KCl-induced dephosphorylation of GSK3beta, but not GSK3alpha. The phosphorylation of Akt was not affected by the overexpression of inhibitor-2. GSK3 activity is known to affect sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) levels. Overexpression of inhibitor-2 or treatment of cells with the GSK3 inhibitors lithium and SB216763 increased the levels of SERCA2. These results indicate that the protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation induced by KCl and that GSK3 activity regulates SERCA2 levels.
King
Taj D
TD
Department of Psychiatry and Behavioral Neurobiology, Sparks Center 1009, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
Gandy
Johanna C
JC
Bijur
Gautam N
GN
D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free; D004721:Endoplasmic Reticulum / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000378:metabolism; D008094:Lithium / Q000378:metabolism; D008301:Maleimides / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D011189:Potassium Chloride / Q000378:metabolism; D054645:Protein Phosphatase 1; D011506:Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D000097847:Protein Phosphatase Inhibitory Proteins
D002118:Calcium; D016895:Culture Media, Serum-Free; D038362:Glycogen Synthase Kinase 3; D007211:Indoles; D008094:Lithium; D008301:Maleimides; D046912:Multiprotein Complexes; D010749:Phosphoprotein Phosphatases; D011189:Potassium Chloride; D054645:Protein Phosphatase 1; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D012694:Serine; C417521:SB 216763; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins; C506946:ATP2A2 protein, human