14-3-3 Proteins directly regulate Ca(2+)/calmodulin-dependent protein kinase kinase alpha through phosphorylation-dependent multisite binding.
Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaMKKalpha) plays critical roles in the modulation of neuronal cell survival as well as many other cellular activities. Here we show that 14-3-3 proteins directly regulate CaMKKalpha when the enzyme is phosphorylated by protein kinase A on either Ser74 or Ser475. Mutational analysis revealed that these two serines are both functional: the CaMKKalpha mutant with a mutation at either of these residues, but not the double mutant, was inhibited significantly by 14-3-3. The mode of regulation described herein differs the recently described mode of 14-3-3 regulation of CaMKKalpha.
Ichimura
Tohru
T
Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Tokyo, Japan. ichimura@nda.ac.jp
Taoka
Masato
M
Hozumi
Yasukazu
Y
Goto
Kaoru
K
Tokumitsu
Hiroshi
H
D048948:14-3-3 Proteins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D002384:Catalysis / Q000187:drug effects; D002417:Cattle; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013552:Swine
D048948:14-3-3 Proteins; D050505:Mutant Proteins; D010768:Phosphoserine; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase