Modulation of ceramide-activated protein phosphatase 2A activity by low molecular weight aromatic compounds.
Protein phosphatase 2A (PP2A) is one of the most important and abundant serine/threonine phosphatases in mammalian tissues and plays a role in gene expression, cell division, and signal transduction. PP2A is activated by ceramide, which is produced by the hydrolysis of membrane sphingomyelin in response to a variety of stress-related stimuli. To further study the role of ceramide-mediated signal transduction in cellular processes such as senescence and apoptosis, we designed and synthesized a series of low molecular weight aromatic compounds, mainly of the isoquinolone and tetralone classes, and evaluated their ability to inhibit enzymes known to be activated by ceramide. Those enzymes studied were ceramide-activated protein kinase, protein kinase C zeta and PP2A. Of these, only PP2A was found to be inhibited. A few of the compounds inhibited both ceramide-activated as well as basal PP2A activity. In addition, several of the compounds activated PP2A by up to 300% above basal enzyme activity, but only in the presence of ceramide. Thus, modulation (both inhibition and activation) of the catatylic activity of ceramide-activated PP2A is demonstrated by certain low molecular weight aromatic compounds.
Leoni
L M
LM
The Sam and Rose Stein Institute for Research on Aging, and the Department of Medicine, University of California San Diego, La Jolla 92093-0663, USA.
Shih
H C
HC
Deng
L
L
Tuey
C
C
Walter
G
G
Carson
D A
DA
Cottam
H B
HB
D015153:Blotting, Western; D002518:Ceramides / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry / Q000494:pharmacology*; D019169:Jurkat Cells; D007700:Kinetics; D008970:Molecular Weight; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D014407:Tumor Cells, Cultured
D002518:Ceramides; D006838:Hydrocarbons; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2