Hepatocyte deformation induced by cyanobacterial toxins reflects inhibition of protein phosphatases.
The cyclic peptide hepatotoxins microcystin-LR, 7-desmethyl-microcystin-RR and nodularin are potent inhibitors of the protein phosphatases type 1 and type 2A. Their potency of inhibition resembles calyculin-A and to a lesser extent okadaic acid. These hepatotoxins increase the overall level of protein phosphorylation in hepatocytes. Evidence is presented to indicate that in hepatocytes the morphological changes and effects on the cytoskeleton are due to phosphatase inhibition. The potency of these compounds in inducing hepatocyte deformation is similar to their potency in inhibiting phosphatase activity. These results suggest that the hepatotoxicity of these peptides is related to inhibition of phosphatases, and further indicate the importance of the protein phosphorylation in maintenance of structural and homeostatic integrity in these cells.
Eriksson
J E
JE
Dept. Biology, Abo Akademi Univ., Turku, Finland.
Toivola
D
D
Meriluoto
J A
JA
Karaki
H
H
Han
Y G
YG
Hartshorne
D
D
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins; D002645:Chickens; D000458:Cyanobacteria / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008387:Marine Toxins / Q000494:pharmacology*; D052998:Microcystins; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011506:Proteins / Q000494:pharmacology*; D000097847:Protein Phosphatase Inhibitory Proteins
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008387:Marine Toxins; D052998:Microcystins; D010456:Peptides, Cyclic; D010749:Phosphoprotein Phosphatases; D011506:Proteins; C021042:protein phosphatase inhibitor-1; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins; C063998:nodularin; C063855:microcystin RR; C057862:cyanoginosin LR