Defective nitrovasodilator-stimulated protein phosphorylation and calcium regulation in cGMP-dependent protein kinase-deficient human platelets of chronic myelocytic leukemia.
The presence and functional role of the cyclic nucleotide signal transduction system was investigated in platelets from patients with myeloproliferative disorders. Platelets from certain patients with chronic myelocytic leukemia showed decreased expression of cGMP-dependent protein kinase, and platelets from two such patients were studied in some detail. These platelets had very little if any cGMP-dependent protein kinase but a normal level of cAMP-dependent protein kinase. They also contained a normal level of VASP (vasodilator-stimulated phosphoprotein, a specific substrate of both cAMP- and cGMP-dependent protein kinase), as well as a functionally intact prostaglandin E1-stimulated cAMP-mediated VASP phosphorylation. In contrast, sodium nitroprusside-stimulated VASP phosphorylation was severely impaired in these cGMP-dependent protein kinase-deficient platelets, despite an exaggerated cGMP response to sodium nitroprusside. Furthermore, whereas selective activation of the cGMP-dependent protein kinase by 8-(4-chlorophenylthio)-cGMP strongly inhibited the ADP- or thrombin-evoked calcium mobilization from intracellular stores in normal platelets, this agonist-evoked calcium response was not inhibited by the cGMP analog in cGMP-dependent protein kinase-deficient platelets. The results demonstrate a defect in the nitrovasodilator-/cGMP-regulated signal transduction system in human platelets from some patients with myeloproliferative disorders, and underscore that a cGMP-dependent protein kinase regulatory system, distinct from that of cAMP-dependent protein kinase or other cGMP-dependent effectors is operative in normal human platelets.
Medizinische Universitätsklinik, Klinische Forschergruppe, Universität Würzburg, Federal Republic of Germany.
M
M
Eigenthaler
H
H
Ullrich
J
J
Geiger
K
K
Horstrup
P
P
Hönig-Liedl
D
D
Wiebecke
U
U
Walter
D001792:Blood Platelets / Q000201:enzymology*; D001798:Blood Proteins / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002384:Catalysis; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010750:Phosphoproteins / Q000097:blood*; D011494:Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D014664:Vasodilation
D001798:Blood Proteins; D010750:Phosphoproteins; D009599:Nitroprusside; D009569:Nitric Oxide; D011494:Protein Kinases; D006152:Cyclic GMP; D002118:Calcium