DEFECTIVE NITROVASODILATOR-STIMULATED PROTEIN-PHOSPHORYLATION AND CALCIUM REGULATION IN CGMP-DEPENDENT PROTEIN KINASE-DEFICIENT HUMAN PLATELETS OF CHRONIC MYELOCYTIC-LEUKEMIA
M. Eigenthaler et al., DEFECTIVE NITROVASODILATOR-STIMULATED PROTEIN-PHOSPHORYLATION AND CALCIUM REGULATION IN CGMP-DEPENDENT PROTEIN KINASE-DEFICIENT HUMAN PLATELETS OF CHRONIC MYELOCYTIC-LEUKEMIA, The Journal of biological chemistry, 268(18), 1993, pp. 3526-3531
The presence and functional role of the cyclic nucleotide signal trans
duction system was investigated in platelets from patients with myelop
roliferative disorders. Platelets from certain patients with chronic m
yelocytic leukemia showed decreased expression of cGMP-dependent prote
in kinase, and platelets from two such patients were studied in some d
etail. These platelets had very little if any cGMP-dependent protein k
inase but a normal level of cAMP-dependent protein kinase. They also c
ontained 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-m
ediated VASP phosphorylation. In contrast, sodium nitroprusside-stimul
ated VASP phosphorylation was severely impaired in these cGMP-dependen
t protein kinase-deficient platelets, despite an exaggerated cGMP resp
onse to sodium nitroprusside. Furthermore, whereas selective activatio
n of the cGMP-dependent protein kinase by 8-(4-chlorophenylthio)-cGMP
strongly inhibited the ADP- or thrombin-evoked calcium mobilization fr
om intracellular stores in normal platelets, this agonist-evoked calci
um response was not inhibited by the cGMP analog in cGMP-dependent pro
tein kinase-deficient platelets. The results demonstrate a defect in t
he nitrovasodilator-/cGMP-regulated signal transduction system in huma
n platelets from some patients with myeloproliferative disorders, and
underscore that a cGMP-dependent protein kinase regulatory system, dis
tinct from that of cAMP-dependent protein kinase or other cGMP-depende
nt effectors is operative in normal human platelets.