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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3429-3434
Thrombopoietin potentiates collagen receptor signaling in
platelets through a phosphatidylinositol 3-kinase-dependent
pathway
Jean-max Pasquet,
Barbara S. Gross,
Marie-Pierre Gratacap,
Lynn Quek,
Sophie Pasquet,
Bernard Payrastre,
Gijsbert van Willigen,
Joanne C. Mountford, and
Steve P. Watson
From the Department of Pharmacology, University of Oxford, Oxford,
UK; the Department of Haematology (G03.647), University Hospital,
Utrecht, The Netherlands; and U326 INSERM, Hopital Purpan, Toulouse,
France.
Collagen activates platelets through a tyrosine kinase-dependent
pathway, involving phospholipase C 2. Functional responses such as
aggregation and secretion induced by collagen are potentiated by
preincubation with thrombopoietin (TPO). In this study, we show that
collagen and thrombopoietin activate the phosphatidylinositol 3-kinase
(PI 3-kinase) pathway and that this contributes to their respective
actions. The structurally distinct inhibitors of PI 3-kinase,
wortmannin, and LY294002, completely inhibit formation of
phosphatidylinositol 3,4,5-trisphosphate by collagen. This leads to a
substantial reduction in the formation of inositol phosphates and
phosphatidic acid, 2 indices of PLC activity, and the consequent
inhibition of intracellular Ca++
[Ca++]i, aggregation and secretion.
Potentiation of the collagen response by TPO is prevented in the
presence of wortmannin and LY294002. However, when the 2 PI 3-kinase
inhibitors are given after the addition of TPO but before the collagen,
recovery of potentiation is observed. This suggests that potentiation
is mediated through activation of PI 3-kinase. TPO stimulates
aggregation of platelets from a low percentage of donors and this is
also blocked by wortmannin. These results suggest that the PI 3-kinase
pathway plays an important role in signaling by collagen and in the
priming action of TPO.
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