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Vol. 273, Issue 1, 13-16, January 2, 1998
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,,,
From the Kimmel Cancer Institute and Cardeza Foundation for
Hematologic Research, Thomas Jefferson University, Philadelphia,
Pennsylvania 19107, the The aggregation of human platelets is an
important physiological hemostatic event contingent upon
receptor-dependent activation of the surface integrin
Department of Biochemistry,
University of Dundee, Dundee Scotland DD1 4HN, United Kingdom, and the
§ Division of Medicinal Chemistry and Pharmaceutics, The
University of Kentucky, Lexington, Kentucky 40536
IIb
3 and subsequent binding of
fibrinogen. Aggregating platelets form phosphatidylinositol
3,4-bisphosphate (PtdIns(3,4)P2), which has been reported
to stimulate in vitro the activity of the proto-oncogenic
protein kinase PKB/Akt, as has phosphatidylinositol 3,4,5-trisphosphate
(PtdIns(3,4,5)P3). It has been assumed that
PtdIns(3,4)P2 is synthesized by either 5-phosphatase-catalyzed hydrolysis of PtdIns(3,4,5)P3
produced by phosphoinositide 3-kinase (PI3K) or phosphorylation by PI3K of PtdIns4P. We investigated the route(s) by which
PtdIns(3,4)P2 is formed after directly activating
IIb3 with anti-ligand-induced binding
site Fab fragment and report that aggregation does not lead to the
generation of PtdIns(3,4,5)P3, but to transient formation of PtdIns3P and generation of PtdIns(3,4)P2, the latter
primarily by PtdIns3P 4-kinase. Both this novel pathway and the
activation of PKB/Akt are inhibited by the PI3K inhibitor, wortmannin,
and the calpain inhibitor, calpeptin, constituting the first evidence that PtdIns(3,4)P2 can stimulate PKB/Akt in
vivo in the absence of PtdIns(3,4,5)P3.
Integrin-activated generation of the second messenger
PtdIns(3,4)P2 thus depends upon a route distinct from that
known to be utilized initially by growth factors. This pathway is of
potential general relevance to the function of integrins.
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