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J Biol Chem, Vol. 273, Issue 45, 29600-29606, November 6, 1998
,,,
From Involvement of the pleckstrin homology (PH)
domain in the insulin-stimulated activation of protein kinase B (PKB)
was investigated in human embryonic kidney 293 cells. Different PKB
constructs that contain mutations or deletions in the PH domain were
transfected into cells, and the results on the basal and
insulin-induced kinase activities were analyzed. Deletion of the entire
PH domain ( INSERM U 145, Faculté de Médecine,
Avenue de Valombrose, 06107 Nice Cédex 2, France and the
¶ Friedrich Miescher Institute, CH 4002 Basel, Switzerland
PH-PKB) did not impair the kinase activity; in contrast,
the basal activity was elevated with respect to wild-type PKB. In
addition, PH-PKB was responsive to insulin, and as for wild-type
PKB, this was dependent on phosphoinositide 3-kinase. By contrast, a
point mutation within the PH domain that impairs phospholipid binding
(R25C) resulted in a construct that was not responsive to insulin.
However, this defect was overcome by mutations that mimic the
phosphorylation state of the active kinase. The increase in the basal
activity of PH-PKB was shown to be due to an elevation in the level
of phosphorylation of this construct. In addition, the subcellular localization of PH-PKB, as determined by both immunofluorescence and
fractionation, was predominately cytosolic, and PH-PKB was present
in the plasma membrane at much lower levels compared with wild-type
PKB. These data show that phosphorylation is the major factor
regulating the activity of PKB and that either removal of the PH domain
or binding of phospholipids is required to permit this phosphorylation.
In addition, membrane localization does not appear to be required for
the activation process, but instead, binding of PKB to membrane
phospholipids permits a conformational change in the molecule that
allows for phosphorylation.
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