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J Biol Chem, Vol. 273, Issue 19, 11937-11943, May 8, 1998
From the Akt is a serine/threonine kinase that requires a
functional phosphatidylinositol 3-kinase to be stimulated by insulin
and other growth factors. When directed to membranes by the addition of
a src myristoylation sequence, Akt becomes constitutively
active. In the present study, a conditionally active version of Akt was constructed by fusing the Akt containing the myristoylation sequence to
the hormone binding domain of a mutant murine estrogen receptor that
selectively binds 4-hydroxytamoxifen. The chimeric protein was
expressed in NIH3T3 cells and was shown to be stimulated by hormone
treatment 17-fold after only a 20-min treatment. This hormone treatment
also stimulated an approximate 3-fold increase in the phosphorylation
of the chimeric protein and a shift in its migration on SDS gels.
Activation of this conditionally active Akt resulted in the rapid
stimulation of the 70-kDa S6 kinase. This conditionally active Akt was
also found to rapidly stimulate in these cells the phosphorylation of
properties of PHAS-I, a key protein in the regulation of protein
synthesis. The conditionally active Akt, when expressed in 3T3-L1
adipocytes, was also stimulated, although its rate and extent of
activation was less then in the NIH3T3 cells. Its stimulation was shown
to be capable of inducing glucose uptake into adipocytes by stimulating
translocation of the insulin-responsive glucose transporter GLUT4 to
the plasma membrane.
Construction and Characterization of a Conditionally Active
Version of the Serine/Threonine Kinase Akt
,,,,,
Department of Molecular Pharmacology,
Stanford University School of Medicine, Stanford, California 94305, the § Howard Hughes Medical Institute, University of
Pennsylvania School of Medicine, Clinical Research Building,
Philadelphia, Pennsylvania 19104-6148, and the ¶ Department of
Pharmacology, University of Virginia School of Medicine,
Charlottesville, Virginia 22908
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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