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J. Biol. Chem., Vol. 276, Issue 49, 46079-46087, December 7, 2001
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From the Phosphatidylinositol (PI) 3-kinase is required
for insulin-stimulated translocation of GLUT4 to the surface of muscle
and fat cells. Recent evidence suggests that the full stimulation of
glucose uptake by insulin also requires activation of GLUT4, possibly
via a p38 mitogen-activated protein kinase (p38
MAPK)-dependent pathway. Here we used L6 myotubes
expressing Myc-tagged GLUT4 to examine at what level the signals
regulating GLUT4 translocation and activation bifurcate. We compared
the sensitivity of each process, as well as of signals leading to GLUT4
translocation (Akt and atypical protein kinase C) to PI 3-kinase
inhibition. Wortmannin inhibited insulin-stimulated glucose uptake with
an IC50 of 3 nM. In contrast, GLUT4myc
appearance at the cell surface was less sensitive to inhibition
(IC50 = 43 nM). This dissociation between
insulin-stimulated glucose uptake and GLUT4myc translocation was not
observed with LY294002 (IC50 = 8 and 10 µM,
respectively). The sensitivity of insulin-stimulated activation of
PKC
Differential Effects of Phosphatidylinositol 3-Kinase Inhibition
on Intracellular Signals Regulating GLUT4 Translocation and Glucose
Transport*
§¶,
,**,§§,§,¶¶,, and§
Programme in Cell Biology, Hospital for Sick
Children, Toronto, Ontario M5G 1X8, Canada, the § Department
of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8,
Canada, and the ¶¶ Institute of Medical Science, University
of Toronto, Toronto, Ontario M5S 1A8, Canada
/
, Akt1, Akt2, and Akt3 to wortmannin (IC50 = 24, 30, 35, and 60 nM, respectively) correlated closely with
inhibition of GLUT4 translocation. In contrast,
insulin-dependent p38 MAPK phosphorylation was efficiently reduced in cells pretreated with wortmannin, with an IC50
of 7 nM. Insulin-dependent p38
and p38
MAPK activities were also markedly reduced by wortmannin
(IC50 = 6 and 2 nM, respectively). LY294002 or
transient expression of a dominant inhibitory PI 3-kinase construct
(
p85), however, did not affect p38 MAPK phosphorylation. These
results uncover a striking correlation between PI 3-kinase, Akt,
PKC/, and GLUT4 translocation on one hand and their segregation from glucose uptake and p38 MAPK activation on the other, based on
their wortmannin sensitivity. We propose that a distinct, high affinity
target of wortmannin, other than PI 3-kinase, may be necessary for
activation of p38 MAPK and GLUT4 in response to insulin.
*
This work was supported by a grant from the Canadian
Diabetes Association of Canada (to A. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Visiting Scientist from the People's Republic of China,
supported by the Visiting Scientist Program at the Hospital for Sick Children.
**
Supported by a summer studentship from the Research Training
Institute at the Hospital for Sick Children.
Present address: Dept. of Biology, York University,
Toronto, Ontario M3J 1P3, Canada.
§§
Supported by a joint postdoctoral fellowship from the Banting and
Best Diabetes Center (University of Toronto) and Novo Nordisc Canada.
To whom correspondence should be addressed: Program in
Cell Biology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-6392; Fax: 416-813-5028; E-mail:
amira@sickkids.ca.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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