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J Biol Chem, Vol. 274, Issue 34, 23858-23867, August 20, 1999
,
From the Howard Hughes Medical Institute, A critical component of vertebrate
cellular differentiation is the acquisition of sensitivity to a
restricted subset of peptide hormones and growth factors. This accounts
for the unique capability of insulin (and possibly insulin-like growth
factor-1), but not other growth factors, to stimulate glucose uptake
and anabolic metabolism in heart, skeletal muscle, and adipose tissue.
This selectivity is faithfully recapitulated in the cultured adipocyte line, 3T3-L1, which responds to insulin, but not platelet-derived growth factor (PDGF), with increased hexose uptake. The
serine/threonine protein kinases Akt1 and Akt2, which have been
implicated as mediators of insulin-stimulated glucose uptake, as well
as glycogen, lipid, and protein synthesis, were shown to mirror this
selectivity in this tissue culture system. This was particularly
apparent in 3T3-L1 adipocytes overexpressing an epitope-tagged form of
Akt2 in which insulin activated Akt2 10-fold better than PDGF.
Similarly, in 3T3-L1 adipocytes, only insulin stimulated
phosphorylation of Akt's endogenous substrate, GSK-3 Departments of Biology and Medicine, University of Pennsylvania
Medical School, Philadelphia, Pennsylvania 19104
. Other
signaling molecules, including phosphatidylinositol 3-kinase, pp70
S6-kinase, mitogen-activated protein kinase, and PHAS-1/4EBP-1, did not
demonstrate this selective responsiveness to insulin but were instead
activated comparably by both insulin and PDGF. Moreover, concurrent
treatment with PDGF and insulin did not diminish activation of
phosphatidylinositol 3-kinase, Akt, or glucose transport, indicating
that PDGF did not simultaneously activate an inhibitory mechanism.
Interestingly, PDGF and insulin comparably stimulated both Akt
isoforms, as well as numerous other signaling molecules, in
undifferentiated 3T3-L1 preadipocytes. Collectively, these data suggest
that differential activation of Akt in adipocytes may contribute to
insulin's exclusive mediation of the metabolic events involved in
glucose metabolism. Moreover, they suggest a novel mechanism by which
differentiation-dependent hormone selectivity is conferred
through the suppression of specific signaling pathways operational in
undifferentiated cell types.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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