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(Received for publication, January 28, 1997)
From the Division of Cell Biology, La Jolla Institute for Allergy
and Immunology, San Diego, California 92121
Phosphatidylinositol 3-kinase (PI3-K) has been
implicated in the regulation of cell proliferation in many cell types.
We have previously shown that in T cells the PI3-K inhibitor,
wortmannin, interferes with activation of the mitogen-activated kinase,
Erk2, after T cell receptor (TcR) stimulation. To further explore the involvement of PI3-K in T cell activation, we created a set of potentially dominant negative PI3-K constructs comprising individual or
tandem domains of the regulatory p85 subunit and tested their effect on
downstream signaling events like Erk2 activation and transcription from
an NFAT (nuclear factor of
activated T cells) element taken from the
interleukin-2 promoter. Following TcR stimulation, activation of Erk2
was only inhibited by a previously described truncated form of p85 that
cannot bind the catalytic subunit, but not by other constructs of p85.
In contrast, several mutant p85 alleles had dramatic effects on NFAT
activation. Most interestingly, the N-terminal SH2 domain had an
inhibitory effect, whereas a mutant p85 containing only the two SH2
domains enhanced basal NFAT activity in a Ras-dependent
manner. Ionomycin induced synergistic activation of NFAT in cells
expressing p85 mutants that contained the C-terminal SH2 domain.
Analysis of phosphotyrosine-containing proteins bound to truncated p85
constructs revealed cooperative binding of the two SH2 domains but no
apparent differences between the N- and C-terminal SH2 domains.
Wortmannin did not interfere with NFAT activation, although it
inhibited PI3-K and Erk2 activation in the same experiment. These
results suggest that PI3-K is involved in NFAT activation through a
complex adaptor function of its regulatory subunit and that its lipid
kinase activity is dispensable for this effect.
Volume 272, Number 22,
Issue of May 30, 1997
pp. 14483-14488
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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