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Vol. 273, Issue 1, 200-206, January 2, 1998
,,§
From the Departments of The most frequently found alteration of the
epidermal growth factor receptor (EGFR) in human tumors is a deletion
of exons 2-7. This receptor, termed EGFRvIII, can transform NIH 3T3
cells, and the frequent expression of this variant implies that it
confers a selective advantage upon tumor cells in vivo.
Although EGFRvIII is a constitutively activated tyrosine kinase, there
is no increase in Ras·GTP levels and low levels of mitogen-activated
protein kinase activity in NIH 3T3 cells expressing this variant. We
investigated whether phosphatidylinositol (PI) 3-kinase was an effector
in transformation by the EGFRvIII. High levels of PI 3-kinase activity were constitutively present in EGFRvIII-transformed cells and were
dependent upon the kinase activity of the receptor. While mitogen-activated protein kinase activity was quickly down-regulated to
basal levels after 12 h of continuous EGFR activation, there was a
3-fold increase in PI 3-kinase activity in cells expressing normal EGFR
and an 8-fold increase in cells expressing EGFRvIII after 48 h.
This increased activity may reflect enhanced binding to EGFRvIII and
the presence of novel PI 3-kinase isoforms. Treatment with the PI
3-kinase inhibitors wortmannin and LY294002 blocked both
anchorage-independent growth and growth in low serum media and also
resulted in morphological reversion of EGFRvIII-transformed cells.
These results support an essential role for PI 3-kinase in
transformation by this EGFR variant.
Microbiology and Immunology
and § Biochemistry and Molecular Pharmacology, Kimmel Cancer
Institute, Thomas Jefferson University, Philadelphia, Pennsylvania
19107 and the ¶ Division of Oncology, Seattle Veterans
Administration Medical Center, Seattle, Washington 98108
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