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(Received for publication, December 10, 1996, and in revised form, January 30, 1997)
From the Although it has been well established that
constitutive activation of receptor tyrosine kinases leads to cellular
transformation, the signal relay pathways involved have not been
systematically investigated. In this study we used a panel of
platelet-derived growth factor (PDGF)
Volume 272, Number 14,
Issue of April 4, 1997
pp. 9011-9018
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
or
Phosphatidylinositol 3 Kinase
§
,§
Schepens Eye Research Institute, Harvard
Medical School, Boston, Massachusetts 02114, § University
of Colorado Health Sciences Center, Department of Pharmacology,
Denver, Colorado 80262, and ¶ Section of Virology and Oncology,
Division of Biology, Kansas State University,
Manhattan, Kansas 66506
receptor mutants (-PDGFR),
which selectively activate various signal relay enzymes to define which
signaling pathways are required for PDGF-dependent growth
of cells in soft agar. The host cell line for these studies was Ph
cells, a 3T3-like cell that expresses normal levels of the -PDGFR
but no PDGF-
receptor (-PDGFR). Hence, this cell system can be
used to study signaling of mutant PDGFRs or / chimeras. We
constructed chimeric receptors containing the PDGFR extracellular
domain and the PDGFR cytoplasmic domain harboring various
phosphorylation site mutations. The mutants were expressed in Ph cells,
and their ability to drive PDGF-dependent cellular
transformation (growth in soft agar) was assayed. Cells infected with
an empty expression vector failed to grow in soft agar, whereas
introduction of the chimera with a wild-type -PDGFR cytoplasmic
domain gave rise to a large number of colonies. In contrast, the
N2F5 chimera, in which the binding sites for
phospholipase C
(PLC-), RasGTPase-activating protein,
phosphatidylinositol 3 kinase (PI3K), and SHP-2 were eliminated, failed
to trigger proliferation. Restoring the binding sites for
RasGTPase-activating protein or SHP-2 did not rescue the
PDGF-dependent response. In contrast, receptors capable of associating
with either PLC- or PI3K relayed a growth signal that was comparable
to wild-type receptors in the soft agar growth assay. These findings
indicate that the PDGF receptor activates multiple signaling pathways
that lead to cellular transformation, and that either PI3K or PLC-
are key initiators of such signal relay cascades.
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