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J Biol Chem, Vol. 275, Issue 7, 5111-5119, February 18, 2000
From the Department of Pathology, Georgetown University Medical
Center, Washington, D. C. 20007
The E5 oncoprotein of bovine papillomavirus type
1 is a Golgi-resident, 44-amino acid polypeptide that can transform
fibroblast cell lines by activating endogenous platelet-derived growth
factor receptor
E5 Oncoprotein Mutants Activate Phosphoinositide 3-Kinase
Independently of Platelet-derived Growth Factor Receptor
Activation*
,
(PDGF-R). However, the recent discovery of E5
mutants that exhibit strong transforming activity but minimal PDGF-R
tyrosine phosphorylation indicates that E5 can potentially use
additional signal transduction pathway(s) to transform cells. We now
show that two classes of E5 mutants, despite poorly activating the PDGF-R, induce tyrosine phosphorylation and activation of
phosphoinositide 3-kinase (PI 3-K) and that this activation is
resistant to a selective inhibitor of PDGF-R kinase activity,
tyrphostin AG1296. Consistent with this independence from PDGF-R
signaling, the E5 mutants fail to induce significant cell proliferation
in the absence of PDGF, unlike wild-type E5 or the sis
oncoprotein. Despite differences in growth factor requirements,
however, both wild-type E5 and mutant E5 cell lines form colonies in
agarose. Interestingly, activation of PI 3-K occurs without concomitant
activation of the ras-dependent
mitogen-activated protein kinase pathway. The known ability of
constitutively activated PI 3-K to induce anchorage-independent cell
proliferation suggests a mechanism by which the mutant E5 proteins
transform cells.
*
Support for this project was provided by National Institutes
of Health Grant RO1CA53371 (NCI) (to R. S.).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.
This author made significant contributions to this study.
§
To whom correspondence should be addressed: Dept. of Pathology,
Georgetown University Medical Center, 3900 Reservoir Rd., NW,
Washington, DC 20007. Tel.: 202-687-1704; Fax: 202-687-8934; E-mail:
schleger@gusun.georgetown.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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