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Journal of Virology, April 2000, p. 3037-3045, Vol. 74, No. 7
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Erythroid Cells Rendered Erythropoietin Independent by Infection
with Friend Spleen Focus-Forming Virus Show Constitutive Activation of
Phosphatidylinositol 3-Kinase and Akt Kinase: Involvement of
Insulin Receptor Substrate-Related Adapter Proteins
Kazuo
Nishigaki,1
Charlotte
Hanson,2
Takashi
Ohashi,3
Delores
Thompson,1
Karen
Muszynski,2 and
Sandra
Ruscetti1,*
Basic Research
Laboratory1 and
SAIC-Frederick,2 Frederick Cancer
Research and Development Center, National Cancer Institute, Frederick,
Maryland, and Tokyo Medical and Dental University, Tokyo,
Japan3
Received 26 October 1999/Accepted 4 January 2000
The erythroleukemia-inducing Friend spleen focus-forming virus
(SFFV) encodes a unique envelope glycoprotein which allows erythroid
cells to proliferate and differentiate in the absence of erythropoietin
(Epo). In an effort to understand how SFFV causes Epo independence, we
have been examining erythroid cells rendered factor independent by SFFV
infection for constitutive activation of signal-transducing molecules.
Previous studies from our laboratory showed that various
signal-transducing molecules known to be activated by Epo, including
Stat proteins and components of the Raf-1/MAP kinase pathway, are
constitutively activated in SFFV-infected erythroid cells in the
absence of Epo. Since another signal transduction pathway involving
activation of phosphatidylinositol 3-kinase (PI 3-kinase) after Epo
stimulation plays an important role in erythroid cell proliferation and
differentiation, we carried out studies to determine if this pathway
was also activated in SFFV-infected cells in the absence of Epo. Our
studies show that PI 3-kinase is constitutively activated in erythroid
cells rendered factor independent by infection with SFFV and that PI
3-kinase activity, but not Epo receptor tyrosine phosphorylation, is
required for the proliferation of these cells in the absence of Epo. We
further show that in SFFV-infected erythroid cells grown in the absence of Epo, PI 3-kinase associates with the insulin receptor substrate (IRS)-related adapter molecules IRS-2, Gab1, and Gab2, which are constitutively tyrosine phosphorylated in SFFV-infected cells. Finally,
Akt, a protein kinase that is one of the downstream effectors of PI
3-kinase, and SHIP, a lipid phosphatase that is important for Akt
activation through PI 3-kinase, are both tyrosine phosphorylated in
SFFV-infected cells grown in the absence of Epo. Our results indicate
that induction of Epo independence by SFFV requires the activation of
PI 3-kinase and suggest that constitutive activation of this kinase in
SFFV-infected cells may occur primarily through interaction of PI
3-kinase with constitutively phosphorylated IRS-related adapter molecules.
*
Corresponding author. Mailing address: Basic Research
Laboratory, Bldg. 469, Room 205, NCI-FCRDC, Frederick, MD 21702-1201. Phone: (301) 846-5740. Fax: (301) 846-6164. E-mail:
ruscetti{at}ncifcrf.gov.
Journal of Virology, April 2000, p. 3037-3045, Vol. 74, No. 7
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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