Mol Cell Biol, May 1998, p. 2835-2844, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599
Received 24 November 1997/Returned for modification 7 January 1998/Accepted 17 February 1998
The Epstein-Barr virus latent membrane protein 1 (LMP1) oncoprotein
causes multiple cellular changes, including induction of epidermal
growth factor receptor (EGFR) expression and activation of the NF-
B
transcription factor. LMP1 and the cellular protein CD40, which also
induces EGFR expression, interact with the tumor necrosis factor
receptor-associated factor (TRAF) proteins. The LMP1 carboxy-terminal
activation region 1 signaling domain interacts specifically with the
TRAFs and is essential for EGFR induction through a mechanism
independent of NF-
B alone. LMP1 and CD40 share a common TRAF binding
motif, PXQXT. In this study, the PXQXT motifs in both LMP1 and CD40
were altered and mutant proteins were analyzed for induction of EGFR
expression. Replacement of the T residue with A in CD40 completely
blocked induction of the EGFR, while the same mutation in LMP1 did not
affect EGFR induction. Replacement of both P and Q residues with A's
in LMP1 reduced EGFR induction by >75%, while deletion of PXQXT
blocked EGFR induction. These results genetically link EGFR induction
by LMP1 to the TRAF signaling pathway. Overexpression of TRAF2 potently
activates NF-
B, although TRAF2 did not induce expression of the EGFR
either alone or in combination with TRAF1 and TRAF3. In vivo analyses of the interaction of the TRAFs with LMP1 variants mutated in the PXQXT
domain indicate that high-level induction of EGFR expression requires
interaction with TRAF1, -2, and -3. However, exogenous expression of
TRAF3 decreased EGFR induction mediated by either LMP1 or CD40. These
data suggest that TRAF-mediated activation of EGFR expression requires
assembly of a complex containing the appropriate stoichiometry of TRAF
proteins clustered at the cell membrane with LMP1.
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