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Vol. 273, Issue 3, 1568-1573, January 16, 1998
From the Cell Growth Regulation Laboratory, Department of Clinical
Investigation, The University of Texas M. D. Anderson Cancer
Center, Houston, Texas 77030
Binding of extracellular ligands to
epidermal growth factor receptors (EGFR) activate signal transduction
pathways associated with cell proliferation, and these events are
inhibited by monoclonal antibodies against EGFR. Since efficient DNA
repair in actively growing cells may require growth factor signaling,
it was of interest to explore any linkage between EGFR-mediated
signaling and DNA-dependent protein kinase (DNA-PK), an
enzyme believed to be involved in repairing double strand breaks and
V(D)J recombination. We report that anti-EGFR monoclonal antibodies
(mAbs), and not EGFR ligands, trigger a specific early physical
interaction between EGFR and a 350-kDa catalytic subunit of DNA or its
regulatory heterodimeric complex Ku70/80, in a variety of cell types,
both in vivo and in vitro. Inhibition of EGFR
signaling by anti-EGFR mAb was accompanied by a reduction in the levels
of the DNA-PK and its activity in the nuclear fraction. Confocal
imaging revealed that a substantial amount of DNA-PK was co-localized
with EGFR in anti-EGFR mAb-treated cells. Anti-EGFR mAb-induced
physical interaction between EGFR and DNA-PK or Ku70/80 was dependent
on the presence of EGFR, but not on the levels of EGFR. The EGFR
associated with DNA-PK or Ku70/80 retains its intrinsic kinase
activity. Our findings demonstrate the existence of a novel cellular
pathway in mammalian cells that involves physical interactions between
EGFR and DNA-PK or Ku70/80 in response to inhibition of EGFR signaling.
Our present observations suggest a possible role of EGFR signaling in
maintenance of the nuclear levels of DNA-PK, and interference in EGFR
signaling may possibly result in the impairment of DNA repair activity
in the nuclei in anti-EGFR mAb-treated cells.
Physical Interaction between Epidermal Growth Factor Receptor and
DNA-dependent Protein Kinase in Mammalian Cells
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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