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Vol. 10, Issue 5, 1621-1636, May 1999
Department of Medicine, University of Ottawa, and Division of Tumor
Biology, Northeastern Ontario Regional Cancer Centre, Sudbury, Ontario
P3E 5J1, Canada
Epidermal growth factor (EGF) stimulates the homodimerization of
EGF receptor (EGFR) and the heterodimerization of EGFR and ErbB2. The
EGFR homodimers are quickly endocytosed after EGF stimulation as a
means of down-regulation. However, the results from experiments on the
ability of ErbB2 to undergo ligand-induced endocytosis are very
controversial. It is unclear how the EGFR-ErbB2 heterodimers might
behave. In this research, we showed by subcellular fractionation, immunoprecipitation, Western blotting, indirect immunofluorescence, and
microinjection that, in the four breast cancer cell lines MDA453,
SKBR3, BT474, and BT20, the EGFR-ErbB2 heterodimerization levels were
positively correlated with the ratio of ErbB2/EGFR expression levels.
ErbB2 was not endocytosed in response to EGF stimulation. Moreover, in
MDA453, SKBR3, and BT474 cells, which have very high levels of
EGFR-ErbB2 heterodimerization, EGF-induced EGFR endocytosis was
greatly inhibited compared with that in BT20 cells, which have a very
low level of EGFR-ErbB2 heterodimerization. Microinjection of an ErbB2
expression plasmid into BT20 cells significantly inhibited
EGF-stimulated EGFR endocytosis. Coexpression of ErbB2 with EGFR in
293T cells also significantly inhibited EGF-stimulated EGFR
endocytosis. EGF did not stimulate the endocytosis of ectopically
expressed ErbB2 in BT20 and 293T cells. These results indicate that
ErbB2 and the EGFR-ErbB2 heterodimers are impaired in EGF-induced
endocytosis. Moreover, when expressed in BT20 cells by microinjection,
a chimeric receptor composed of the ErbB2 extracellular domain and the
EGFR intracellular domain underwent normal endocytosis in response to
EGF, and this chimera did not block EGF-induced EGFR endocytosis. Thus,
the endocytosis deficiency of ErbB2 is due to the sequence of its
intracellular domain.
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