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(Received for publication, March 3, 1997, and in revised form, August 20, 1997)
,
From the Previous studies have demonstrated a requirement
for the nonreceptor tyrosine kinase, cellular Src (c-Src), in epidermal
growth factor (EGF)-induced mitogenesis and a synergistic interaction between c-Src and EGF receptor (EGFR) in tumorigenesis. Although endocytic internalization of EGFR may be thought to attenuate EGF-stimulated signaling, recent evidence suggests that signaling through Ras can be amplified by repeated encounters of
endosome-localized, receptor·Shc·Grb2·Sos complexes with the
plasma membrane, where Ras resides almost exclusively. Based on these
reports, we examined EGFR trafficking behavior in a set of single and
double c-Src/EGFR C3H10T1/2 overexpressors to determine if c-Src
affects basal receptor half-life, ligand-induced internalization,
and/or recycling. Our results show that overexpression of c-Src causes
no change in EGFR half-life but does produce an increase in the
internalization rate constant of EGF·EGFR complexes when the
endocytic apparatus is not stoichiometrically saturated; this effect of
c-Src on EGFR endocytosis is negligible at high receptor occupancy in
cells overexpressing the receptor. In neither case are EGFR
recycling rate constants affected by c-Src. These data indicate a
functional role for c-Src in receptor internalization, which in
turn could alter some aspects of EGFR signaling related to mitogenesis
and tumorigenesis.
Department of Chemical Engineering and
Center for Biomedical Engineering, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139 and § Department
of Microbiology and Cancer Center, University of Virginia Health
Sciences Center, Charlottesville, Virginia 22903
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