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J. Cell Biol.,
Volume 143, Number 5, November 30, 1998 1317-1328
* Division of Cell Biology and Immunology, Department of Pathology, University of Utah Medical School, Salt Lake City, Utah
84132; Autocrine EGF-receptor (EGFR) ligands
are normally made as membrane-anchored precursors
that are proteolytically processed to yield mature, soluble peptides. To explore the function of the membrane-anchoring domain of EGF, we expressed artificial EGF
genes either with or without this structure in human
mammary epithelial cells (HMEC). These cells require
activation of the EGFR for cell proliferation. We found
that HMEC expressing high levels of membrane-
anchored EGF grew at a maximal rate that was not increased by exogenous EGF, but could be inhibited by
anti-EGFR antibodies. In contrast, when cells expressed EGF lacking the membrane-anchoring domain
(sEGF), their proliferation rate, growth at clonal densities, and receptor substrate phosphorylation were not
affected by anti-EGFR antibodies. The sEGF was
found to be colocalized with the EGFR within small cytoplasmic vesicles. It thus appears that removal of the
membrane-anchoring domain converts autocrine to intracrine signaling. Significantly, sEGF inhibited the organization of HMEC on Matrigel, suggesting that spatial restriction of EGF access to its receptor is necessary
for organization. Our results indicate that an important
role of the membrane-anchoring domain of EGFR
ligands is to restrict the cellular compartments in which
the receptor is activated.
Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Burn Unit, Cambridge,
Massachusetts 02139; and § Division of Bioengineering & Environmental Health, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
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