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J. Biol. Chem., Vol. 276, Issue 17, 13644-13649, April 27, 2001
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From the The receptor for the type 1 insulin-like
growth factor (IGF-I) has been implicated in cellular
transformation and the acquisition of an invasive/metastatic phenotype
in various tumors. Following ligand binding, the IGF-I receptor is
internalized, and the receptor·ligand complex dissociates as the
ligand is degraded by endosomal proteinases. In the present study we
show that the inhibition of endosomal IGF-I-degrading enzymes in human
breast and murine lung carcinoma cells by the cysteine proteinase
inhibitors, E-64 and CA074-methyl ester, profoundly altered receptor
trafficking and signaling. In treated cells, intracellular ligand
degradation was blocked, and although the receptor and two substrates,
Shc and Insulin receptor substrate, were hyperphosphorylated on
tyrosine, IGF-I-induced DNA synthesis, anchorage-independent growth,
and matrix metalloproteinase synthesis were inhibited. The results
suggest that ligand processing by endosomal proteinases is a key step
in receptor signaling and function and a potential target for therapy.
Inhibition of Endosomal Insulin-like Growth Factor-I
Processing by Cysteine Proteinase Inhibitors Blocks Receptor-mediated
Functions*
§,
,
Department of Surgery, McGill
University Health Center, Royal Victoria Hospital, Montreal, Quebec H3A
1A4, Canada, ¶ Department of Anatomy and Cell Biology, McGill
University, Montreal, Quebec H3A 2B2, Canada, and Faculté
de Pharmacie Paris XI, INSERM U510, 92296 Chatenay-Malabry, France
*
This study was supported mainly by a grant from the Medical
Research Council of Canada (to P. B.) and also by a grant from the
National Cancer Institute of Canada (to J. J. M. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Surgery,
McGill University Health Center, Royal Victoria Hospital, Rm. H6.25,
Montreal, Quebec H3A 1A4, Canada. Tel.: 514-842-1231 (ext. 6692); Fax:
514-843-1411; E-mail: pnina.brodt@muhc.mcgill.ca.
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