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Volume 272, Number 26, Issue of June 27, 1997 pp. 16514-16520
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Membrane-associated Insulin-like Growth Factor-binding Protein-3 Inhibits Insulin-like Growth Factor-I-induced Insulin-like Growth Factor-I Receptor Signaling in Ishikawa Endometrial Cancer Cells

(Received for publication, December 3, 1996, and in revised form, April 18, 1997)

Michael Karas , Michael Danilenko , Daniel Fishman , Derek LeRoith ^§ , Joseph Levy and Yoav Sharoni

From the Departments of Clinical Biochemistry and  Immunology and Microbiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center of Kupat Holim, Beer-Sheva 84105, Israel and the ^§ Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892

The function of cell surface-associated insulin-like growth factor-binding proteins (IGFBPs) is controversial. Both inhibition and facilitation of IGF action as well as IGF-independent effects have been reported. We examined the influence of endogenous cell surface-associated IGFBPs on IGF-I receptor (IGF-IR) function in Ishikawa endometrial cancer cells by comparing the effects of IGF-I and its truncated analog des-(1-3)-IGF-I on several components of the IGF-IR signal transduction pathway in the absence of significant amounts of soluble IGFBPs. IGF-I and des-(1-3)-IGF-I are known to have similar affinities for IGF-IR, although the affinity of des-(1-3)-IGF-I for IGFBPs is greatly reduced. Here we show that the two ligands were equipotent not only in IGF-IR binding but also in receptor activation in NIH 3T3 cells overexpressing IGF-IR and possessing a relatively small number of cell surface-associated IGFBPs. In contrast, des-(1-3)-IGF-I manifested a remarkably higher potency as compared with IGF-I in inducing short and middle term cellular responses in IGF-IR-transfected Ishikawa endometrial cancer cells possessing a high number of both the receptor and the cell membrane-bound IGFBP-3. Thus, this difference in the effects of IGF-I and des-(1-3)-IGF-I can be attributed to the attenuation of IGF-I-mediated IGF-IR signaling by membrane-bound IGFBP-3.

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