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.
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.
Karas
M
M
Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center of Kupat Holim, Beer-Sheva 84105, Israel.
Danilenko
M
M
Fishman
D
D
LeRoith
D
D
Levy
J
J
Sharoni
Y
Y
D016475:3T3 Cells; D000818:Animals; D016889:Endometrial Neoplasms / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D018972:Insulin-Like Growth Factor Binding Protein 3; D008565:Membrane Proteins; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1