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Transferrin Is an Insulin-Like Growth Factor-Binding Protein-3 Binding Protein¹

Children’s Hospital of Philadelphia (S.A.W.), University of Pennsylvania, Philadelphia, Pennsylvania 19104; Department of Pharmacology (T.B.G.), University of Texas, Southwestern Medical Center, Dallas, Texas 75235; Department of Pediatrics (P.F.C.-S.), Duke University, Durham, North Carolina 27710; Diagnostic Systems Laboratories, Inc. (A.K.), Webster, Texas 77598; and Mattel Children’s Hospital at UCLA (B.L., P.C.), University of California at Los Angeles, Los Angeles, California 90095-1752

Address all correspondence and requests for reprints to: Pinchas Cohen, M.D., Professor and Director of Research and Training, Division of Endocrinology, Department of Pediatrics, Mattel Children’s Hospital at UCLA, 10833 Le Conte Avenue, MDCC 22-315, Los Angeles, California 90095-1752. E-mail: hassy{at}mednet.ucla.edu

Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) possesses both growth-inhibitory and -potentiating effects on cells that are independent of IGF action and are mediated through specific IGFBP-3 binding proteins/receptors located at the cell membrane, cytosol, or nuclear compartments and in the extracellular matrix. We have here characterized transferrin (Tf) as one of these IGFBP-3 binding proteins. Human serum was fractionated over an IGFBP-3 affinity column, and a 70-kDa protein was eluted, sequenced, and identified (through database searching and Western immunoblot) as human Tf. Tf bound IGFBP-3 but had negligible affinity to the other five IGFBPs, and iron-saturated holo-Tf bound IGFBP-3 more avidly than unsaturated Tf. Biosensor interaction analysis confirmed that this interaction is specific and sensitive, with a high association rate similar to IGF-I, and suggested that binding occurs in the vicinity of the IGFBP-3 nuclear localization site. As an independent confirmation of this interaction, using a yeast two-hybrid system, we cloned Tf from a human liver complementary DNA library as an IGFBP-3 protein partner. Tf treatment blocked IGFBP-3-induced cell proliferation in bladder smooth muscle cells, and IGFBP-3-induced apoptosis in prostate cancer cells. In summary, we have employed a combination of techniques to demonstrate that Tf specifically binds IGFBP-3, and we showed that this interaction has important physiological effects on cellular events.

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