Regulation of insulin-like growth factor-I (IGF-I) delivery by IGF binding proteins and receptors.
Delivery of growth factors via the bloodstream for the treatment of various diseases is regulated in part by interactions with cell surface binding elements. Understanding the kinetics of growth factor binding and transport by cells would, therefore, be advantageous. This report quantifies the binding, internalization, and transport of insulin-like growth factor-I (IGF-I) across bovine aortic endothelial cells (BAEC) cultured in vitro. Binding analysis indicated that IGF binding proteins (IGFBPs), primarily localized with the extracellular matrix, were the primary IGF-I binding elements in our system, with twice as many binding sites (8.0 +/- 1.9 x 10(4) per cell) as IGF-I receptors (IGF-IR) (3.9 +/- 0.6 x 10(4) per cell). Internalization of IGF-I by IGF-IR, but not IGFBPs, was detected, however both receptor and IGFBP binding were shown to inhibit rather than enhance the transport of intact IGF-I, albeit in different ways. IGFBPs retained IGF-I in the apical region while IGF-IR binding led to protein degradation. Based on our computational modeling and experimental data, we hypothesize that IGFBPs could function as a reservoir for IGF-I, sequestering it for later release and transport, and that this reservoir function of the IGFBPs could be used to promote controlled localized delivery of IGF-I.
Department of Chemical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA. kfw@vt.edu
Julie M D
JM
Paye
Kimberly
K
Forsten-Williams
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D004705:Endocytosis; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000627:therapeutic use; D021381:Protein Transport; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1