Insulin-like growth factors (IGFs) are proteins that stimulate osteoblast activity. IGF-I is secreted by osteoblasts and so may function in an autocrine manner to regulate their function. Factors that affect the action or production of IGF-I are therefore likely to be important in the pathogenesis and treatment of bone diseases characterized by inactive osteoblast activity. IGF-binding proteins (IGFBPs) affect the function of osteoblast-like cells by modulating the binding of IGF-I with its surface receptor. IGFBP-5 is known to enhance IGF-I stimulation of osteoblast activity and in addition, to have independent effects on osteoblast function. This independent effect may be related to its ability to bind to a 420 kDa osteoblast membrane protein which becomes phosphorylated upon exposure to IGFBP-5. To further investigate the mechanisms in which IGFBP-5 controls osteoblast activity the current proposal will determine the identity of the IGFBP-5-receptor by expression cloning and by established purification and sequencing methods. Osteoblasts transfected with IGFBP-5-receptor constructs and IGFBP-5-receptor antibodies will be used to establish structure-function relationships between the receptor and its phosphorylating activities. Receptor phosphorylation will also be characterized by identifying phosphorylation binding sites and substrate specificities. Structural studies will be conducted to assess internalization and nuclear localization of IGFBP-5 and selected peptide substitutions of the putative nuclear localization sequence will be used to define minimum structural requirements for the nuclear transport of IGFBP-5. The results of these studies should define novel mechanisms in which IGFBP-5 stimulates osteoblast function and may suggest strategies to alter these processes in ways that enhance osteoblast activity and improve defective bone formation in osteoporosis.
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