IGF-II is thought to function through activation of the IGF-I receptor (IGF-IR) and the A isoform of the IR, with the IGF-IR being relevant to tumorigenesis and the IR to both tumorigenesis and metabolic control. In the paraneoplastic syndrome of nonislet cell tumor hypoglycemia, tumor-derived IGF-II has been proposed to exert both proliferative and metabolic effects, exemplifying this dual mode of action. Increased levels of IGF-II precursors ("big" and pro-IGF-II) have been reported in the circulation of nonislet cell tumor patients and have been proposed to exert greater or different effects than mature IGF-II. However, most studies have not defined which version is being investigated, and the relative activation of the IR and IGF-IR by IGF-II precursors has not been delineated. In this study,wedetermined the distribution of IGF-II isoforms in normalhumanplasma and their ability to activate the alternative versions of the IR. The majority (71%) of total IGF-II in human plasma was the mature form, while "big" and pro-IGF-II comprised 16% and 13%, respectively, with more variation seen in the levels of mature IGF-II. In IGF-IR- deficient cells expressing similar levels of human IR-A or IR-B, mature and "big" IGF-II exhibited similar activation of IR signaling, while pro-IGF-II exhibited significantly less activation. Downstream activation of Akt by mature and "big" IGF-II was greater in IR-A cells, consistent with previous reports of the greater affinity of IR-A for IGF-II. Thus, both IGF-II precursor forms are present in human plasma but do not preferentially activate the IR.
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