title: Plasma distribution and signaling activities of IGF-II precursors.
abstract: 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, we determined the distribution of IGF-II isoforms in normal human plasma 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.
authors.affiliation: Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Alicia G
authors.initials: AG
authors.lastname: Marks
authors.forename: Julie M
authors.initials: JM
authors.lastname: Carroll
authors.forename: Jonathan Q
authors.initials: JQ
authors.lastname: Purnell
authors.forename: Charles T
authors.initials: CT
authors.lastname: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D000882:Haplorhini; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D016400:Lymphoma, Large-Cell, Immunoblastic; D008297:Male; D051379:Mice; D008875:Middle Aged; D020033:Protein Isoforms; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D055815:Young Adult
chemical_list: D020033:Protein Isoforms; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1