Insulin-like growth factor-(IGF)-II is a major paracrine and autocrine acting peptide related to IGF-I and (pro) insulin that is especially involved in prenatal growth and development. IGF-II also serves as a second signal for oncogene-induced tumorgenesis. IGF-II inhibits apoptosis in various cell types and stimulates cell proliferation. IGF-II actions are mediated through the IGF-I receptor, the insulin receptor, and presumably another yet uncharacterized receptor. In addition, IGF-II also binds to the IGF-II/mannose-6-phosphate receptor. This receptor both mediates the targeting of mannose-6-phosphate containing lysosomal enzymes to the lysosome, and the endocytosis of IGF-II, resuling in its delivery to the lysosome and subsequent degradation. The gene for human insulin-like growth factor-II (IGF-II) consists of nine exons with four promoters and its expression is tissue specific and developmentally regulated, which leads to multiple transcripts that all encode the same monomeric IGF-II precursor. The IGF-II gene is only paternally expressed in most human tissues except for the liver and the central nervous system. The primary IGF-II translation product (pre-pro-IGF-II) contains 180 amino acids, including a N-terminal signal peptide of 24 amino acid residues, the 67 amino acids long mature IGF-II (7.5 kDa), and an 89 residue extension at the C-terminus . The latter has been designated the E-domain. Post-translational processing of pre-pro-IGF-II involves removal of the N-terminal leader sequence, addition of sialic acid containing O-linked oligosaccharides on Thr 75 (and possibly other sites) of the E-domain, followed by sequential proteolytic cleavage of the latter extension to the mature protein.
Many tumors highly express the IGF-II gene compared to normal tissue. Over-expression of IGF-II in tumors has been attributed to loss of imprinting and mutations in tumor suppressor genes. It seems likely that many neoplastic cells are not capable of adequate processing of the relatively high amounts of pro-IGF-II produced. The syndrome of non-islet cell tumor induced hypoglycemia (NICTH) may represent extreme cases of excessive production of high Mr IGF-II, often by a large tumor. Sera of these patients specifically contain relatively high levels of differently glycosylated tumor-derived pro-IGF-IIE [68-88] associated with considerably enhanced direct insulin action on various tissues, ultimately leading to episodes of hypoglycemia. So far we diagnosed more than 20 cases of NICTH. We obtained evidence that especially patients with a gastrointestinal tumor have a high risk of developing NICTH.
Recently, a 34-amino acid peptide, corresponding to a fragment of pro-IGF-IIE, Asp69-Leu102 (i.e. E [69-102] and termed preptin) was isolated from secretory granules from cultured murine beta-TC6-F7 beta-cells. Preptin is also present in beta cells of isolated rat islets and undergoes glucose-mediated co-secretion with insulin. Synthetic preptin, but not synthetic E [69-84], increases insulin secretion from glucose-stimulated beta-TC6-F7 cells, while its infusion into isolated, perfused rat pancreas increases the second phase of glucose-mediated insulin secretion markedly. These findings strongly suggest that this fragment of the E-domain of pro-IGF-II exhibits intrinsic biological activity and represents a physiological amplifier of glucose-mediated insulin secretion. The potential benefit of pro-IGF-IIE [68-88] and preptin, i.e. with respect to the preservation of beta cell function and hence an improvement of glucose homeostasis has not been explored in animal models of insulin resistance or type 2 diabetes.
Thus, although the literature is scarce on this subject and the underlying mechanisms unknown, there appear to be differences in biological activities between the mature 7.5 kD IGF-II, E-extension containing pro-IGF-II forms, and fragments of the E-domain, respectively. Therefore, it is tempting to speculate that alterations in the enzymatic processing of pro-IGF-II, as seen under several patho-physiological conditions (see above), in fact modulates the intrinsic biological activity of IGF-II.
This project is supervised by Jaap van Doorn
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last update: 14 January 2009