Abstract
Insulin-like growth factor II (IGF-II) is a major embryonic growth factor belonging to the insulin-like growth factor family, which includes insulin and IGF-I. Its expression in humans is tightly controlled by maternal imprinting, a genetic restraint that is lost in many cancers, resulting in up-regulation of both mature IGF-II mRNA and protein expression. Additionally, increased expression of several longer isoforms of IGF-II, termed "pro" and "big" IGF-II, has been observed. To date, it is ambiguous as to what role these IGF-II isoforms have in initiating and sustaining tumorigenesis and whether they are bioavailable. We have expressed each individual IGF-II isoform in their proper O-glycosylated format and established that all bind to the IGF-I receptor and both insulin receptors A and B, resulting in their activation and subsequent stimulation of fibroblast proliferation. We also confirmed that all isoforms are able to be sequestered into binary complexes with several IGF-binding proteins (IGFBP-2, IGFBP-3, and IGFBP-5). In contrast to this, ternary complex formation with IGFBP-3 or IGFBP-5 and the auxillary protein, acid labile subunit, was severely diminished. Furthermore, big-IGF-II isoforms bound much more weakly to purified ectodomain of the natural IGF-II scavenging receptor, IGF-IIR. IGF-II isoforms thus possess unique biological properties that may enable them to escape normal sequestration avenues and remain bioavailable in vivo to sustain oncogenic signaling.
Highlights
Aberrant processing of the pro-Insulin-like growth factor II (IGF-II) transcript produces pro- and big-IGF-II, which are secreted in a range of cancers
Coomassie-stained gels showed proteins in each isolated fraction were of correct size and, as evidenced by smearing of the sample, most likely O-glycosylated
Using homogeneous preparations of recombinant, O-glycosylated IGF-II isoforms corresponding to those high molecular weight IGF-II isoforms associated with a number of cancers such as hepatocellular carcinoma, gastric carcinoma, and colon carcinoma [14], we have identified characteristics to suggest that increased bioavailability of one or more isoforms may provide a selective growth advantage to tumors
Summary
Aberrant processing of the pro-IGF-II transcript produces pro- and big-IGF-II, which are secreted in a range of cancers. Previous attempts to answer questions related to the properties of individual IGF-II isoforms have used recombinant, unglycosylated proteins expressed in Escherichia coli This has led to yet more discrepancies; for example, whether the induction of Akt signaling by pro-IGF-II 1–156 is less than [2] or greater than [19] that induced by mature IGF-II. What these studies fail to address is the fact that the majority of IGF-II isoforms are O-glycosylated and how this post-translational modification may impact on the biological activity. We compared the performance of these homogenous preparations in a suite of biochemical and biological assays to mature IGF-II
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
