ReviewIGFBP-6 five years on; not so ‘forgotten’?
Introduction
Insulin-like growth factor binding protein (IGFBP)-6 is a member of the family of six high affinity IGFBPs that regulate IGF activity and may also have IGF-independent actions [1]. It as an O-linked glycoprotein that is unique among IGFBPs because of its 20–100-fold IGF-II binding preference. When I last reviewed IGFBP-6 in 1999, I described it as the ‘forgotten binding protein’ since it had been studied less intensively than the other IGFBPs [2]. At that time, it was known that IGF-II is an autocrine growth factor for many tumors and that IGFBP-6 is a relatively specific IGF-II inhibitor. Further, IGFBP-6 expression was known to be associated with non-proliferative states and inhibition of tumor cell growth, and it was upregulated by differentiating agents. It was therefore postulated that the major role of IGFBP-6 was to inhibit IGF-II actions and that this may be significant in the context of tumor inhibition. There was little evidence at that time for IGF-independent actions of IGFBP-6. Little specific structural information was available other than O-glycosylation inhibiting IGFBP-6 proteolysis but having no effect on high affinity IGF binding. Since 1999, considerable progress has been made in understanding its roles, actions and structure–function relationships, and this progress is summarized in this review.
Section snippets
IGFBP-6 and cancer
A number of cellular processes are perturbed in cancer. Unregulated proliferation and/or increased survival are hallmarks of cancer cells, and autocrine IGF-II activation may play a part in these processes. Additionally, alterations in adhesion and migration are required in order for cancer cells to metastasize. IGFBP-6 inhibits all of these processes in cancer cells that express autocrine IGF-II such as rhabdomyosarcoma, neuroblastoma and colon cancer [3].
Does IGFBP-6 have IGF-independent actions?
There has been a great deal of recent interest in IGF-independent actions of IGFBPs, particularly with respect to IGFBP-3 and -5 [1]. In most studies, the effects of IGFBP-6 are due to inhibition of IGF actions. For example, apart from the widely described preferential effect of IGFBP-6 on IGF-II vs IGF-I actions [2], inhibition of the actions of IGF-II and a number of IGF-II mutants on myoblast differentiation and proliferation by IGFBP-6 was proportional to their IGFBP-6 binding affinities
IGFBP-6 regulation – lessons from gene array studies
Traditionally, studies of gene expression have focussed on the response of a small number of genes to a small number of interventions. Since investigators choose the genes to be studied, this approach results in a bias in favour of known ‘genes of interest’. In contrast, gene array studies, in which up to 15,000 genes can be studied simultaneously, provide a relatively unbiased overview of gene regulation. Since 2000, over 40 papers showing regulation of IGFBP-6 expression have been published.
A transgenic model of IGFBP-6 overexpression in the central nervous system
Transgenic mice overexpressing IGFBP-6 in the central nervous system (CNS) under the control of the GFAP promoter were transiently growth-retarded in the first month of life, during which time circulating IGFBP-6 levels were increased and IGF-I levels were decreased [56]. IGF-II levels were not measured, but are known to decline postnatally, so a possible mechanism for this transient effect would be inhibition of IGF-II-mediated postnatal growth. Within the CNS, cerebellar size was
Structure/function relationships of IGFBP-6
IGFBP-6, in common with all of the IGFBPs, has a three-domain structure (Fig. 1) [1]. The N- and C-terminal domains are each internally disulfide-linked and are highly conserved between all IGFBPs. These domains each contribute to high affinity IGF binding. IGFBP-6 lacks two conserved N-terminal cysteines and therefore the GCGCC motif that is found in IGFBPs 1–5. The N-terminal disulfide bonds of IGFBP-6 therefore differ from those of IGFBP-1 [62], but all others are conserved, including the
Conclusions
Over the last five years, considerable progress has been made in understanding the biology of IGFBP-6, including further defining its actions and regulation, as well as generating structural information that is unique amongst IGFBPs. This has occurred in the context of advances in the IGF field generally, to the point where inhibitors of IGF action are being seriously considered as cancer therapeutics [72]. IGFBPs, including IGFBP-6, are endogenous inhibitors of IGF actions in many situations,
Acknowledgements
The author’s studies described in this review were funded by grants from the National Health and Medical Research Council of Australia, the Australian Research Council, the Austin Hospital Medical Research Foundation, and the Melbourne Research Grants Scheme. The author thanks Dr. Ping Fu and Mr. Geoffrey Brasier for their thoughtful comments.
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Current ideas on the biology of IGFBP-6: More than an IGF-II inhibitor?
2016, Growth Hormone and IGF ResearchCitation Excerpt :A few years later, three more IGFBPs, including IGFBP-6, were identified and cloned [9–13]. Although IGFBP-6 is a member of the IGFBP family and shares most of its common properties, it has a number of distinct functional and structural characteristics [14–16]. The most prominent of these is its ~ 50-fold binding preference for IGF-II over IGF-I [9–11,17], compared with the equal or slight IGF-II preference of IGFBPs 1–5.