40 YEARS OF IGF1: IGF-binding proteins

Abstract

Insulin-like growth factor binding proteins (IGFBPs) 1-6 bind IGFs but not insulin with high affinity. They were initially identified as serum carriers and passive inhibitors of IGF actions.However, subsequent studies showed that, although IGFBPs inhibit IGF actions in many circumstances, they may also potentiate these actions. IGFBPs are widely expressed in most tissues, and they are flexible endocrine and autocrine/paracrine regulators of IGF activity, which is essential for this important physiological system. More recently, individual IGFBPs have been shown to have IGF-independent actions. Mechanisms underlying these actions include (i) interaction with non-IGF proteins in compartments including the extracellular space and matrix, the cell surface and intracellularly; (ii) interaction with and modulation of other growth factor pathways including EGF, TGF-β and VEGF; and (iii) direct or indirect transcriptional effects following nuclear entry of IGFBPs. Through these IGF-dependent and IGF-independent actions, IGFBPs modulate essential cellular processes including proliferation, survival, migration, senescence, autophagy and angiogenesis. They have been implicated in a range of disorders including malignant, metabolic, neurological and immune diseases. A more complete understanding of their cellular roles may lead to the development of novel IGFBP-based therapeutic opportunities.Page 2 of 51 3The somatomedin hypothesis, which postulated that growth hormone activity was mediated by a 1 serum factor, was published in 1957 (Salmon and Daughaday 1957). In the 1960s, several 2 circulating somatomedin activities were identified and attributed to peptides sized 5~8 kDa that had 3 both growth promoting and insulin-like metabolic effects. A paradox of these early observations 4 was that normoglycaemia was maintained in vivo despite the circulating concentrations of 5 somatomedins being sufficient to cause profound hypoglycaemia. Following the purification of 6 these small somatomedin peptides, it was observed that almost all of the circulating somatomedin 7 activity was found in a number of chromatographic peaks with apparent molecular weights greater 8 than 30~40 kDa and further studies indicated that this was due to binding by plasma binding 9proteins (Hintz and Liu 1977;Megyesi, et al. 1975;Zapf, et al. 1975). The apparent hypoglycaemia 10 paradox could then be resolved if somatomedin activity was inhibited by association with these 11 binding proteins. Of note, these early studies already demonstrated that insulin did not bind to these 12 proteins. 13 14In the following years, the somatomedin activities were identified as IGF-I and IGF-II, and they 15 were sequenced and cloned. IGF binding proteins (IGFBPs) 1-3 were the first to be identified and 16 purified, with IGFBPs 4-6 being subsequently described (Rajaram, et al. 1997;Rechler 1993). By 17 the early 1990s, all six members of this high affinity IGFBP family had been cloned and a number 18 of key structural and sequence similarities identified. Addition...

Polyploid Adipose Stem Cells Shift the Balance of IGF1/IGFBP2 to Promote the Growth of Breast Cancer

“…The explanation for the increase in efficacy may be the massive production of IGF1 by ASC.B6 cells, which contributes to the 4T1 cell proliferation in an in vitro assay (13). We show here that ASC.B6derived factors induce Akt phosphorylation, hence switch on the PI3K/Akt signaling pathway, and thereby promote cell survival, proliferation, growth and cellular metabolic pathways (17,21) In addition, we have identified IGFBP2 in the secretome of vASCs, which sequesters IGF1 and thereby regulates its accessibility and function (15). IGFBP2 was missing from ASC.B6 cells, and supplementation with a recombinant protein abolished tumor cell proliferation, and also mitigated the ASC.B6-induced Akt phosphorylation.…”

“…Searching for additional differentially expressed factors, we found an abundant protein in the supernatant of vASCs, which was absent from ASC.B6 (Figure 2A). Liquid chromatography-mass spectrometry analysis identified this 32 kDa protein as Insulin-like growth factorbinding protein 2 (IGFBP2), a member of the insulin-like growth factor regulating proteins (15). We confirmed by Western blotting that vASCs at p3 expressed and secreted huge amount of IGFBP2, vASCs at later passages (p16) decreased its expression, while ASC.B6 completely downregulated it (Figure 2B).…”

“…to members of the Insulin like growth factor-binding protein family (IGFBPs). The six members of this family bind IGFs with high affinity, and as they are expressed in most tissues, they play important role in the regulation of IGF activity both on endocrine and autocrine/paracrine levels (15). The importance of the IGF/IGFBP system in cancer progression has been emphasized recently: IGFs are autocrine factors for many cancers, while IGFBPs hinder tumor growth by inhibiting IGF functions, such as cell proliferation, survival, and migration/invasion.…”

Unique transcriptomic landscapes identified in idiopathic spontaneous and infection related preterm births compared to normal term births

“…Within the unique isPTB signature, we observed significant over-representation of genes in insulin 153 like growth factor signaling pathway: IGFBP1, IGFBP2, IGFBP6, C3, MELTF, CP, TNC, and CHDRL1. The 154 upregulation of the IGFBPs could have multiple paracrine and autocrine implications throughout the context 155 preferentially binds IGF2, reducing their bioavailability to activate IGF signaling [14]. The aberrant increase 157 in IGFBP1, IGFBP2, and IGFBP6 in isPTB placentas may suggest a reduction in IGF signaling, however we 158 do not see reduced fetal weight in the majority of our samples suggesting placental supply to maintain fetal 159 growth via the mTOR pathway is not affected [15,16].…”

Whole‐genome sequence analysis reveals candidate genomic footprints and genes associated with reproductive traits in Thoroughbred horse

“…In assessing the genetic basis underlying the low reproductive efficiency of Thoroughbred, we identified several candidate genes that are associated with reproductive traits in horse and other species. The IGFBP2 and IGFBP5 genes were identified (F ST , top 1%) in candidate selection regions on ECA6 that may have been influenced by directional selection (Table 1) target cells (Bach, 2018;Juengel et al, 2010). IGFBP2, a key member of the IGF family, is present in follicular fluid and subject to dynamic changes during follicle growth and maturation (Spitschak & Hoeflich, 2018).…”