The role and regulation of IGFBP-1 phosphorylation in fetal growth restriction

Abstract

Fetal growth restriction (FGR) increases the risk of perinatal complications and predisposes the infant to developing metabolic, cardiovascular, and neurological diseases in childhood and adulthood. The pathophysiology underlying FGR remains poorly understood and there is no specific treatment available. Biomarkers for early detection are also lacking. The insulin-like growth factor (IGF) system is an important regulator of fetal growth. IGF-I is the primary regulator of fetal growth, and fetal circulating levels of IGF-I are decreased in FGR. IGF-I activity is influenced by a family of IGF binding proteins (IGFBPs), which bind to IGF-I and decrease its bioavailability. During fetal development the predominant IGF-I binding protein in fetal circulation is IGFBP-1, which is primarily secreted by the fetal liver. IGFBP-1 binds IGF-I and thereby inhibits its bioactivity. Fetal circulating levels of IGF-I are decreased and concentrations of IGFBP-1 are increased in FGR. Phosphorylation of human IGFBP-1 at specific sites markedly increases its binding affinity for IGF-I, further limiting IGF-I bioactivity. Recent experimental evidence suggests that IGFBP-1 phosphorylation is markedly increased in the circulation of FGR fetuses suggesting an important role of IGFBP-1 phosphorylation in the regulation of fetal growth. Understanding of the significance of site-specific IGFBP-1 phosphorylation and how it is regulated to contribute to fetal growth will be an important step in designing strategies for preventing, managing, and/or treating FGR. Furthermore, IGFBP-1 hyperphosphorylation at unique sites may serve as a valuable biomarker for FGR.

Fig. 1

Using a cell culture model for hypoxia and nutritional deprivation, distinct variability in the sites of phosphorylation of IGFBP-1 and differences in IGF-I affinity were reported. It was shown that residues Ser101/119/169 were common to both stress stimuli. a There was a significant Increase in IGFBP-1 phosphorylation (at Ser169 + Ser98) that was associated with 264 -fold higher IGF-I affinity in hypoxia. b Under leucine deprivation a 21- fold increase in IGFBP-1 phosphorylation at Ser119 correlated with 21 × higher affinity for IGF-I (Seferovic et al. .)

Fig. 2

Functional impact of the site-specific phosphorylation of IGFBP-1 was clearly demonstrated in human FGR, a condition characterized by various degrees of hypoxia and decreased nutrient availability. It was indicated that higher IGFBP-1 phosphorylation at Ser98/101 but most notably, at Ser169 correlated with lower birth weight. (Abu Shehab et al. 2010)

Fig. 3

Distinct variability in the sites of phosphorylation of IGFBP-1 in two different conditions of stress. Residues Ser101/119/169 were common to both stress stimuli, but there were clear differences in IGFBP-1 phosphorylation patterns between hypoxia and leucine deprivation. In particular, a dramatic increase in phosphorylation at Ser169 as well as at a new site Ser98 was observed in hypoxia. However, the most significant change in leucine deprivation was a marked increase in phosphorylation at Ser119. These findings provide novel evidence of sensitive regulation of IGF-I bioavailability in response to individual stress stimuli mediated by altered hyperphosphorylation of IGFBP-1 (Seferovic et al. ; Abu Shehab et al. 2010, 2014)

Fig. 4

Role of IGFBP-1 phosphorylation in regulation of IGF-I bioavailability in FGR. It is proposed that hypoxia and nutritional deprivation-induced IGFBP-1 phosphorylation is mediated by inhibition of mTOR signaling and stimulation of CK2 activity in fetal liver resulting in reduced IGF-1 bioavailability and fetal growth in FGR. (Abu Shehab et al. 2014)