Fetal growth restriction (FGR) is associated with decreased nutrient availability and reduced insulin-line growth factor (IGF)-I bioavailability via increased IGF binding protein (IGFBP)-1 phosphorylation. While protein kinase C (PKC) is implicated in IGFBP-1 hyperphosphorylation in nutrient deprivation, the mechanisms remain unclear. We hypothesised that the interaction of PKCα with protein kinase CK2β and activation of PKCα under leucine deprivation (L0) mediate fetal hepatic IGFBP-1 hyperphosphorylation. Parallel Reaction Monitoring Mass Spectrometry (PRM-MS) followed by PKCα knockdown demonstrated the PKCα isoform interacts with IGFBP-1 and CK2β under L0. Pharmacological PKCα activation with phorbol 12-myristate 13-acetate (PMA) increased whereas inhibition with bisindolylmaleimide II (Bis II) decreased IGFBP-1 phosphorylation (Ser101/119/169, Ser98 + 101 and Ser169 + 174), respectively. Furthermore, PMA mimicked L0-induced PKCα translocation and IGFBP-1 expression. PKCα expression was increased in baboon fetal liver in FGR, providing biological relevance in vivo. In summary, we report a novel nutrient-sensitive mechanism for PKCα in mediating IGFBP-1 hyperphosphorylation in FGR.

胎儿生长受限 (FGR) 与通过增加的 IGF 结合蛋白 (IGFBP)-1 磷酸化降低营养可用性和降低胰岛素线生长因子 (IGF)-I 生物利用度有关。虽然蛋白激酶 C (PKC) 与营养剥夺中的 IGFBP-1 过度磷酸化有关，但其机制仍不清楚。我们假设PKCα与蛋白激酶CK2β的相互作用和亮氨酸剥夺（L0）下PKCα的激活介导胎儿肝脏IGFBP-1过度磷酸化。平行反应监测质谱 (PRM-MS) 和 PKCα 敲低表明 PKCα 亚型在 L0 下与 IGFBP-1 和 CK2β 相互作用。佛波醇 12-肉豆蔻酸酯 13-乙酸 (PMA) 的药理 PKCα 活化增加，而双吲哚马来酰亚胺 II (Bis II) 的抑制降低 IGFBP-1 磷酸化 (Ser101/119/169, Ser98 + 101 和 Ser169 + 174），分别。此外，PMA 模拟 L0 诱导的 PKCα 易位和 IGFBP-1 表达。FGR 狒狒胎肝中 PKCα 表达增加，提供生物学相关性在体内。总之，我们报告了一种新的 PKCα 介导 FGR 中 IGFBP-1 过度磷酸化的营养敏感机制。