IGFBP-1 hyperphosphorylation in response to nutrient deprivation is mediated by activation of protein kinase Cα (PKCα). (1st October 2021)

• Record Type: Journal Article
• Authors: Chen, Allan W.; Biggar, Kyle; Nygard, Karen; Singal, Sahil; Zhao, Tiffany; Li, Cun; Nathanielsz, Peter W.; Jansson, Thomas; Gupta, Madhulika B.
• Is Part Of: Molecular and cellular endocrinology. Volume 536(2021)
• Publication Date: 2021-10-01
• Subjects: Fetal growth restriction -- Placental insufficiency -- Protein interaction -- Protein kinase CK2 -- Baboon; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2021.111400
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: 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. Highlights: Fetal growth restriction (FGR) is associated with IGFBP-1 hyperphosphorylation. Leucine deprivation (L0) increases IGFBP-1 phosphorylation and is linked to FGR. L0 induces PKCα/CK2/IGFBP-1 interactions and PKCα activation via translocation. Fetal liver PKCα expression is increased in a baboon model of FGR. PKCα mediated IGFBP-1 phosphorylation represents a new mechanism underpinning FGR.