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

Allan W. Chen, Kyle Biggar, Karen Nygard, Sahil Singal, Tiffany Zhao, Cun Li, Peter W. Nathanielsz, Thomas Jansson, Madhulika B. Gupta

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number111400
JournalMolecular and Cellular Endocrinology
Volume536
DOIs
StatePublished - Oct 1 2021
Externally publishedYes

Keywords

  • Baboon
  • Fetal growth restriction
  • Placental insufficiency
  • Protein interaction
  • Protein kinase CK2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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