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IGFBP-1 hyperphosphorylation in response to leucine deprivation is mediated by the AAR pathway

Niyati Malkani1, Thomas Jansson2, Madhulika B Gupta3

  • 1Department of Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.

Molecular and Cellular Endocrinology
|May 10, 2015
PubMed

Insights

Leucine deprivation impacts fetal growth by altering Insulin-like growth factor binding protein-1 (IGFBP-1) phosphorylation. The amino acid response (AAR) pathway, not mTOR, controls IGFBP-1 secretion and hyperphosphorylation during nutrient scarcity.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Developmental Biology

Background:

  • Insulin-like growth factor-1 (IGF-I) is crucial for fetal growth.
  • IGF-I bioavailability is regulated by IGF binding protein-1 (IGFBP-1) phosphorylation.
  • Leucine deprivation leads to IGFBP-1 hyperphosphorylation, contributing to fetal growth restriction (FGR).

Purpose of the Study:

  • To investigate the roles of the amino acid response (AAR) and mechanistic target of rapamycin (mTOR) pathways in mediating IGFBP-1 secretion and phosphorylation under leucine deprivation in HepG2 cells.

Main Methods:

  • HepG2 cells were subjected to leucine deprivation.
  • mTOR pathway was modulated using rapamycin, DEPTOR siRNA, or raptor+rictor siRNA.
  • AAR was blocked using U0126 or ERK/GCN2 siRNA.
  • CK2 activity was inhibited using TBB.
  • IGFBP-1 secretion and phosphorylation (pSer101/pSer119/pSer169) were analyzed.

Main Results:

  • mTOR inhibition or activation influenced IGFBP-1 secretion but not its phosphorylation during leucine deprivation.
  • Blocking the AAR pathway prevented both IGFBP-1 secretion and hyperphosphorylation induced by leucine deprivation.
  • CK2 inhibition attenuated IGFBP-1 phosphorylation.

Conclusions:

  • The amino acid response (AAR) pathway plays a critical role in regulating both IGFBP-1 secretion and hyperphosphorylation in response to leucine deprivation.
  • The mTOR pathway independently influences IGFBP-1 secretion but not phosphorylation under these conditions.
  • These findings elucidate the distinct roles of AAR and mTOR in IGFBP-1 regulation during nutrient stress, relevant to fetal growth.

Keywords:
AARHepG2 cellsIGFBP-1 phosphorylationLeucine deprivationmTOR

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