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

Niyati Malkani; Thomas Jansson; Madhulika B Gupta

doi:10.1016/j.mce.2015.04.031

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

Mol Cell Endocrinol. 2015 Sep 5:412:182-95. doi: 10.1016/j.mce.2015.04.031. Epub 2015 May 5.

Authors

Niyati Malkani¹, Thomas Jansson², Madhulika B Gupta³

Affiliations

¹ Department of Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.
² Department of Obstetrics & Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
³ Department of Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Pediatrics, University of Western Ontario, London, Canada; Children's Health Research Institute, University of Western Ontario, London, ON, Canada. Electronic address: mbgupta@uwo.ca.

Abstract

Insulin-like growth factor-1 (IGF-I) is the key regulator of fetal growth. IGF-I bioavailability is markedly diminished by IGF binding protein-1 (IGFBP-1) phosphorylation. Leucine deprivation strongly induces IGFBP-1 hyperphosphorylation, and plays an important role in fetal growth restriction (FGR). FGR is characterized by decreased amino acid availability, which activates the amino acid response (AAR) and inhibits the mechanistic target of rapamycin (mTOR) pathway. We investigated the role of AAR and mTOR in mediating IGFBP-1 secretion and phosphorylation in HepG2 cells in leucine deprivation. mTOR inhibition (rapamycin or raptor + rictor siRNA), or activation (DEPTOR siRNA) demonstrated a role of mTOR in leucine deprivation-induced IGFBP-1 secretion but not phosphorylation. When the AAR was blocked (U0126, or ERK/GCN2 siRNA), both IGFBP-1 secretion and hyperphosphorylation (pSer101/pSer119/pSer169) due to leucine deprivation were prevented. CK2 inhibition by TBB also attenuated IGFBP-1 phosphorylation in leucine deprivation. These results suggest that the AAR and mTOR independently regulate IGFBP-1 secretion and phosphorylation in response to decreased amino acid availability.

Keywords: AAR; HepG2 cells; IGFBP-1 phosphorylation; Leucine deprivation; mTOR.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Carrier Proteins / metabolism
Hep G2 Cells
Humans
Insulin-Like Growth Factor Binding Protein 1 / metabolism*
Leucine / deficiency
Phosphorylation
Protein Processing, Post-Translational
Rapamycin-Insensitive Companion of mTOR Protein
Regulatory-Associated Protein of mTOR
Signal Transduction
Sirolimus / pharmacology
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / metabolism

Substances

Adaptor Proteins, Signal Transducing
Carrier Proteins
IGFBP1 protein, human
Insulin-Like Growth Factor Binding Protein 1
RICTOR protein, human
RPTOR protein, human
Rapamycin-Insensitive Companion of mTOR Protein
Regulatory-Associated Protein of mTOR
MTOR protein, human
TOR Serine-Threonine Kinases
Leucine
Sirolimus

Abstract

Publication types

MeSH terms

Substances

Grants and funding