Nuclear MEK1 sequesters PPARγ and bisects MEK1/ERK signaling: a non-canonical pathway of retinoic acid inhibition of adipocyte differentiation

PLoS One. 2014 Jun 24;9(6):e100862. doi: 10.1371/journal.pone.0100862. eCollection 2014.

Abstract

Uncontrolled adipogenesis and adipocyte proliferation have been connected to human comorbidities. Retinoic acid (RA) is known to inhibit adipocyte differentiation, however the underlying mechanisms have not been adequately understood. This study reports that RA acting as a ligand to RA receptors (RARs and RXRs) is not a sine qua non to the inhibition of adipogenesis. Our intriguing observation of a negative correlation between increased retinoylation and adipogenesis led us to explore retinoylated proteins in adipocytes. Exportin (CRM1) was found to be retinoylated, which in turn can affect the spatio-temporal regulation of the important signaling molecule mitogen-activated protein kinase kinase 1 (MEK1), likely by disrupting its export from the nucleus. Nuclear enrichment of MEK1 physically sequesters peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipogenesis, from its target genes and thus inhibits adipogenesis while also disrupting the MEK1-extracellular-signal regulated kinase (ERK) signaling cascade. This study is first to report the inhibition of adipocyte differentiation by retinoylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology*
  • Adipocytes / metabolism
  • Adipogenesis
  • Animals
  • Cell Differentiation / genetics
  • Exportin 1 Protein
  • Karyopherins / metabolism
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 1 / physiology*
  • MAP Kinase Signaling System
  • Mice
  • PPAR gamma / metabolism*
  • PPAR gamma / physiology
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Tretinoin / metabolism
  • Tretinoin / physiology*

Substances

  • Karyopherins
  • PPAR gamma
  • Receptors, Cytoplasmic and Nuclear
  • Tretinoin
  • MAP Kinase Kinase 1
  • Map2k1 protein, mouse

Grants and funding

This work was supported by the Department of Science & Technology SERC-FAST Track project to PG, Department of Biotechnology-India project BT/01/IYBA/2009 and CSIR 12th Plan Network project Infectious Disease and Biodiscovery (BSC0210 & BSC0120) to PG and facilities provided by IMTech-CSIR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.