Nuclear receptors: integration of multiple signalling pathways through phosphorylation

Cell Signal. 2003 Apr;15(4):355-66. doi: 10.1016/s0898-6568(02)00115-8.

Abstract

Nuclear receptors (NRs) orchestrate the transcription of specific gene networks in response to binding of their cognate ligand. They also act as mediators in a variety of signalling pathways through integrating diverse phosphorylation events. NR phosphorylation concerns all three major domains, the N-terminal activation function (AF-1), the ligand-binding and the DNA binding domains. Often, phosphorylation of NRs by kinases that are associated with general transcription factors (e.g. cdk7 within TFIIH), or activated in response to a variety of signals (MAPKs, Akt, PKA, PKC), facilitates the recruitment of coactivators or of components of the transcription machinery and, therefore, cooperates with the ligand to enhance transcription activation. But phosphorylation can also contribute to the termination of the ligand response through inducing DNA dissociation or NR degradation or through decreasing ligand affinity. These different modes of regulation reveal an unexpected complexity of the dynamics of NR-mediated transcription. In addition, deregulation of NR phosphorylation may impact their action in certain diseases or cancers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • DNA-Binding Proteins / metabolism
  • Down-Regulation
  • Hormones / physiology
  • Humans
  • Neoplasms / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / physiology*
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Signal Transduction / physiology*
  • Transcription, Genetic / physiology
  • Up-Regulation

Substances

  • DNA-Binding Proteins
  • Hormones
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Protein-Serine-Threonine Kinases