Interested in promotions? | Click here >>

Nuclear Receptors

© Cell Signaling Technology. All Rights Reserved.
highlighted node

Pathway Description:

The nuclear receptor superfamily are ligand-activated transcription factors that play diverse roles in cell differentiation/development, proliferation, and metabolism and are associated with numerous pathologies such as cancer, cardiovascular disease, inflammation, and reproductive abnormalities. Members of this family contain an N-terminal transactivation domain, a highly conserved central region zinc-finger DNA binding domain, and a C-terminal ligand-binding domain. Ligand binding to its correlate nuclear receptor results in transactivation of specific genes within a target tissue.

In addition to ligand binding, nuclear receptor activity can be modulated through the action of numerous growth factor and cytokine signaling cascades that result in receptor phosphorylation or other post-translational modifications, typically within the N-terminal transactivation domain. For example, the estrogen receptor is phosphorylated on multiple serine residues that affect receptor activity. Ser118 may be the substrate of the transcription regulatory kinase CDK7, whereas Ser167 may be phosphorylated by p90RSK and Akt. Phosphorylation of Ser167 may confer resistance to tamoxifen in breast cancer patients. Type I nuclear receptors, also called steroid receptors, include the estrogen receptor, androgen receptor, progesterone receptor, mineralocorticoid receptor, and glucocorticoid receptor. Steroid hormone ligands for this subgroup of receptors travel from their respective endocrine gland through the bloodstream bound to steroid binding globulin. Some type I nuclear receptors are activated, in part, upon binding their respective ligand in the cytoplasmic compartment. The ligand-receptor complex dissociates from HSP90 and enters the nucleus where it homodimerizes and binds to hormone response elements within the promoter of a target gene. The receptor transactivation domain is responsible for interaction at the promoter with co-activators such as acetyltransferases and the general transcription machinery, resulting in transcriptional activation.

Type II nonsteroid nuclear receptors include the thyroid hormone receptors (TRα and β), retinoic acid receptors (RARα, β, and γ), vitamin D receptor (VDR), and peroxisome proliferator-activated receptors (PPARα, β, and γ). Members of this family heterodimerize with the retinoid X receptor (RXR). Prior to ligand binding, receptor heterodimers are located in the nucleus as part of complexes with histone deacetylases (HDACs) and other co-repressors that keep target DNA in a tightly wound conformation, preventing exposure to transacting factors. Ligand binding results in co-repressor dissociation, chromatin derepression, and transcriptional activation.

Orphan nuclear receptors are nuclear receptors where the endogenous ligands have not been identified. Structural studies suggest that some of the orphan receptors may not bind ligands. This class of nuclear receptors includes small heterodimer partner (SHP), reverse orientation c-ErbA (Rev-Erbα and β), testicular receptor 2 and 4 (TR2 and 4), tailless homolog orphan receptor (TLX), photoreceptor-specific NR (PNR), chicken ovalbumin upstream promoter transcription factor 1 and 2 (COUP-TF1 and 2), Nur77, Nur-related protein 1 (NURR1), neuron derived orphan receptor 1 (NOR1), estrogen-related receptor (ERR α, β, and γ), and germ cell nuclear factor (GCNF). Most of these receptors regulate transcription by binding to their target DNA elements either as monomers or homodimers and recruiting chromatin modifying coactivators and the transcription machinery. Nur77 and NURR1 can also heterodimerize with RXRs and these heterodimers are able to respond to RXR ligands to regulate transcription.

 Selected Reviews:

We would like to thank Prof. David J. Mangelsdorf, University of Texas Southwestern Medical Center for reviewing this diagram.

created November 2012

revised January 2020

  • KinaseKinase
  • PhosphatasePhosphatase
  • Transcription FactorTranscription Factor
  • CaspaseCaspase
  • ReceptorReceptor
  • EnzymeEnzyme
  • pro-apoptoticpro-apoptotic
  • pro-survivalpro-survival
  • GTPaseGTPase
  • G-proteinG-protein
  • AcetylaseAcetylase
  • DeacetylaseDeacetylase
  • Ribosomal subunitRibosomal subunit
  • Direct Stimulatory ModificationDirect Stimulatory Modification
  • Direct Inhibitory ModificationDirect Inhibitory Modification
  • Multistep Stimulatory ModificationMultistep Stimulatory Modification
  • Multistep Inhibitory ModificationMultistep Inhibitory Modification
  • Tentative Stimulatory ModificationTentative Stimulatory Modification
  • Tentative Inhibitory ModificationTentative Inhibitory Modification
  • Separation of Subunits or Cleavage ProductsSeparation of Subunits or Cleavage Products
  • Joining of SubunitsJoining of Subunits
  • TranslocationTranslocation
  • Transcriptional Stimulatory ModificationTranscriptional Stimulatory Modification
  • Transcriptional Inhibitory ModificationTranscriptional Inhibitory Modification