Signaling by Nuclear Receptors

Stable Identifier
R-HSA-9006931
Type
Pathway
Species
Homo sapiens
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Nuclear receptors (NRs) are ligand-activated transcription factors that bind to small lipid based molecules to regulate gene expression and other cellular process. This family includes receptors for steroid hormones and derivatives (such as estrogen, progesterone, glucocorticoids, Vitamin D, oxysterols and bile acids, among others) as well as receptors for retinoic acids, thyroid hormones and fatty acids and their derivatives. These ligands are able to diffuse directly through cellular membranes as a result of their lipophilic nature (reviewed in Beato et al, 1996; Holzer et al, 2017). The 48 human nuclear receptors share a conserved modular structure that consists of a sequence specific DNA-binding domain and a ligand-binding domain, in addition to various other protein-protein interaction domains. Upon interaction with ligand, NRs bind to the regulatory regions of target genes as homo- or heterodimers, or more rarely, as monomers. At the promoter, NRs interact with other activators and repressors to regulate gene expression (reviewed Beato et al, 1996; Simons et al, 2014; Hah and Kraus, 2010). A number of nuclear receptors are cytoplasmic in the absence of ligand and exist as part of a heat shock protein complex that regulates their cellular location, protein stability, competency to bind steroid hormones and transcriptional activity (Echeverria and Picard, 2010). Ligand-binding to these receptors promotes dimerization and nuclear translocation. Other nuclear receptors are contstitutively nuclear and their chromatin-modifying activities are regulated by ligand binding (reviewed in Beato et al, 1996). In addition to the classic transcriptional response, NRs also have a role in rapid, non-nuclear signaling originating from receptors localized at the plasma membrane. Ligand-binding to these receptors intitiates downstream phospholipase- and kinase-based signaling cascades (reviewed in Schwartz et al, 2016; Levin and Hammes, 2016). Signaling by estrogen, liver X and retinoic acid receptors are currently described here.

Literature References
PubMed ID Title Journal Year
24284822 Minireview: dynamic structures of nuclear hormone receptors: new promises and challenges

Simons, SS, Edwards, DP, Kumar, R

Mol. Endocrinol. 2014
27729652 Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors

Levin, ER, Hammes, SR

Nat. Rev. Mol. Cell Biol. 2016
23810978 Hormone-regulated transcriptomes: lessons learned from estrogen signaling pathways in breast cancer cells

Hah, N, Kraus, WL

Mol. Cell. Endocrinol. 2014
28527568 Evolution of Nuclear Receptors and Ligand Signaling: Toward a Soft Key-Lock Model?

Holzer, G, Markov, GV, Laudet, V

Curr. Top. Dev. Biol. 2017
8733009 Transcriptional regulation by steroid hormones

Beato, M, Chávez, S, Truss, M

Steroids 1996
27288742 Rapid steroid hormone actions via membrane receptors

Schwartz, N, Verma, A, Bivens, CB, Schwartz, Z, Boyan, BD

Biochim. Biophys. Acta 2016
20006655 Molecular chaperones, essential partners of steroid hormone receptors for activity and mobility

Echeverria, PC, Picard, D

Biochim. Biophys. Acta 2010
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