Signal Transduction Pathways: Overview

Cellular & Molecular Biology, Signal Transduction Processes

Last Updated: October 18, 2023

Introduction to Mechanisms of Signal Transduction

Signal transduction at the cellular level refers to the movement of signals from outside the cell to inside. The movement of signals can be simple, like that associated with receptor molecules of the acetylcholine class: receptors that constitute channels which, upon ligand interaction, allow signals to be passed in the form of small ion movement, either into or out of the cell. These ion movements result in changes in the electrical potential of the cells that, in turn, propagates the signal along the cell.

For detailed discussion of various signal transduction processes that are not covered in this page go to:

Signal Transduction Pathways: Cyclic Nucleotides and Kinases

Signal Transduction Pathways: G-Proteins and GPCR

Signal Transduction Pathways: MAK Kinases

Signal Transduction Pathways: Nucleotides

Signal Transduction Pathways: Phosphatases

Signal Transduction Pathways: Phospholipids

Signal Transduction Pathways: PKC Family

More complex signal transduction involves the coupling of ligand-receptor interactions to many intracellular events. These events include phosphorylation by tyrosine kinases and/or serine/threonine kinases. The human genome contains 90 genes that encode tyrosine kinase enzymes including both receptor type and non-receptor type enzymes. Protein phosphorylation changes enzyme activities and protein conformations. The eventual outcome is an alteration in cellular activity and changes in the program of genes expressed within the responding cells.

Please refer to the Growth Factors and Other Cellular Regulators page for descriptions of the growth factors described in this page and the explanation of their abbreviations.

Classifications of Signal Transducing Receptors

Signal transducing receptors are of three general classes:

1. Receptors that penetrate the plasma membrane and have intrinsic enzymatic activity. Receptors that have intrinsic enzymatic activities include those that are tyrosine kinases (e.g. PDGFinsulinEGF and FGF receptors), tyrosine phosphatases (e.g. CD45 [cluster determinant-45] protein of T cells and macrophages), guanylate cyclases (e.g. natriuretic peptide receptors) and serine/threonine kinases (e.g. activin and TGF-β receptors). Receptors with intrinsic tyrosine kinase activity are capable of autophosphorylation (specifically ligand-induced transphosphorylation) as well as phosphorylation of other substrates. Additionally, several families of receptors lack intrinsic enzyme activity, yet are coupled to intracellular non-receptor tyrosine kinases by direct protein-protein interactions.

2. Receptors that are coupled, inside the cell, to GTP-binding and hydrolyzing proteins (termed G-proteins). Receptors of the class that interact with G-proteins all have a structure that is characterized by seven transmembrane spanning domains and as such are sometimes referred to as serpentine receptors. These receptors all belong the superfamily of G-protein coupled receptors, GPCR. Examples of this class are the adrenergic receptors, odorant receptors, and certain hormone receptors (e.g. glucagon, angiotensin, vasopressin and bradykinin).

3. Receptors that are found intracellularly and upon ligand binding migrate to the nucleus where the ligand-receptor complex directly affects gene transcription. Because this class of receptors is intracellular and functions in the nucleus as transcription factors they are commonly referred to as the nuclear receptors. Receptors of this class include the large family of steroid and thyroid hormone receptors. Receptors in this class have a ligand-binding domain, a DNA-binding domain and a transcriptional activator domain.

Receptor Tyrosine Kinases (RTK)

The receptor tyrosine kinase (RTK) family of transmembrane ligand-binding proteins is comprised of 58 members in the human genome. Each of the RTK exhibit similar structural and functional characteristics. Most RTK are monomers, and their domain structure includes an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain possessing the tyrosine kinase activity. The insulin and insulin-like growth factor receptors are the most complex in the RTK family being disulfide linked heterotetramers.

The amino acid sequences of the tyrosine kinase domains of RTK are highly conserved with those of cAMP-dependent protein kinase (PKA) within the ATP binding and substrate binding regions. Some RTK have an insertion of non-kinase domain amino acids into the kinase domain termed the kinase insert. RTK proteins are classified into families based upon structural features in their extracellular portions (as well as the presence or absence of a kinase insert) which include the cysteine rich domains, immunoglobulin-like domains, leucine-rich domains, Kringle domains, cadherin domains, fibronectin type III repeats, discoidin I-like domains, acidic domains, and EGF-like domains. Based upon the presence of these various extracellular domains, the 58 proteins of the RTK family have been sub-divided into at least 20 different subfamilies.

Table of the Characteristics of the Common Classes of RTK

ClassFamily NameExamplesStructural Features of Class
IErbB Receptor FamilyEGF receptor (ERBB1); NEU/HER2 (ERBB2); HER3 (ERBB3); HER4 (ERBB4)cysteine-rich sequences; receptors dimerize in response to ligand binding; numerous ligands bind and activate the EGFR (ERBB1) including EGF, TGF-α, and amphiregulin
IIInsulin Receptor Familyinsulin receptor (InsR); IGF-1 receptor (IGF1R); insulin receptor-related receptor (IRR)cysteine-rich sequences; characterized by disulfide-linked heterotetramers
IIIPDGF Receptor FamilyPDGF receptors (PDGFα and PDGFβ); c-Kit, CSF-1 receptor (CSFR); fms-related tyrosine kinase 3 (FLT3)contain 5 immunoglobulin-like domains; contain the kinase insert
IVVEGF Receptor Familyvascular endothelial cell growth factor (VEGF) receptor-1 (VEGFR-1; also known as fms-related tyrosine kinase-1 (FLT1); kinase insert domain receptor (VEGFR-2); fms-related tyrosine kinase 4 (VEGFR-3)contain 7 immunoglobulin-like domains as well as the kinase insert domain
VFGF Receptor Familyfibroblast growth factor receptor 1 (FGFR1); FGFR2; FGFR3; FGFR4contain 3 immunoglobulin-like domains as well as the kinase insert; acidic domain
VIINeurotrophin Receptor Familyneurotrophic tyrosine kinase receptor type 1 (TrkA); TrkB; TrkCcontains several closely spaced leucine-rich regions (LRRs); one or two cysteine-rich domains; two immunoglobulin-like domains; no kinase insert
VIIIROR Familyreceptor tyrosine kinase-like orphan receptor type 1 (ROR1); ROR2 
XHGF Receptor Familymet proto-oncogene (Met); macrophage stimulating receptor 1 (MST1R, also Ron)heterodimeric like the class II receptors except that one of the two protein subunits is completely extracellular. The HGF receptor is a proto-oncogene that was originally identified as the MET oncogene

schematic representation of various receptor tyrosine kinase (RTK) sub-types
Diagrammatic representation of several members of the receptor tyrosine kinase (RTK) family. Several members of each receptor sub-family are indicated below each representative. The Roman numerals above the first seven sub-types correspond to those sub-types described in the Table above. These RTK sub-types do not represent the entire RTK family sub-types. The Alk protein of the class XIX RTK subfamily refers to anaplastic lymphoma kinase and is distinct from the activin receptor-like kinase (ALK) subfamily of receptor serine/threonine kinases (RSK).

Many receptors that have intrinsic tyrosine kinase activity, as well as the tyrosine kinases that are associated with cell surface receptors, contain tyrosine residues, that upon phosphorylation, interact with other proteins of the signaling cascade. These other proteins contain a domain of amino acid sequences that are homologous to a domain first identified in the SRC proto-oncogene. These domains are termed SH2 domains (SRC homology domain 2). The typical SH2 domain is approximately 100 amino acids in length. Different SH2 domains recognize different tyrosine phosphorylated residues based upon the presence of the tyrosine phosphate as well as the amino acid sequences surrounding the tyrosine residue. These variable domains are, therefore, what determine the specificity of SH2 domain-containing protein binding. At least 110 different proteins are expressed in humans that contain SH2 domains. Another conserved protein-protein interaction domain identified in many signal transduction proteins is related to a third domain in SRC identified as the SH3 domain. Typical SH3 domains are composed of approximately 60 amino acid residues.

The interactions of SH2 domain-containing proteins with RTK or receptor associated tyrosine kinases leads to tyrosine phosphorylation of the SH2 containing proteins. The result of the phosphorylation of SH2 containing proteins that have enzymatic activity is an alteration (either positively or negatively) in that activity. Several SH2 containing proteins that have intrinsic enzymatic activity include phospholipase Cγ (PLCγ, PLC-gamma), the proto-oncogene RAS associated GTPase activating protein (rasGAP), phosphatidylinositol-3-kinase (PI3K), protein phosphatase-1C (PTP1C; encoded by the PTPN6 gene), as well as members of the SRC family of protein tyrosine kinases (PTK).

Non-Receptor Protein Tyrosine Kinases (PTK)

Humans express 32 genes that encode intracellular (cytosolic) PTK that are responsible for phosphorylating a variety of intracellular proteins on tyrosine residues following activation of cellular growth and proliferation signals. The proteins in the PTK superfamily can be divided into ten distinct subgroups where the archetypal PTK subgroup is related to the SRC protein that is a tyrosine kinase first identified as the transforming protein in Rous sarcoma virus and identified as v-src. Subsequently, a cellular homolog was identified and originally designated c-src. Numerous proto-oncogenes were identified as the transforming proteins carried by retroviruses as a result of transduction of host DNA into the viral genome.

The SRC family tyrosine kinases include SRC, BLK, FGR, FRK, FYN, HCK, LCK, LYN, and YES1. The other nine PTK families include those enzymes related to the Abelson tyrosine kinase (ABL and ABLL), the C-terminal SRC kinase (CSK and MATK), the feline sarcoma kinase (FES and FER), the Janus kinase (JAK1, JAK2, JAK3, and TYK2), the protein tyrosine kinase 2 kinase (PTK2 and PTK2B), the protein tyrosine kinase 6 kinase (PTK6 and SRMS), the spleen tyrosine kinase (SYK and ZAP70), the tyrosine kinase expressed in hepatocellular carcinoma kinase (TEC, BMX, BTK, ITK, and TXK), and the tyrosine kinase non-receptor kinase (TNK1 and TNK2).

Most of the proteins of the various families of non-receptor PTK couple to cellular receptors that lack enzymatic activity themselves. This class of receptor includes all of the cytokine receptors (e.g. the interleukin-2 receptor, IL2R) as well as the CD4 and CD8 cell surface glycoproteins of T cells, the T cell antigen receptor (TCR), the B cell receptor (BCR), immunoglobulin receptors (IR), erythropoietin receptor (EPOR), and the prolactin receptors.

An example of an alteration in receptor activity in response to association with an intracellular PTK is the nicotinic acetylcholine receptor (AChR). These receptors comprise an ion channel consisting of five distinct subunits (alpha: α, beta: β, gamma: γ, delta: δ, and epsilon: ε). The β, γ, and δ subunits are tyrosine phosphorylated in response to acetylcholine binding which leads to an increase in the rate of desensitization to acetylcholine.

Receptor Serine/Threonine Kinases (RSK)

The receptors for the TGF-β (TGF-beta) superfamily of ligands have intrinsic serine/threonine kinase activity. A more complete description of the TGF-β signaling cascade can be found in the Signaling by Wnts and the TGFs-β/BMP Families page.

There are more than 30 multifunctional proteins of the TGF-β superfamily which also includes the activins, inhibins and the bone morphogenetic proteins (BMP). This superfamily of proteins can induce and/or inhibit cellular proliferation or differentiation and regulate migration and adhesion of various cell types. The signaling pathways utilized by the TGF-β, activin and BMP receptors are different than those for receptors with intrinsic tyrosine kinase activity or that associate with intracellular tyrosine kinases.

At least 12 RSK have been characterized as being expressed in humans. These receptors can be divided into two subfamilies identified as the type I and type II receptors. The type I RSKs are also known as activin receptors or activin receptor-like kinases, ALKs. Ligands first bind to the type II receptors which then leads to interaction with the type I receptors. The type II protein phosphorylates the kinase domain of the type I partner leading to displacement of proteins called subunit (or protein) partners. The displacement of these protein partners allows for the binding and phosphorylation of particular members of the Smad family. Once phosphorylated, the particular Smad will migrate to the nucleus and act as complexes that regulate the expression of specific target genes. One predominant effect of TGF-β is regulation of progression through the cell cycle. One nuclear protein involved in the responses of cells to TGF-β is the proto-oncogene, MYC which directly affects the expression of genes harboring MYC-binding elements.

Table of Human Receptor Serine Threonine Kinases (RSK)

ClassReceptor NameCommon AbbreviationGene Symbol
Iactivin A receptor, type IALK2ACVR1
Iactivin A receptor, type IBALK4ACVR1B
Iactivin A receptor, type ICALK7ACVR1C
Iactivin A receptor type II-like 1ALK1ACVRL1
Ibone morphogenetic protein (BMP) receptor, type IABMPR1ABMPR1A
Ibone morphogenetic protein (BMP) receptor, type IBBMPR1BBMPR1B
Itransforming growth factor beta (TGF-β) receptor 1TGFBR1TGFBR1
IIactivin A receptor, type IIAActR2ACVR2A
IIactivin A receptor, type IIBActR2BACVR2B
IIanti-Mullerian hormone receptor, type IIMISR2AMHR2
IIbone morphogenetic protein (BMP) receptor, type IIBMPR2BMPR2
IItransforming growth factor beta (TGF-β) receptor IITGFBR2TGFBR2

Intracellular Hormone Receptors (Nuclear Receptors)

The steroid/thyroid hormone receptor superfamily [e.g. glucocorticoid (GR), vitamin D (VDR), retinoic acid (RAR) and thyroid hormone (TR) receptors] is a class of proteins that reside in the cytoplasm, or the nucleus, and bind their lipophilic hormone ligands in these locations since the hormones are capable of freely penetrating the hydrophobic plasma membrane. Because these receptors bind ligand intracellularly and then interact with DNA directly they are more commonly called the nuclear receptors (NR). In addition to binding hormone, all receptors of this class are capable of directly activating gene transcription.

All of the steroid hormones (e.g. progesterone, aldosterone, estradiol, cortisol) bind their receptors in the cytosol, whereas the non-steroidal hormones that bind nuclear receptors (e.g. thyroid hormones, calcitriol, retinoic acid), do so within the nucleus.

The cytosol localized nuclear hormones are “trapped” in this location through interaction with proteins of the heat shock family. When steroid hormones bind their receptors in the cytosol the ligand-receptor complex is dissociated from the heat shock proteins and the complex migrates to nucleus where it binds to specific DNA sequences termed hormone response elements (HRE). The binding of the complex to an HRE results in altered transcription rates of the associated gene.

The non-steroidal hormones that activate nuclear receptors are constitutively present in the nucleus bound to their target genes in the absence of their cognate hormones. These receptors exhibit potent transcriptional repression function in the absence of hormones and the repressor function is mapped to the domain that is responsible for binding ligand.

Analysis of the human genome has revealed 48 nuclear receptor genes that can be classified into seven defined subfamilies. Many of these genes are capable of yielding more than one receptor isoform. The nuclear receptors all contain a ligand-binding domain (LBD), a DNA-binding domain (DBD) and, in most cases, two activation function domains (identified as AF-1 and AF-2). The activity of the AF-1 domain is independent of the presence of ligand bound to the LBD, whereas the activity of the AF-2 domain is dependent upon ligand being bound to the LBD. Based upon the sequences of these two domains the nuclear receptor family is divided into six sub-families.

Some members of the family bind to DNA as homodimers such as is the case for subfamily III receptors which comprises the steroid receptors such as the estrogen receptor (ER), mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR), and the glucocorticoid receptor (GR). Other family members (such as all subfamily I members) bind to DNA as heterodimers through interactions with the retinoid X receptors (RXR). In addition to the steroid hormone and thyroid hormone receptors there are numerous additional family members that bind lipophilic ligands. These include the retinoid X receptors (RXR), the liver X receptors (LXR), the farnesoid X receptors (FXR) and the peroxisome proliferator-activated receptors (PPAR).

Table of the Nuclear Receptor Families

Receptor NomenclatureReceptor Common NameHuman Gene Name
Type 1A: Thyroid Hormone Receptors
NR1A1thyroid hormone receptor-αTHRA
NR1A2thyroid hormone receptor-βTHRB
Type 1B: Retinoic Acid Receptors (RAR)
NR1B1retinoic acid receptor-α (RARα)RARA
NR1B2retinoic acid receptor-β (RARβ)RARB
NR1B3retinoic acid receptor-γ (RARγ)RARG
Type 1C: Peroxisome Proliferator-Activated Receptors (PPAR)
NR1C1peroxisome proliferator-activated receptor-α (PPARα)PPARA
NR1C2peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)PPARD
NR1C3peroxisome proliferator-activated receptor-γ (PPARγ)PPARG
Type 1D: Reverse ERBA Receptors
NR1D1Thyroid hormone receptor, α-1-like (Rev-erbα)THRAL
NR1D2Rev-erbα-related receptor (Rev-erbγ)RVR
Type 1F: RAR-Related Orphan Receptors
NR1F1RAR-related orphan receptor-αRORA
NR1F2RAR-related orphan receptor-βRORB
NR1F3RAR-related orphan receptor-γRORC
Type 1H: Liver X Receptor-Like Receptors
NR1H2liver X receptor-β (LXRβ)NR1H2
NR1H3liver X receptor-α (LXRα)NR1H3
NR1H4farnesoid X receptor (FXR)NR1H4
NR1H5farnesoid X receptor-β (FXRβ)NR1H5P
Type 1I: Vitamin D Receptor-Like Receptors
NR1I1vitamin D receptor (VDR)VDR
NR1I2pregnane X receptor (PXR)NR1I2
NR1I3constitutive androstane receptor (CAR)NR1I3
Type 2A: Hepatocyte Nuclear Factor-4 (HNF4) Receptors
NR2A1hepatocyte nuclear factor-4-α (HNF-4α)HNF4A
NR2A2hepatocyte nuclear factor-4-γ (HNF-4γ)HNF4G
Type 2B: Retinoid X Receptors (RXR)
NR2B1retinoid X receptor-α (RXRα)RXRA
NR2B2retinoid X receptor-β (RXRβ)RXRB
NR2B3retinoid X receptor-γ (RXRγ)RXRG
Type 2C: Testis Receptors
NR2C1testes receptor 2TR2
NR2C2testicular nuclear receptor 4TR4, TAK1
Type 2E: Orphan Ligand Receptors
NR2E1homolog of Drosophila taillessTLX
NR2E3photoreceptor-specific nuclear receptorPNR
Type 2F: Chicken Ovalbumin Upstream Promoter Transcription Factor-Related Receptors
NR2F1chicken ovalbumin upstream promoter transcription factor 1TFCOUPI
NR2F2chicken ovalbumin upstream promoter transcription factor 2TFCOUPII
NR2F6ERBA-related 2EAR2
Type 3A: Estrogen Receptors
NR3A1estrogen receptor-αESR1
NR3A2estrogen receptor-βESR2
Type 3B: Estrogen Receptor-Related Receptors
NR3B1estrogen receptor-relatedαESRRA
NR3B2estrogen receptor-relatedβESRRB
NR3B3estrogen receptor-relatedγESRG
Type 3C: Steroid Receptors
NR3C1glucocorticoid receptorGCCR
NR3C2mineralocorticoid receptorMR
NR3C3progesterone receptorPGR
NR3C4androgen receptorAR
Type 4A: Orphan Ligand Receptors
NR4A1nerve growth factor (NGF)-induced factor BNGFI-B
NR4A2nuclear receptor-related 1NURR1
NR4A3neuron-derived orphan receptor 1NOR1
Type 5A: Orphan Ligand Receptors
NR5A1steroidogenic factor 1SF1
NR4A2liver receptor homolog 1LRH-1
Type 6A: Orphan Ligand Receptors
NR6A1germ cell nuclear factorGCNF
Type 0B: DAX-Like Receptors
NR0B1DAX1NR0B1
NR0B2small heterodimer partner, SHPNR0B2

Although all members of the NR family possess activation function domains that are responsible for the regulation of transcription of target genes, the regulation of transcription is much more complex due to the association of numerous coregulatory proteins. These coregulatory proteins are of two distinct classes: those that function to co-activate the NR and those that function to co-repress the receptor complex. Co-activators are found to be associated with ligand-bound NR and, thereby, induce gene expression. Co-repressors selectively repress gene expression through interaction with NR that are ligand free or bound to antagonists.

In addition, coregulators can be classified into two main groups: one that modifies histones (e.g, by acetylation/deacetylation or methylation/demethylation) and the other that includes ATP-dependent chromatin remodeling factors. These remodeling factors modulate promoter accessibility to other transcription factors as well as to the basal transcriptional machinery. The properties of several members of each class of coregulator are discussed below.

Retinoid X Receptors: RXR

The RXR represent a class of receptors that bind the retinoid 9-cis-retinoic acid. There are three isotypes of the RXR: RXRα, RXRβ, and RXRγ and each isotype is composed of several isoforms. The RXR serve as obligatory heterodimeric partners for numerous members of the nuclear receptor family including those discussed below (PPAR, LXR, and FXR). In the absence of a heterodimeric binding partner the RXR are bound to hormone response elements (HRE) in DNA and are complexed with co-repressor proteins that include histone deacetylases (HDACs) and nuclear receptor corepressor 1 (NCoR1), or silencing mediator of retinoid and thyroid hormone receptor (SMRT; also called NCoR2).

RXRα is widely expressed with highest levels liver, kidney, spleen, placenta, and skin. The critical role for RXRα in development is demonstrated by the fact that null mice are embryonic lethals. RXRβ is important for spermatogenesis and RXRγ has a restricted expression in the brain and muscle.

Peroxisome Proliferator-Activated Receptors: PPAR

The PPAR family is composed of three family members: PPARα, PPARβ/δ, and PPARγ. Each of these receptors forms a heterodimer with the RXR. For more detailed information on the PPAR visit the PPAR page.

The first family member identified was PPARα and it was found by virtue of it binding to the fibrate class of anti-hyperlipidemic drugs and resulting in the proliferation of peroxisomes in hepatocytes, hence the derivation of the name of the protein. Although PPARγ and PPARδ are related to PPARα they do not stimulate peroxisome proliferation. Subsequently it was shown that PPARα is the endogenous receptor for polyunsaturated fatty acids. PPARα is highly expressed in the liver, skeletal muscle, heart, and kidney. Its function in the liver is to induce hepatic peroxisomal fatty acid oxidation during periods of fasting. Expression of PPARα is also seen in macrophage foam cells and vascular endothelium. Its role in these cells is thought to be the activation of anti-inflammatory and anti-atherogenic effects.

PPARγ is a master regulator of adipogenesis and is most abundantly expressed in adipose tissue. Low levels of expression are also observed in liver and skeletal muscle. PPARγ was identified as the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs. The mechanism of action of the TZDs is a function of the activation of PPARγ activity and the consequent activation of adipocytes leading to increased fat storage and secretion of insulin-sensitizing adipocytokines such as adiponectin.

PPARδ is expressed in most tissues and is involved in the promotion of mitochondrial fatty acid oxidation, energy consumption, and thermogenesis. PPARδ serves as the receptor for polyunsaturated fatty acids and VLDL. Current pharmacologic targeting of PPARδ is aimed at increasing HDL levels in humans since experiments in animals have shown that increased PPARδ levels result in increased HDL and reduced levels of serum triglycerides.

Liver X Receptors: LXR

There are two forms of the LXR: LXRα and LXRβ. The LXRs form heterodimers with the RXR and as such can regulate gene expression either upon binding oxysterols (e.g. 22R-hydroxycholesterol) or 9-cis-retinoic acid. Because the LXRs bind oxysterols they are important in the regulation of whole body cholesterol levels. The function of LXR in the liver is to mediate cholesterol metabolism by inducing the expression of SREBP-1c. SREBP-1c is a transcription factor involved in the control of the expression of numerous genes including several involved in cholesterol synthesis. For more detailed information on the LXR visit the LXR page.

Farnesoid X Receptors: FXR

There are two genes encoding FXR identified as FXRα and FXRβ. In humans at least four FXR isoforms have been identified as being derived from the FXRα gene as a result of activation from different promoters and the use of alternative splicing; FXRα1, FXRα2, FXRα3, and FXRα4. The FXR gene is also known as the NR1H4 gene (for nuclear receptor subfamily 1, group H, member 4). The FXR genes are expressed at highest levels in the intestine and liver.

FXR forms a heterodimer with members of the RXR family. Following heterodimer formation the complex binds to specific sequences in target genes resulting in regulated expression. One major target of FXR is the small heterodimer partner (SHP) gene. Activation of SHP expression by FXR results in inhibition of transcription of SHP target genes. Of significance to bile acid synthesis, SHP represses the expression of the cholesterol 7-hydroxylase gene (CYP7A1). CYP7A1 is the rate-limiting enzyme in the synthesis of bile acids from cholesterol.

The FXR were originally identified by their ability to bind farensol (an isoprene derivative) metabolites. However, subsequent research has demonstrated that FXR are receptors for bile acids which is the primary mechanism by which bile acids negatively regulate their own expression. In addition to binding bile acids, FXR have been shown to bind polyunsaturated fatty acids (PUFA) such as the omega-3 PUFA docosahexaenoic acid (DHA) and α-linolenic acid (ALA). Most recently, FXR has been shown to bind the androgen hormone, androsterone, derived via testosterone metabolism. For more detailed information on the FXR visit the FXR page.

Pregnane X Receptors: PXR

A particular receptor of this family that has been shown to bind numerous structurally unrelated chemicals was originally identified as the pregnane X receptor (PXR). PXR is highly expressed in the liver and is involved in mediating drug-induced multi-drug clearance. For this reason PXR is  important in protecting the body from harmful metabolites. An additional physiologically significant function of PXR is in the regulation of bile acid synthesis. PXR is a recognized receptor for lithocholic acid and other bile acid precursors. PXR activation leads to repression of bile acid synthesis due to its physical association with hepatocyte nuclear factor 4α (HNF-4α) causing this transcription factor to no longer be able to associate with the transcriptional co-activator PGC-1α (PPARγ co-activator 1α) which ultimately leads to loss of transcription factor activation of the rate-limiting enzyme of bile acid synthesis CYP7A1 which, as described above, is also the target of FXR action. In addition to regulation of bile acid metabolism, PXR represses the expression of the gluconeogenic enzyme PEPCK.

In addition to the nuclear receptors discussed here additional members are being identified all the time such at the estrogen related receptors (ERRβ and ERRγ), the retinoid-related orphan receptor (RORα), and the constitutive androstane receptor (CAR).

Nuclear Receptor Coactivators

The first nuclear receptor coactivator to be identified was steroid receptor coactivator-1 (SRC-1). To date, more than 400 coregulators (both coactivators and corepressors) have been identified. There are now known to exist three SRC gene families. SRC-1 (encoded by the NCOA1 gene), SRC-2 (also known as GRIP1 for glucocorticoid receptor-interacting protein 1 and TIF2 for transcriptional intermediary factor 2) encoded by the NCOA2 gene, and SRC-3 (also known as AIB1 for amplified in breast cancer 1 and TRAM-1 for thyroid hormone receptor activator molecule 1) encoded by the NCOA3 gene. The three members of the SRC family contain homologous domains and share between 50% and 54% amino acid sequence similarity. There is also a diverse family of enzymes that interact with and modify SRCs which includes histone acetyltransferases (HAT)histone methyltransferases (HMT), kinases, phosphatases, ubiquitin ligases, and small ubiquitin-related modifier (SUMO) ligases.

Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) is another critical NR coregulator. PGC-1α has been shown be involved in the regulation of metabolism and energy homeostasis. Indeed, expression levels of PGC-1α have been associated with genetic diseases associated with impaired mitochondrial function, including type 2 diabetes and obesity. Another important coactivator is cAMP response-element binding protein (CREB)-binding protein, CBP. CBP is closely related to another protein identified as p300 forming a family identified as p300-CBP.

Humans express seven genes in the CREB subfamily of the basic leucine zipper (bZIP) family of transcription factors. The seven CREB gene are identified as CREB1, CREB3, CREB5, and CREB3-like 1, 2, 3, and 4 (CREB3L1, CREB3L2, CREB3L3, and CREB3L4). The CREB3L3 encoded protein is commonly identified as CREBH. The CREB1 encoded proteins are most closely related in structure and function to two additional transcription factors called cAMP response element modulator (CREM) and activating transcription factor 1 (ATF-1). Another member of the activating transcription factor (ATF) family, ATF-4, was originally identified as CREB2.

CBP and p300 possess intrinsic histone acetyltransferase (HAT) activity that leads to relaxation of the chromatin structure near a NR target gene. Other chromatin remodeling complexes, such as coactivator-associated arginine methyltransferase 1 (CARM1), can also stimulate gene transcription by NRs as well as other transcription factors in combination with the SRC family of coactivators.

In addition to acting a coactivators for NRs, the SRC family proteins also interact with many different types of transcription factors and potentiate their transcriptional activity. These include p53, signal transducers and activators of transcription (STATs), nuclear factor-κB (NF-κB), hypoxia-inducible factor 1 (HIF1), and hepatocyte nuclear factor-4 (HNF4) to name just a few. Several extracellular stimuli, such as growth factors and cytokines, that activate membrane-spanning signal transducing receptors, generating phosphorylation codes on SRCs that lead to increased coactivator affinity for the androgen receptor (AR), estrogen receptor-alpha (ERα), and progesterone receptor (PR).

model of nuclear receptor (NR) coactivator complex assembly at a target gene
Model for nuclear receptor (NR) interactions with coactivators: An example of the transcription factor complexes associated with both the RXR and PPAR heterodimeric transcription factor complex at an HRE, and several basal transcription factors associated with RNA pol II at a target gene transcriptional start site. Binding of ligand to a particular PPAR results in assembly of the complete coregulatory (in this case coactivator) complex. Formation of the complex induces histone modifications (such as acetylation, Ac; and methylation, Me) that in turn alter chromatin structure allowing entry of the basal transcriptional machinery including RNA pol II. The complete assembly then leads to activation of target gene transcription.

Nuclear Receptor Corepressors

As a general rule it has been established that when nuclear receptors are free of activating ligand they preferentially interact with corepressor complexes to mediate transcriptional repression. Nuclear receptor corepressor 1 (NCoR1) and silencing mediator of retinoic and thyroid receptors (SMRT) are the most well-characterized NR corepressor complexes. The core NCoR/SMRT protein complex consists of NCoR/SMRT, transducin β-like 1/related 1 (TBL1/TBLR1), histone deacetylase 3 (HDAC3), and G-protein pathway suppressor 2 (GPS2). NCoR and SMRT serve as the docking sites for corepressor complex assembly. NCoR/SMRT bind NR and associate with each of the other complex subunits.

As discussed above, when the NR interacts with ligand, transcriptional activation results due to the ability of the NR-ligand complex to recruit coactivator proteins and displace corepressor proteins. Nuclear receptor corepressors can inhibit the transcriptional activity of most members of the NR superfamily. As always in biology, there are a few exceptions to the general rule of  unliganded NR binding corepressors. These exceptions include LCoR (ligand-dependent nuclear-receptor corepressor), RIP140 (receptor-interacting protein-140) and REA (repressor of estrogen-receptor activity). These repressors bind to NR in a ligand-dependent manner and compete with coactivators by displacing them. In addition, there are several coregulatory factors, such as the ATP-dependent chromatin remodeling complexes SWI/SNF (switching of mating type/sucrose non-fermenting, chromatin remodeling complex), which have been shown to be involved in the regulation of both transcriptional activation and repression.

model of nuclear receptor (NR) corepressor complex assembly at a target gene
Model for nuclear receptor (NR) interactions with corepressor: An example of the transcription corepressor complexes associated with both the RXR and RAR heterodimeric transcription factor complex at an HRE, and several basal transcription factors associated with RNA pol II at a target gene transcriptional start site. The presence of histone deacetylases (e.g. HDAC3) leads to removal of any chromatin activating histone acetylation sites causing formation of transcriptionally repressed chromatin structure.