Cell Signaling

Index to this page

Introduction

Cells must be ready to respond to essential signals in their environment. These are often chemicals in the extracellular fluid (ECF) from: They may also respond to

Signaling molecules may trigger:

  1. an immediate change in the metabolism of the cell (e.g., increased glycogenolysis when a liver cell detects adrenaline);
  2. an immediate change in the electrical charge across the plasma membrane (e.g., the source of action potentials);
  3. a change in the gene expression — transcription — within the nucleus. (These responses take more time.)
It is the third category that is the topic of this page.

So this page examines some of the major pathways by which the arrival of a chemical signal at a cell turns on a new pattern of gene expression.

Two categories of signaling molecules (steroids and nitric oxide) diffuse into the cell where they bind internal receptors.

The others, e.g., proteins, bind to receptors displayed at the surface of the cell. These are transmembrane proteins whose

Steroid Receptors

Steroids are small hydrophobic molecules that can freely diffuse across the plasma membrane, through the cytosol, and into the nucleus.

Receptors

Steroid receptors are homodimers of zinc-finger proteins that reside within the nucleus (except for the glucocorticoid receptor which resides in the cytosol until it binds its ligand).

Until their ligand finds them, some steroid receptors within the nucleus associate with histone deacetylases (HDACs), keeping gene expression repressed in those regions of the chromosome.

Ligands

Some steroids that regulate gene expression:

Mechanism

Link to stereoscopic view of the glucocorticoid receptor bound to the promoter sequence of DNA.

Nitric Oxide (NO) Receptors

Receptors

The signaling functions of NO begin with its binding to protein receptors in the cell. The binding sites can be either:

Mechanism

In either case, binding triggers an allosteric change in the protein which, in turn, triggers the formation of a "second messenger" within the cell. The most common protein target for NO seems to be guanylyl cyclase, the enzyme that generates the second messenger cyclic GMP (cGMP).
Link to discussion of the various functions that depend on NO signaling.

G-Protein-Coupled Receptors (GPCRs)

Receptors

These are transmembrane proteins that wind 7 times back and forth through the plasma membrane. Humans have over 800 different GPCRs.

Ligands

Some of the many ligands that alter gene expression by binding GPCRs:

Mechanism

In addition to their roles in affecting gene expression, GPCRs regulate many immediate effects within the cell that do not involve gene expression. Links to some examples.

Turning GPCRs Off

A cell must also be able to stop responding to a signal.

Several mechanisms cooperate in turning GPCRs off.

Frizzled Receptors and Wnt Signaling

Receptors

Frizzled receptors, like GPCRs, are transmembrane proteins that wind 7 times back and forth through the plasma membrane.

Ligands

Their ligands are Wnt proteins. These get their name from two of the first to be discovered, proteins encoded by

The roles of β-catenin

β-catenin molecules connect actin filaments to the cadherins that make up adherens junctions that bind cells together.

Any excess β-catenin is quickly destroyed by a multiprotein degradation complex. (One component is the protein encoded by the APC tumor suppressor gene.)

The degradation complex

But undegraded β-catenin takes on a second function: it becomes a potent transcription factor.

Mechanism

(Note the similarities to the strategy used by the NF-κB signaling pathway.)

Wnt-controlled gene expression plays many roles:

External Link
Animation of Wnt Signaling
Please let me know by e-mail if you find a broken link in my pages.)

The Hedgehog Signaling Pathway

Receptor

Patched (Ptc) — a 12-pass transmembrane protein embedded in the plasma membrane.

Ligands

Secreted hedgehog proteins (Hh) that diffuse to their targets. Mammals have three hedgehog genes encoding three different proteins. However, hedgehog was first identified in Drosophila, and the bristly phenotype produced by mutations in the gene gave rise to the name.

Mechanism

Hedgehog signaling plays many important developmental roles in the animal kingdom. For example, Mutations or other sorts of regulatory errors in the hedgehog pathway are associated with a number of birth defects as well as some cancers. Basal-cell carcinoma, the most common skin cancer (and, in fact, the most common of all cancers in much of the world), usually has mutations causing

The Notch Signaling Pathway

This pathway is found throughout the animal kingdom. It differs from many of the other signaling pathways discussed here in that the ligands as well as their receptors are transmembrane proteins embedded in the plasma membrane of cells. Thus, signaling in this pathway requires direct cell-to-cell contact.

Receptors

Notch proteins are single-pass transmembrane glycoproteins. They are encoded by four genes in vertebrates. However, the first notch gene was discovered in Drosophila where its mutation produced notches in the wings.

Ligands

Their ligands are also single-pass transmembrane proteins. There are many of them and often several versions within a family (such as the serrate and delta protein families).

Mechanism

When a cell bearing the ligand comes in contact with a cell displaying the notch receptor, the external portion of notch is cleaved away from the cell surface (and engulfed by the ligand-bearing cell by endocytosis). The internal portion of the notch receptor is cut away from the interior of the plasma membrane and travels into the nucleus where it activates transcription factors that turn the appropriate genes on (and off).

It would appear that proper development of virtually all organs (e.g., brain, immune system, pancreas, GI tract, heart, blood vessels, mammary glands) depends on notch signaling. Notch signaling appears to be a mechanism by which one cell tells an adjacent cell which path of differentiation to take (or not take).

Defects in notch signaling have been implicated in some cancers, e.g. melanoma.


Cytokine Receptors

Dozens of cytokine receptors have been discovered. Most of these fall into one or the other of two major families:
  1. Receptor Tyrosine Kinases (RTKs) and
  2. Receptors that trigger a JAK-STAT pathway.

1. Receptor Tyrosine Kinases (RTKs)

Receptors

The receptors are transmembrane proteins that span the plasma membrane just once. 58 different RTKs are found in humans.

Ligands

Some ligands that trigger RTKs:

Mechanism

Turning RTKs Off

A cell must also be able to stop responding to a signal. For growth factor receptors, failure to do so could lead to uncontrolled mitosis = cancer. For the RTKs, this is done by quickly engulfing and destroying the ligand-receptor complex by receptor-mediated endocytosis.

Proto-Oncogenes

It should not be surprising that anything which leads to the inappropriate expression of receptors that trigger cell division could lead to cancer (uncontrolled cell division).

An example:

The gene (EGFR) encoding the receptor for epidermal growth factor (EGF) is a proto-oncogene. Mutations in EGFR are common in several human cancers. Cetuximab (Erbitux®), a monoclonal antibody that blocks the epidermal growth factor receptor, shows promise against some colorectal cancers as well as cancers of the head and neck.

Two tyrosine kinase inhibitors

block the action of the EGF receptors on the cells of certain lung cancers and have shown some promise against these cancers.

Mutant versions of some of the "second-order" kinases are also associated with cancer:

2. JAK-STAT Pathways

Receptors

These consist of 2 identical single-pass transmembrane proteins (i.e., homodimers) embedded in the plasma membrane. Each of their cytoplasmic ends binds a molecule of a Janus kinase ("JAK").

Ligands

Many ligands trigger JAK-STAT pathways:

Mechanism

The JAK-STAT pathways are much shorter and simpler than the pathways triggered by RTKs, and so the response of cells to these ligands tends to be much more rapid.

Transforming Growth Factor-beta (TGF-β) Receptors

Receptors

Two types of single-pass transmembrane proteins that, when they bind their ligand, become kinases that attach phosphate groups to serine and/or threonine residues of their target proteins.

Ligands

Ligands for these receptors include:

Mechanism

Tumor-Suppressor Genes

The TGF-β signaling pathway suppresses the cell cycle in several ways. So it is not surprising that defects in the pathway are associated with cancer.

Mutations in the genes encoding are found in many cancers including pancreatic and colon cancer. Thus all these genes qualify as tumor-suppressor genes.

Tumor Necrosis Factor-alpha (TNF-α) Receptors and the NF-κB Pathway

TNF-α is made by macrophages and other cells of the immune system.

Receptors

Trimers of 3 identical cell-surface transmembrane proteins.

Ligands

Mechanism

In May 2003, the US FDA approved a proteasome inhibitor, called bortezomib (Velcade®) for treatment of multiple myeloma, a cancer of plasma cells. [More]

The monoclonal antibody infliximab binds to TNF-α, and shows promise against some inflammatory diseases such as rheumatoid arthritis.

In addition to its effects of gene expression, activation of the TNF-α receptor can lead to apoptosis of the cell. [Link]

The T-Cell Receptor for Antigen (TCR)

T cells use a transmembrane dimeric protein as a receptor for a particular combination of an antigen fragment nestled in the cleft [View] of a histocompatibility molecule.

Receptors

Link to How the T-cell receptor (TCR) is formed from gene fragments.

Ligands

Link to discussions of

Mechanism

Activation of the TCR (when aided by costimulator molecules also present in the plasma membrane — View)

The immunosuppressant drugs tacrolimus and cyclosporine inhibit calcineurin thus reducing the threat of transplant rejection by T cells.

Activation of the TCR, when accompanied by an as-yet-unidentified second signal, causes NF-AT to associate with a different transcription factor (designated Foxp3). Instead of activating the T cell, this turns on genes that convert the cell into a suppressive regulatory T cell (Treg) instead — Link.

Conclusions

Reading this page may help explain why such a large proportion of the genome of animals is devoted to genes involved in cell signaling.

Welcome&Next Search

13 November 2014