Signal Transduction Pathways

Signal transduction pathway definition

The term signal transduction pathway is used to describe the branched molecular network through which signaling molecules are sequentially activated (or deactivated) to carry out a specific cellular function. The signal transduction pathway is set off when a ligand binds to a cell-surface receptor during cell signaling.

The three stages of cell signaling and the signal transduction pathway

Cell signaling is the process by which a cell responds to messages from its external environment through protein receptors. When a ligand binds to a receptor--a protein that is found inside or on the surface of the target cell--a signal is transmitted, triggering a specific cellular process.

A signal transduction pathway has three basic stages:

1. Signal reception: The cell detects a signal when a chemical signal called a ligand binds to a receptor protein on the cell surface.

2. Signal transduction: The signaling molecule changes the cell-surface receptor protein. The signal is relayed by each molecule changing the next molecule in the pathway.

3. Cellular response: The signal initiates a specific cellular process.

Signal transduction pathway diagram and steps

The process of signal transduction is depicted in Figure 1 below.

Fig. 1 This diagram shows the three stages of cell signaling or signal transduction.

Cell Signaling Steps: Signal Reception

Molecules that deliver signals are called ligands, while the protein molecules in the cell to which ligands bind are called receptors. When a ligand binds to an internal receptor, the signal does not need to be passed onto other receptors or messengers. On the other hand, when a ligand binds to a cell-surface receptor, the signal is passed on to other molecules in a process called signal transduction.

Cell Signaling Steps: Signal Transduction

In a signal transduction pathway, second messengers, enzymes, and activated proteins interact with specific proteins, which are consequently activated in a chain reaction that converts extracellular signals to intracellular signals and ultimately triggers a specific cellular response.

Interactions that take place before a certain point are called upstream events, while those that take place after such point are called downstream events.

Most of the cell's proteins can influence downstream processes depending on the conditions within the cell. The interaction of two or more signaling pathways can cause a single pathway to branch off toward different endpoints. In addition, the same ligands are frequently involved in the transmission of different signals in different cell types. The difference in response is linked to variations in protein expression among cell types. Another factor is the signal integration of the pathways, which occurs when signals from two or more separate cell-surface receptors combine to trigger the same cell response.

Enzymatic cascades can also enhance the impact of extracellular signals. The signal may be initiated when a single ligand binds to a single receptor. However, the activation of an enzyme-linked receptor can activate several copies of a signaling cascade component, amplifying the signal.

Because of these complications, a signal transduction pathway can be better described as a branching network than a linear chain.

Once the signal is relayed from the external environment of the cell into the inner surface of the plasma membrane, it can take two major routes toward the cell interior depending on the type of receptor that is activated, that is, by second messenger or by protein recruitment.

Via second messenger

The first type of receptor transmits a signal from its cytoplasmic region to an adjacent enzyme–called an effector–which produces a second messenger. Second messengers are small intracellular mediators that either activate or deactivate certain proteins. It can either diffuse through the cytosol or stay embedded in the plasma membrane. Second messengers tend to be more prominent in the signaling pathway when a rapid, widespread response is needed.

An example of a second messenger is the calcium ion (Ca2+) which, in response to a signal, is released in large quantities and quickly diffused through the cytosol. Calcium ions are responsible for the mediation and coordination of skeletal muscle cell contraction. Like calcium ions, other water-soluble second messengers including cAMP and cGMP diffuse through the cytosol. On the other hand, lipid-soluble messengers such as diacylglycerol (DAG) diffuse through the interior of the plasma membrane where other key signaling proteins are embedded.

Signaling can be terminated by eliminating the extracellular messenger molecule. This is carried out by specific enzymes that destroy corresponding molecules. There are also cases in which active receptors are internalized by the cell and degraded together with its ligand.

Signal transduction pathway examples: two important types

Now that we have discussed the basics of the signal transduction pathway, let’s move on to specific examples of signaling transduction pathways.

Here we will discuss the JAK-STAT pathway that plays a role in the transcription of the casein gene during milk production. We will also discuss the Hedgehog Pathway which plays an important role in limb and neural differentiation in vertebrates.

JAK-STAT pathway

Receptor kinases are a type of membrane-bound receptor protein capable of phosphorylation (adding phospate groups to other proteins). Receptor tyrosine kinases (RTK) are receptor kinases that add phosphate groups to tyrosine residue. RTK are activated when a ligand binds to it, causing the RTK to undergo dimerization (two molecules forming a chemical bond), which then activates its phosphorylation function.

The JAK-STAT pathway transmits information from the cell membrane to the nucleus. It plays an important role in the activation of the gene called casein during milk production.

STAT–which stands for signal transducers and activators of transcription–proteins make up the transcription factors that are phosphorylated by some receptor tyrosine kinases (RTK) such as the JAK family.

An endocrine factor called prolactin binds to the extracellular domains of prolactin receptors, resulting in their dimerization. Each of these receptors have a JAK protein kinase bound to them, and with these JAK proteins now brought together, they can phosphorylate the receptors in various sites.

The JAK proteins transform receptors into an RTK. With this, the receptors are now ready to phosphorylate inactive STATs, resulting in their dimerization. The dimers formed are actually the active form of the STAT transcription factors, so they are ready to be moved to the nucleus where they will bind to certain parts of DNA.

In the case of milk production, these transcription factors will bind to the upstream promoter elements of casein, which initiates its transcription.

The Hedgehog Pathway

Members of the Hedgehog protein family bind to protein receptors known as Patched. Patched proteins bind to a signal transducer, the Smoothened protein, and prevents it from functioning.

If Hedgehog does not bind to Patched, the Smoothened protein is not active, and a protein called Cubitus interruptus (Ci) is tethered to the responding cell’s microtubules. The Ci is cleaved while on the microtubules in a way that allows a segment to enter the nucleus and function as a transcriptional repressor. This segment of the Ci protein inhibits transcription by attaching to the enhancers and promoters of specific genes.

On the other hand, if Hedgehog binds to Patched, the Patched protein's shape changes so that it no longer inhibits Smootshened. The entire Ci protein can now move to the nucleus and function as a transcriptional activator of the same genes it would have otherwise repressed.

In vertebrates, the Hedgehog pathway is crucial for limb and neural differentiation. Mice that were bred to be homozygous for a mutant allele of Sonic Hedgehog showed severe limb deformities in addition to cyclopia, or having a single eye in the middle of the forehead (Fig. 2).

Fig. 2: Image depicting two different types of cyclopia.