When a chemical signal binds to receptors on the surface of a cell, it sends out a signal that is relayed through the activation of one molecule after another. This is called a signal transduction pathway, and these pathways involve many proteins and enzymes. So, when any of these components are changed, cellular processes can become dysregulated and cause cancer and other diseases.
Here, we will review what cell signaling and signal transduction pathways before delving into what causes changes in signal transduction pathways and what effects these changes have on various cellular processes. We will also look into specific examples of these changes!
Recap: Cell Signaling And Signal Transduction Pathways
Cells respond to signals from its environment through cell signaling, a process in which a signaling molecule called ligand binds to a receptor protein in or on the surface of the target cell, initiating a specific cellular response.
The process of cell signaling takes place in three basic steps:
Signal reception: the ligand binds to the receptor protein in or on the surface of the target cell.
Signal transduction: the binding of the ligand to the receptor sends a signal that is relayed by receptors or second messengers in a signaling pathway. This step takes place when a ligand binds to a cell-surface receptor. On the other hand, if the ligand binds to an intracellular receptor, the receptor diffuses across the plasma membrane so they do not need to transmit the signal to other receptors or messengers via signal transduction.
Cellular response: the signal reaches its target protein and ultimately initiates a specific cellular process.
Cell signaling must be regulated so that the products of the reactions that are triggered by signaling molecules are produced at the proper time and place. Cell signaling is typically regulated by monitoring and controlling protein levels, localizing protein activities, and modifying the signaling molecule after translation.
Changes In Signal Transduction Pathways Overview
Signal transduction pathway (or signal cascade) refers to the branched molecular network that successively activates (or deactivates) signaling molecules to perform a certain biological function.
When there are changes or disruptions in signal transduction pathways, cellular response may be affected, or in worse cases, cause life-threatening diseases like cancer.
Causes Of Changes In Signal Transduction Pathways
So, what causes changes in signal transduction pathways? In this section, we will discuss three major causes: environmental conditions, mutations, and the presence of inhibitor or activator molecules.
Environmental Conditions
When environmental conditions such as temperature or pH are altered beyond a cell’s livable range, proteins and enzymes in signal transduction pathways can be denatured and lose their ability to function properly.
Denaturation refers to the modification of the molecular structure of a protein (Fig. 1). This involves breaking down weak bonds within a protein molecule that give the protein its highly ordered structure. For this reason, cells that are exposed to conditions outside of their livable range can die.
Mutations
Proteins and enzymes that take part of signal transduction are produced through protein synthesis. Protein synthesis depends on the nucleotide sequence within DNA, so any mutation in DNA will eventually have an impact on the protein that the mutated genes code for.
Because there are so many proteins in a single signal transduction pathway, there is a high risk of pathway disruption. However, not all proteins disrupt the system in the same way.
For example, if the gene that codes for the receptor protein is altered, the whole signal transduction pathway would be disrupted. In contrast, if an enzyme at the end of the signal cascade is altered, the impact on the pathway as a whole may be smaller since this enzyme is just one of hundreds or thousands that are responding to the original signal.
Inhibitors and Activator Molecules
A signal transduction pathway can be altered by a variety of inhibitors and activators, including substances like pesticides and some medications.
There are many different kinds of inhibitors that have the power to alter an enzyme's role in a signal transduction pathway, including:
Competitive inhibitors physically block the active site, preventing the substrate from entering.
Noncompetitive inhibitors bind to a different site on the enzyme but also hinder reaction catalysis.
Uncompetitive inhibitors bind to the enzyme-substrate complex, thereby preventing catalysis.
On the other hand, activators are molecules that reversibly or irreversibly bind to receptor proteins. Activators have the ability to activate pathways that would not have been activated otherwise. Many pesticides, for example, are strong activators of signal transduction pathways in neurons, resulting in hyperactivity in insect brains and, eventually, death.
Example Of How Changes In Signal Transduction Pathways Alter Cellular Response
In this section, we will discuss how changes in signal transduction pathways cause changes in cellular response. We will tackle two specific examples: changes in the insulin signaling pathway as well as cancer-causing dysregulation of signal transduction pathways.
Changes In Insulin Signaling Pathways
The hormone insulin is produced by the beta-cells in the pancreas. When pancreatic cells detect high levels of glucose in the bloodstream, insulin is released. Insulin molecules travel through the bloodstream until each molecule reaches a receptor tyrosine kinase protein on its target cells.
The binding of insulin with the receptor tyrosine kinase causes the dimerization of RTK proteins, which then causes the phosphorylation of their intracellular domains. Then, a phosphorylation cascade is initiated, activating a series of reactions all over the cell, including the binding of a vesicle containing glucose importers with the cell membrane, which then imports glucose from the bloodstream.
What happens when there are changes in this signaling pathway? Let’s say there is a mutation in the gene involved in the production of insulin, changing its shape or chemistry and thereby altering its ability to bind to the receptor. If this happens, the entire signal transduction pathway can be disrupted. This genetic condition causes neonatal diabetes.
Likewise, the genes that code for insulin receptors can be inherited with potentially dangerous mutations, resulting in Donohue syndrome which leads to leprechaunism, which manifests in the affected individual as small stature, bulging eyes, upturned nostrils, and thick lips. These mutations are extremely harmful because they occur at the start of the signal transduction pathway, resulting in full breakdown of the entire route.
Dimerization refers to the production of a dimer from two identical monomer units.
Phosphorylation is the addition of a phosphate group, while phosphorylation cascade is when phosphorylation takes place one after another, causing a series of reactions.
Cancer-causing Types Of Changes In Signal Transduction Pathways
Cancer causes increased cell proliferation–including resistance to apoptosis and other forms of cell death–genetic instability, metabolic changes, and a host of other definitive features, most of which are due to the dysregulation of signal transduction pathways.
The dysregulation of signal transduction pathways can be caused by oncogenic mutations which cause genes to be over expressed or produce proteins with dysregulated activities (Fig. 2).
Proteins affected by these mutations include growth factor receptor tyrosine kinases, lipid kinases, and nuclear receptors which are commonly activated in many physiological responses. Components of developmental signaling pathways such as Notch receptors, as well as downstream nuclear targets such as transcription factors can also be affected.
Another cause of dysregulation is the deletion or mutation of negative regulators which typically function as tumor suppressors, inactivating them. For example, one of the most common mutated genes is a tumor suppressor called p53 which regulates cell proliferation and stress signals that lead to apoptosis and damage responses. When p53 is lost due to deletion or mutation, it can contribute to cancer by reducing cell death and dysregulating the cell cycle.
Apoptosis, or programmed cell death is a mechanism that allows cells to die in a controlled way to prevent potentially harmful molecules from leaving the cell and causing damage to other cells.
Changes in Signal Transduction Pathways - Key takeaways
- Signal transduction pathway (or signal cascade): the branched molecular network that successively activates (or deactivates) signaling molecules to perform a certain biological function.
- When there are changes or disruptions in signal transduction pathways, cellular response may be affected, or in worse cases, cause life-threatening diseases like cancer.
- When environmental conditions such as temperature or pH are altered beyond a cell’s livable range, proteins and enzymes in signal transduction pathways can be denatured and lose their ability to function properly.
- Any mutation in DNA will eventually have an impact on the protein that the mutated genes code for. However, not all proteins disrupt the system in the same way.
- A signal transduction pathway can also be altered by a variety of inhibitors and activators.
References
- Sever R, Brugge JS. Signal transduction in cancer. Cold Spring Harb Perspect Med. 2015 Apr 1;5(4):a006098. doi: 10.1101/cshperspect.a006098. PMID: 25833940; PMCID: PMC4382731.
- “Origins of Cell Compartmentalization | AP Biology | Biology Dictionary.” Biology Dictionary, biologydictionary.net, 18 Dec. 2016, https://biologydictionary.net/ap-biology/4-4-changes-in-signal-transduction-pathways/.
- “Denaturation | Definition, Examples, & Facts.” Encyclopedia Britannica, www.britannica.com, https://www.britannica.com/science/denaturation. Accessed 2 Aug. 2022.
- Reece, Jane B., et al. Campbell Biology. Eleventh ed., Pearson Higher Education, 2016.
- Zedalis, Julianne, et al. Advanced Placement Biology for AP Courses Textbook. Texas Education Agency.
- Lee MJ, Yaffe MB. Protein Regulation in Signal Transduction. Cold Spring Harb Perspect Biol. 2016 Jun 1;8(6):a005918. doi: 10.1101/cshperspect.a005918. PMID: 27252361; PMCID: PMC4888820.
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