The many different ways cells can change their behavior in response to a signal.

Overview: cellular response

Cell signaling pathways vary a lot. Signals (a.k.a. ligands) and receptors come in many varieties, and binding can trigger a wide range of signal relay cascades inside the cell, from short and simple to long and complex.
Despite these differences, signaling pathways share a common goal: to produce some kind of cellular response. That is, a signal is released by the sending cell in order to make the receiving cell change in a particular way.
Generalized diagram of receptor-ligand binding, intracellular signal transduction, and cellular response. The cellular response stage is boxed.
In some cases, we can describe a cellular response at both the molecular level and the macroscopic (large-scale, or visible) level.
  • At the molecular level, we can see changes such as an increase in the transcription of certain genes or the activity of particular enzymes.
  • At the macroscopic level, we may be able to see changes in the outward behavior or appearance of the cell, such as cell growth or cell death, that are caused by the molecular changes.
In this article, we'll look at examples of cellular responses to signaling that happen at both the "micro" and "macro" levels.

Gene expression

Many signaling pathways cause a cellular response that involves a change in gene expression. Gene expression is the process in which information from a gene is used by the cell to produce a functional product, typically a protein. It involves two major steps, transcription and translation.
  • Transcription makes an RNA transcript (copy) of a gene's DNA sequence.
  • Translation reads information from the RNA and uses it to make a protein.
    Here is a little more detail about how gene expression happens in eukaryotic cells:
    1. The deoxyribonucleic acid (DNA) sequence of a gene is copied (transcribed) into ribonucleic acid (RNA), a step called transcription. The RNA is modified in the nucleus to make a functional messenger RNA (mRNA).
    2. The mRNA leaves the nucleus and enters the cytosol. There, it directs synthesis of a protein, indicating which amino acids should be added to the chain. This step is called translation.
    You can learn more about gene expression in the video on transcription and translation.
Signaling pathways can target either or both steps to alter the amount of a particular protein produced in a cell.

Example: Growth factor signaling

We can use the growth factor signaling pathway from the signal relay article as an example to see how signaling pathways alter transcription and translation.
This growth factor pathway has many targets, which it activates through a signaling cascade that involves phosphorylation (addition of phosphate groups to molecules). Some of the pathway's targets are transcription factors, proteins that increase or decrease transcription of certain genes. In the case of growth factor signaling, the genes have effects that lead to cell growth and division1^1. One transcription factor targeted by the pathway is c-Myc, a protein that can lead to cancer when it is too active ("too good" at promoting cell division)2,3^{2,3}.
Image showing two ways in which the growth factor signaling pathway regulates gene expression to produce a cellular response of cell growth and proliferation. Growth factors signaling acts through a cascade to activate an ERK kinase, and the image shows two types of targets the ERK kinase acts on. (In reality, it has many others. We are just look at these two cases as examples.)
1) Transcriptional regulation. The ERK kinase phosphorylates and activates the transcription factor c-Myc. c-Myc binds to DNA to alter expression of target genes, activating genes that promote cell growth and proliferation. The genes are transcribed into mRNA, which can be translated in the cytosol to make proteins.
2). Translational regulation. The ERK kinase phosphorylates MNK1, a protein in the cytosol that enhances translation of mRNAs, especially ones with complex secondary structure (that form hairpins). The greater translation of these mRNAs results in higher levels of the corresponding proteins.
The growth factor pathway also affects gene expression at the level of translation. For instance, one of its targets is a translational regulator called MNK1. Active MNK1 increases the rate of mRNA translation, especially for certain mRNAs that fold back on themselves to make hairpin structures (which would normally block translation). Many key genes regulating cell division and survival have mRNAs that form hairpin structures, and MNK1 allows these genes to be expressed at high levels, driving growth and division4,5^{4,5}.
Notably, neither c-Myc nor MNK1 is a "final responder" in the growth factor pathway. Instead, these regulatory factors, and others like them, promote or repress the production of other proteins (the orange blobs in the illustration above) that are more directly involved in carrying out cell growth and division.

Cellular metabolism

Some signaling pathways produce a metabolic response, in which metabolic enzymes in the cell become more or less active. We can see how this works by considering adrenaline signaling in muscle cells. Adrenaline, also known as epinephrine, is a hormone (produced by the adrenal gland) that readies the body for short-term emergencies. If you’re nervous before a test or competition, your adrenal gland is likely to be pumping out epinephrine.
When epinephrine binds to its receptor on a muscle cell (a type of G protein-coupled receptor), it triggers a signal transduction cascade involving production of the second messenger molecule cyclic AMP (cAMP). This cascade leads to phosphorylation of two metabolic enzymes— that is, addition of a phosphate group, causing a change in the enzymes' behavior.
The first enzyme is glycogen phosphorylase (GP). The job of this enzyme is to break down glycogen into glucose. Glycogen is a storage form of glucose, and when energy is needed, glycogen must be broken down. Phosphorylation activates glycogen phosphorylase, causing lots of glucose to be released.
The second enzyme that gets phosphorylated is glycogen synthase (GS). This enzyme is involving in building up glycogen, and phosphorylation inhibits its activity. This ensures that no new glycogen molecules are built when the current need is for glycogen to be broken down.
Through regulation of these enzymes, a muscle cell rapidly gets a large, ready pool of glucose molecules. The glucose is available for use by the muscle cell in response to a sudden surge of adrenaline—the “fight or flight” response.

Big-picture outcomes of cell signaling

The types of responses we’ve discussed above are events at the molecular level. However, a signaling pathway typically triggers a molecular event (or a whole array of molecular events) to in order to produce some larger outcome.
For instance, growth factor signaling causes a variety of molecular changes, including activation of the c-Myc transcription factor and MNK1 translational regulator, to promote the larger response of cell proliferation (growth and division). Similarly, epinephrine triggers the activation of glycogen phosphorylase and the breakdown of glycogen in order to provide a muscle cell with fuel for a rapid response.
Other important large-scale outcomes of cell signaling include cell migration, changes in cell identity, and induction of apoptosis (programmed cell death).

Example: Apoptosis

When a cell is damaged, unneeded, or potentially dangerous to an organism, it may undergo programmed cell death, or apoptosis. Apoptosis allows a cell to die in a controlled manner that prevents the release of potentially damaging molecules from inside the cell.
Internal signals (such as those triggered by damaged DNA) can lead to apoptosis, but so can signals from outside the cell. For example, most animal cells have receptors that interact with the extracellular matrix, a supportive network of proteins and carbohydrates. If the cell moves away from the extracellular matrix, signaling through these receptors stops, and the cell undergoes apoptosis. This system keeps cells from traveling through the body and proliferating out of control (and is "broken" in cancer cells that metastasize, or spread to new sites).
Apoptosis is also essential for normal embryological development. In vertebrates, for example, early stages of development include the formation of tissue between what will become individual fingers and toes. During the course of normal development, these unneeded cells must be eliminated, enabling fully separated fingers and toes to form. A cell signaling mechanism triggers apoptosis, which destroys the cells between the developing digits.
This section of the foot of a 15-day-old mouse embryo shows areas of tissue between the toes, which apoptosis will eliminate before the mouse is born. Image credit: "Response to the signal: FIgure 2," by OpenStax College, Biology, CC BY 4.0. Modification of work by Michal Mañas

Attribution:

This article is a modified derivative of “Response to the signal,” by OpenStax College, Biology (CC BY 3.0). Download the original article for free at http://cnx.org/contents/185cbf87-c72e-48f5-b51e-f14f21b5eabd@9.85.
The modified article is licensed under a CC BY-NC-SA 4.0 license.

References:

  1. Reece, J. B., Urry, L. A., Cain, M. L., Wasserman, S. A., Minorsky, P. V., and Jackson, R. B. (2011). Cell communication. In Campbell biology (10th ed.). San Francisco, CA: Pearson, 223.
  2. R&D Systems. (2015). The ERK signal transduction pathway. In Articles. Retrieved from https://www.rndsystems.com/resources/articles/erk-signal-transduction-pathway.
  3. Myc. (2015, October 8). Retrieved November 5, 2015 from Wikipedia: https://en.wikipedia.org/wiki/Myc.
  4. Wendel, H.-G. Silva, R. L. A., Malina, A., Mills, J. R., Zhu, H., Ueda, T., Watanabe-Fukunaga, R., Fukunaga, R., Teruya-Feldstein, J., Pelletier, J., and Lowe, S. W. (2007). Dissecting eIF4E action in tumorigenesis. Genes Dev., 21(24), 3232-3237. http://dx.doi.org/10.1101/gad.1604407.
  5. Hay, N. (2010). Mnk earmarks EIF4E for cancer therapy. PNAS, 107(32), 13975-13976. http://dx.doi.org/10.1073/pnas.1008908107.

References:

Berg, J. M., Tymoczko, J. L., and Stryer, L. (2002). Epinephrine and glucagon signal the need for glycogen breakdown. In Biochemistry (5th ed., section 21.3). New York, NY: W. H. Freeman. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK22429/.
Glycogen synthase. (2016, May 25). Retrieved July 23, 2016 from Wikipedia: https://en.wikipedia.org/wiki/Glycogen_synthase.
Hay, N. (2010). Mnk earmarks EIF4E for cancer therapy. PNAS, 107(32), 13975-13976. http://dx.doi.org/10.1073/pnas.1008908107.
Myc. (2015, October 8). Retrieved November 5, 2015 from Wikipedia: https://en.wikipedia.org/wiki/Myc.
Reece, J. B., Urry, L. A., Cain, M. L., Wasserman, S. A., Minorsky, P. V., and Jackson, R. B. (2011). Cell communication. In Campbell biology (10th ed., pp. 210-231). San Francisco, CA: Pearson.
R&D Systems. (2015). The ERK signal transduction pathway. In Articles. Retrieved from https://www.rndsystems.com/resources/articles/erk-signal-transduction-pathway.
Wendel, H.-G. Silva, R. L. A., Malina, A., Mills, J. R., Zhu, H., Ueda, T., Watanabe-Fukunaga, R., Fukunaga, R., Teruya-Feldstein, J., Pelletier, J., and Lowe, S. W. (2007). Dissecting eIF4E action in tumorigenesis. Genes Dev., 21(24), 3232-3237. http://dx.doi.org/10.1101/gad.1604407.
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