Response to the Cellular Signal

Termination of the Signal Cascade

Signal cascades convey signals to the cell through the phosphorylation of molecules by kinases.

Learning Objectives

Describe the process by which the signal cascade in cell communication is terminated

Key Takeaways

Key Points

  • The chain of events that conveys the signal through the cell is called a signaling pathway or cascade.
  • Phosphorylation, a major component of signal cascades, adds a phosphate group to proteins, thereby changing their shapes and activating or inactivating the protein.
  • Degrading or removing the ligand so it can no longer access its receptor terminates the signal.
  • Enzymes like phosphotases can remove phosphate groups on proteins during dephosphorylation and reverse the cellular modifications produced by signaling cascades.

Key Terms

  • signaling cascade: the chain of events that conveys the signal through the cell
  • phosphorylation: the addition of a phosphate group to a compound; often catalyzed by enzymes
  • dephosphorylation: the removal of phosphate groups from a compound; often catalyzed by enzymes

Termination of the Signal Cascade

Ligand binding to the receptor allows for signal transduction through the cell. The chain of events that conveys the signal through the cell is called a signaling pathway or cascade. Signaling pathways are often very complex because of the interplay between different proteins. A major component of cell signaling cascades is the phosphorylation of molecules by enzymes known as kinases. Phosphorylation adds a phosphate group to serine, threonine, and tyrosine residues in a protein, changing their shapes, and activating or inactivating the protein.

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Phosphorylation: In protein phosphorylation, a phosphate group is added to residues of the amino acids serine, threonine, and tyrosine.

The aberrant signaling often seen in tumor cells is proof that the termination of a signal at the appropriate time can be just as important as the initiation of a signal. One method of terminating or stopping a specific signal is to degrade or remove the ligand so that it can no longer access its receptor. One reason that hydrophobic hormones like estrogen and testosterone trigger long-lasting events is because they bind carrier proteins. These proteins allow the insoluble molecules to be soluble in blood, but they also protect the hormones from degradation by circulating enzymes.

Inside the cell, many different enzymes reverse the cellular modifications that result from signaling cascades. For example, phosphatases are enzymes that remove the phosphate group attached to proteins by kinases in a process called dephosphorylation. Cyclic AMP (cAMP) is degraded into AMP by phosphodiesterase, and the release of calcium stores is reversed by the Ca2+ pumps that are located in the external and internal membranes of the cell.

Cell Signaling and Gene Expression

Gene expression, vital for cells to function properly, is the process of turning on a gene to produce RNA and protein.

Learning Objectives

Describe the regulation of gene expression

Key Takeaways

Key Points

  • Each cell controls when and how its genes are expressed.
  • Malfunctions in the control of gene expression are detrimental to the cell and can lead to the development of many diseases, such as cancer.
  • In prokaryotic cells, the control of gene expression is mostly at the transcriptional level.
  • In eukaryotic cells, the control of gene expression is at the epigenetic, transcriptional, post-transcriptional, translational, and post-translational levels.

Key Terms

  • translation: a process occurring in the ribosome in which a strand of messenger RNA (mRNA) guides assembly of a sequence of amino acids to make a protein
  • gene expression: the transcription and translation of a gene into messenger RNA and, thus, into a protein
  • transcription: the synthesis of RNA under the direction of DNA

Gene Expression

For a cell to function properly, necessary proteins must be synthesized at the proper time. All cells control or regulate the synthesis of proteins from information encoded in their DNA. The process of turning on a gene to produce RNA and protein is called gene expression.

Whether in a simple unicellular organism or a complex multi-cellular organism, each cell controls when and how its genes are expressed. For this to occur, there must be a mechanism to control when a gene is expressed to make RNA and protein; how much of the protein is made; and when it is time to stop making that protein because it is no longer needed. The regulation of gene expression conserves energy and space. It would require a significant amount of energy for an organism to express every gene at all times, so it is more energy efficient to turn on the genes only when they are required. In addition, only expressing a subset of genes in each cell saves space because DNA must be unwound from its tightly-coiled structure to transcribe and translate the DNA. Cells would have to be enormous if every protein were expressed in every cell all the time. The control of gene expression is extremely complex. Malfunctions in this process are detrimental to the cell and can lead to the development of many diseases, including cancer.

Prokaryotic versus Eukaryotic Gene Expression

To understand how gene expression is regulated, we must first understand how a gene codes for a functional protein in a cell. The process occurs in both prokaryotic and eukaryotic cells, just in slightly different manners. Prokaryotic organisms are single-celled organisms that lack a cell nucleus; their DNA floats freely in the cell cytoplasm. To synthesize a protein, the processes of transcription and translation occur almost simultaneously. When the resulting protein is no longer needed, transcription stops. As a result, the primary method to control what type of protein and how much of each protein is expressed in a prokaryotic cell is the regulation of DNA transcription. All of the subsequent steps occur automatically. When more protein is required, more transcription occurs. Therefore, in prokaryotic cells, the control of gene expression is mostly at the transcriptional level.

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Prokaryotic & Eukaryotic Gene Expression: Prokaryotic transcription and translation occur simultaneously in the cytoplasm; regulation occurs at the transcriptional level. Eukaryotic gene expression is regulated during transcription and RNA processing, which take place in the nucleus, and during protein translation, which takes place in the cytoplasm. Further regulation may occur through post-translational modifications of proteins.

Eukaryotic cells, in contrast, have intracellular organelles that add to their complexity. In eukaryotic cells, the DNA is contained inside the cell’s nucleus where it is transcribed into RNA. The newly-synthesized RNA is then transported out of the nucleus into the cytoplasm where ribosomes translate the RNA into protein. The processes of transcription and translation are physically separated by the nuclear membrane: transcription occurs only within the nucleus, and translation occurs only outside the nucleus in the cytoplasm. The regulation of gene expression can occur at all stages of the process. Regulation may occur when the DNA is uncoiled and loosened from nucleosomes to bind transcription factors (epigenetic level); when the RNA is transcribed (transcriptional level); when the RNA is processed and exported to the cytoplasm after it is transcribed (post-transcriptional level); when the RNA is translated into protein (translational level); or after the protein has been made (post-translational level).

Cell Signaling and Cellular Metabolism

The rush of adrenaline that leads to greater glucose availability is an example of an increase in metabolism.

Learning Objectives

Explain how cellular metabolism can be altered

Key Takeaways

Key Points

  • The activation of β-adrenergic receptors in muscle cells by adrenaline leads to an increase in cyclic AMP.
  • Cyclic AMP activates PKA (protein kinase A), which phosphorylates two enzymes.
  • Phophorylation of the first enzyme promotes the degradation of glycogen by activating intermediate GPK that in turn activates GP, which catabolizes glycogen into glucose.
  • Phosphorylation of the second enzyme, glycogen synthase (GS), inhibits its ability to form glycogen from glucose.
  • The inhibition of glucose to form glycogen prevents a futile cycle of glycogen degradation and synthesis, so glucose is then available for use by the muscle cell.

Key Terms

  • cyclic adenosine monophosphate: cAMP, a second messenger derived from ATP that is involved in the activation of protein kinases and regulates the effects of adrenaline
  • epinephrine: (adrenaline) an amino acid-derived hormone secreted by the adrenal gland in response to stress
  • protein kinase A: a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP)

Increase in Cellular Metabolism

As the environments of most organisms are constantly changing, the reactions of metabolism must be finely regulated to maintain a constant set of conditions within cells. Metabolic regulation also allows organisms to respond to signals and interact actively with their environments. Two closely-linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway. For example, an enzyme may show large changes in activity (i.e. it is highly regulated), but if these changes have little effect on the rate of a metabolic pathway, then this enzyme is not involved in the control of the pathway.

The result of one such signaling pathway affects muscle cells and is a good example of an increase in cellular metabolism. The activation of β-adrenergic receptors in muscle cells by adrenaline leads to an increase in cyclic adenosine monophosphate (also known as cyclic AMP or cAMP) inside the cell. Also known as epinephrine, adrenaline is a hormone (produced by the adrenal gland attached to the kidney) that prepares the body for short-term emergencies. Cyclic AMP activates PKA (protein kinase A), which in turn phosphorylates two enzymes. The first enzyme promotes the degradation of glycogen by activating intermediate glycogen phosphorylase kinase (GPK) that in turn activates glycogen phosphorylase (GP), which catabolizes glycogen into glucose. (Recall that your body converts excess glucose to glycogen for short-term storage. When energy is needed, glycogen is quickly reconverted to glucose. ) Phosphorylation of the second enzyme, glycogen synthase (GS), inhibits its ability to form glycogen from glucose. In this manner, a muscle cell obtains a ready pool of glucose by activating its formation via glycogen degradation and by inhibiting the use of glucose to form glycogen, thus preventing a futile cycle of glycogen degradation and synthesis. The glucose is then available for use by the muscle cell in response to a sudden surge of adrenaline—the “fight or flight” reflex.

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Formation of Cyclic AMP: This diagram shows the mechanism for the formation of cyclic AMP (cAMP). cAMP serves as a second messenger to activate or inactivate proteins within the cell.

Cell Signaling and Cell Growth

Cell growth is promoted by ligands known as growth factors.

Learning Objectives

Explain how cell growth is affected by growth factors.

Key Takeaways

Key Points

  • Normally, cells do not divide unless they are stimulated by signals from other cells.
  • Most growth factors, which promote cell growth, bind to cell-surface receptors that are linked to tyrosine kinases.
  • MAP kinase stimulates the expression of proteins that interact with other cellular components to initiate cell division.
  • Uncontrolled cell growth leads to cancer.

Key Terms

  • receptor: a protein on a cell wall that binds with specific molecules so that they can be absorbed into the cell in order to control certain functions
  • growth factor: a naturally-occurring substance capable of stimulating cellular growth, proliferation, and cellular differentiation
  • oncogene: any gene that contributes to the conversion of a normal cell into a cancerous cell when mutated or expressed at high levels

Cell Growth

Cell signaling pathways play a major role in cell division. Cells do not normally divide unless they are stimulated by signals from other cells. The ligands that promote cell growth are called growth factors. Most growth factors bind to cell-surface receptors that are linked to tyrosine kinases. These cell-surface receptors are called receptor tyrosine kinases (RTKs). Activation of RTKs initiates a signaling pathway that includes a G-protein called RAS, which activates the MAP kinase pathway described earlier. The enzyme MAP kinase then stimulates the expression of proteins that interact with other cellular components to initiate cell division. In addition, uncontrolled cell growth leads to cancer; mutations in the genes encoding protein components of signaling pathways are often found in tumor cells.

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Uncontrolled Cell Growth: Colorectal cancer occurs after numerous mutations to a normal cell.

Cancer Biologists & Uncontrolled Cell Growth

Cancer biologists study the molecular origins of cancer with the goal of developing new prevention methods and treatment strategies that will inhibit the growth of tumors without harming the normal cells of the body. Signaling pathways control cell growth. These pathways are controlled by signaling proteins, which are, in turn, expressed by genes. Mutations in these genes can result in malfunctioning signaling proteins. This prevents the cell from regulating its cell cycle, triggering unrestricted cell division and cancer. The genes that regulate the signaling proteins are one type of oncogene: a gene that has the potential to cause cancer. The gene encoding RAS is an oncogene that was originally discovered when mutations in the RAS protein were linked to cancer. Further studies have indicated that 30 percent of cancer cells have a mutation in the RAS gene that leads to uncontrolled growth. If left unchecked, uncontrolled cell division can lead tumor formation and metastasis, the growth of cancer cells in new locations in the body.

Cancer biologists have been able to identify many other oncogenes that contribute to the development of cancer. For example, HER2 is a cell-surface receptor that is present in excessive amounts in 20 percent of human breast cancers. Cancer biologists realized that gene duplication led to HER2 overexpression in 25 percent of breast cancer patients and developed a drug called Herceptin (trastuzumab), a monoclonal antibody that targets HER2 for removal by the immune system. Herceptin therapy helps to control signaling through HER2. Its use, in combination with chemotherapy, has helped to increase the overall survival rate of patients with metastatic breast cancer.

Cell Signaling and Cell Death

When a cell is damaged, unnecessary, or dangerous to an organism, a cell can initiate the mechanism for cell death known as apoptosis.

Learning Objectives

Describe how apoptosis is initiated

Key Takeaways

Key Points

  • Apoptosis allows a cell to die in a controlled manner by preventing the release of damaging molecules from inside the cell.
  • Internal checkpoints to monitor a cell’s health exist; if abnormalities are observed, a cell can also spontaneously initiate the process of apoptosis.
  • In some cases, such as a viral infection or cancer, the cell’s normal checks and balances fail.
  • External signaling can also initiate apoptosis.
  • Apoptosis is also essential for normal embryological development; unnecessary cells that appear during the early stages of development will eventually be eliminated through cell signaling.

Key Terms

  • apoptosis: a process of programmed cell death
  • glycoprotein: a protein with covalently-bonded carbohydrates

Apoptosis

When a cell is damaged, superfluous, or potentially dangerous to an organism, a cell can initiate a mechanism to trigger 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 Signaling

There are many internal checkpoints that monitor a cell’s health; if abnormalities are observed, a cell can spontaneously initiate the process of apoptosis. However, in some cases such as a viral infection or uncontrolled cell division due to cancer, the cell’s normal checks and balances fail.

External Signaling

External signaling can also initiate apoptosis. For example, most normal animal cells have receptors that interact with the extracellular matrix, a network of glycoproteins that provides structural support for cells in an organism. The binding of cellular receptors to the extracellular matrix initiates a signaling cascade within the cell. However, if the cell moves away from the extracellular matrix, the signaling ceases, and the cell undergoes apoptosis. This system keeps cells from traveling through the body and proliferating out of control, as happens with tumor cells that metastasize.

Another example of external signaling that leads to apoptosis occurs in T-cell development. T-cells are immune cells that bind to foreign macromolecules and particles, targeting them for destruction by the immune system. Normally, T-cells do not target “self” proteins (those of their own organism), a process that can lead to autoimmune diseases. In order to develop the ability to discriminate between self and non-self, immature T-cells undergo screening to determine whether they bind to so-called self proteins. If the T-cell receptor binds to self proteins, the cell initiates apoptosis to remove the potentially dangerous cell.

Apoptosis and Embryos

Apoptosis is also essential for normal embryological development. In vertebrates, for example, early stages of development include the formation of web-like tissue between individual fingers and toes. During the course of normal development, these unnecessary 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.

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Apoptosis: The histological section of a foot of a 15-day-old mouse embryo, visualized using light microscopy, reveals areas of tissue between the toes which apoptosis will eliminate before the mouse reaches its full gestational age at 27 days.