21 Chapter 21: Cell Communication and Signaling Cascades

Joshua Reid

Learning Objectives

By the end of this section, students should be able to:

21.1 Describe the four types of signaling found in multicellular organisms.

21.2 Construct a model that demonstrates the key elements of signal transduction pathways by which a signal is converted to a cellular response.

21.3 Justify claims based on scientific evidence that changes in signal transduction pathways can alter cellular response.

21.4 Construct an explanation of how certain drugs affect signal reception and, consequently, signal transduction pathways.

Overview of Cell Communication

Just like you communicate with your classmates face-to-face, using your phone, or via e-mail, cells communicate with each other by both inter’and intracellular signaling. Cells detect and respond to changes in the environment using signaling pathways. Signaling pathways enable organisms to coordinate cellular activities and metabolic processes. Errors in these pathways can cause disease. Signaling cells secrete molecules called ligands that bind to target cells and initiate a chain of events within the target cell. For example, when epinephrine is released, binding to target cells, those cells respond by converting glycogen to glucose. Cell communication can happen over short distances. For example, neurotransmitters are released across a synapse to transfer messages between neurons (Figure 21.2). Gap junctions and plasmodesmata allow small molecules, including signaling molecules, to flow between neighboring cells. Cell communication can also happen over long distances using. For example, hormones released from endocrine cells travel to target cells in multiple body systems. How does a ligand such as a hormone traveling through the bloodstream “know” when it has reached its target organ to initiate a cellular response? Nearly all cell signaling pathways involve three stages: reception, signal transduction, and cellular response.

Cell signaling pathways begin when the ligand binds to a receptor, a protein that is embedded in the plasma membrane of the target cell or found in the cell cytoplasm. The receptors are very specific, and each ligand is recognized by a different one. This stage of the pathway is called reception. Molecules that are nonpolar, such as steroids, diffuse across the cell membrane and bind to internal receptors. In turn, the receptor-ligand complex moves to the nucleus and interacts with cellular DNA. This changes how a gene is expressed. Polar ligands, on the other hand, interact with membrane receptor protein. Some membrane receptors work by changing conformation so that certain ions, such as Na+ and K+, can pass through the plasma membrane. Other membrane receptors interact with a G-protein on the cytoplasmic side of the plasma membrane, which causes a series of reactions inside the cell. Disruptions to this process are linked to several diseases, including cholera.

It is important to keep in mind that each cell has a variety of receptors, allowing it to respond to a variety of stimuli. Some receptors can bind several different ligands; for example, odorant molecules/receptors associated with the sense of smell in animals. Once the signaling molecule and receptor interact, a cascade of events called signal transduction usually amplifies the signal inside the cell.

There are two kinds of communication in the world of living cells. Communication between cells is called intercellular signaling, and communication within a cell is called intracellular signaling. An easy way to remember the distinction is by understanding the Latin origin of the prefixes: inter- means “between” (for example, intersecting lines are those that cross each other) and intra- means “inside” (like intravenous).

Chemical signals are released by signaling cells in the form of small, usually volatile or soluble molecules called ligands. A ligand is a molecule that binds another specific molecule, in some cases, delivering a signal in the process. Ligands can thus be thought of as signaling molecules. Ligands interact with proteins in target cells, which are cells that are affected by chemical signals; these proteins are also called receptors. Ligands and receptors exist in several varieties; however, a specific ligand will have a specific receptor that typically binds only that ligand.

Forms of Signaling

There are four categories of chemical signaling found in multicellular organisms: paracrine signaling, endocrine signaling, autocrine signaling, and direct signaling across gap junctions (Figure 21.1). The main difference between the different categories of signaling is the distance that the signal travels through the organism to reach the target cell. Not all cells are affected by the same signals.

The illustration shows four forms of chemical signaling. In autocrine signaling, a cell targets itself. In signaling across a gap junction, a cell targets a cell connected via gap junctions. In paracrine signaling, a cell targets a nearby cell. In endocrine signaling, a cell targets a distant cell via the bloodstream
Figure 21.1 In chemical signaling, a cell may target itself (autocrine signaling), a cell connected by gap junctions, a nearby cell (paracrine signaling), or a distant cell (endocrine signaling). Paracrine signaling acts on nearby cells, endocrine signaling uses the circulatory system to transport ligands, and autocrine signaling acts on the signaling cell. Signaling via gap junctions involves signaling molecules moving directly between adjacent cells.
Paracrine Signaling

Signals that act locally between cells that are close together are called paracrine signals. Paracrine signals move by diffusion through the extracellular matrix. These types of signals usually elicit quick responses that last only a short amount of time. In order to keep the response localized, paracrine ligand molecules are normally quickly degraded by enzymes or removed by neighboring cells. Removing the signals will reestablish the concentration gradient for the signal, allowing them to quickly diffuse through the intracellular space if released again.

One example of paracrine signaling is the transfer of signals across synapses between nerve cells. A nerve cell consists of a cell body, several short, branched extensions called dendrites that receive stimuli, and a long extension called an axon, which transmits signals to other nerve cells or muscle cells. The junction between nerve cells where signal transmission occurs is called a synapse. A synaptic signal is a chemical signal that travels between nerve cells. Signals within the nerve cells are propagated by fast-moving electrical impulses. When these impulses reach the end of the axon, the signal continues on to a dendrite of the next cell by the release of chemical ligands called neurotransmitters by the presynaptic cell (the cell emitting the signal). The neurotransmitters are transported across the very small distances between nerve cells, which are called chemical synapses (Figure 21.2). The small distance between nerve cells allows the signal to travel quickly; this enables an immediate response, such as, Take your hand off the stove!

When the neurotransmitter binds the receptor on the surface of the postsynaptic cell, the electrochemical potential of the target cell changes, and the next electrical impulse is launched. The neurotransmitters that are released into the chemical synapse are degraded quickly or get reabsorbed by the presynaptic cell so that the recipient nerve cell can recover quickly and be prepared to respond rapidly to the next synaptic signal.

This illustration shows closely juxtaposed bulbous protrusions of presynaptic and postsynaptic cells. The presynaptic cell stores neurotransmitter in synaptic vesicles. When signaling occurs, the vesicles fuse with the cell membrane, thereby releasing the neutrotransmitter, which then binds to receptors on the postsynaptic cell. An enzyme on the surface of the postsynaptic cell destroys the neurotrasmitter, thereby terminating the signal.
Figure 21.2 The distance between the presynaptic cell and the postsynaptic cell—called the synaptic gap—is very small and allows for rapid diffusion of the neurotransmitter. Enzymes in the synapatic cleft degrade some types of neurotransmitters to terminate the signal.
Endocrine Signaling

Signals from distant cells are called endocrine signals, and they originate from endocrine cells. (In the body, many endocrine cells are located in endocrine glands, such as the thyroid gland, the hypothalamus, and the pituitary gland.) These types of signals usually produce a slower response but have a longer-lasting effect. The ligands released in endocrine signaling are called hormones, signaling molecules that are produced in one part of the body but affect other body regions some distance away.

Hormones travel the large distances between endocrine cells and their target cells via the bloodstream, which is a relatively slow way to move throughout the body. Because of their form of transport, hormones get diluted and are present in low concentrations when they act on their target cells. This is different from paracrine signaling, in which local concentrations of ligands can be very high.

Autocrine Signaling

Autocrine signals are produced by signaling cells that can also bind to the ligand that is released. This means the signaling cell and the target cell can be the same or a similar cell (the prefix auto- means self, a reminder that the signaling cell sends a signal to itself). This type of signaling often occurs during the early development of an organism to ensure that cells develop into the correct tissues and take on the proper function. Autocrine signaling also regulates pain sensation and inflammatory responses. Further, if a cell is infected with a virus, the cell can signal itself to undergo programmed cell death, killing the virus in the process. In some cases, neighboring cells of the same type are also influenced by the released ligand. In embryological development, this process of stimulating a group of neighboring cells may help to direct the differentiation of identical cells into the same cell type, thus ensuring the proper developmental outcome.

Direct Signaling Across Gap Junctions

Gap junctions in animals and plasmodesmata in plants are connections between the plasma membranes of neighboring cells. These fluid-filled channels allow small signaling molecules, called intracellular mediators, to diffuse between the two cells. Small molecules, such as calcium ions (Ca2+), are able to move between cells, but large molecules like proteins and DNA cannot fit through the channels. The specificity of the channels ensures that the cells remain independent but can quickly and easily transmit signals. The transfer of signaling molecules communicates the current state of the cell that is directly next to the target cell; this allows a group of cells to coordinate their response to a signal that only one of them may have received. In plants, plasmodesmata are ubiquitous, making the entire plant into a giant communication network.

Reading Question #1

Insulin is a hormone produced by the pancreas to help regulate blood sugar levels. It is an important form of cell signaling. Insulin leaves the Islet cells of the pancreas and travels through the bloodstream to their target. What type of signaling is described here?

A) Paracrine

B) Endocrine

C) Autocrine

D) Gap Junctions


Types of Receptors

Receptors are protein molecules in the target cell or on its surface that bind ligand. There are two types of receptors, internal receptors and cell-surface receptors.

Internal receptors

Internal receptors, also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis (transcription) to mediate gene expression. Gene expression is the cellular process of transforming the information in a cell’s DNA into a sequence of amino acids, which ultimately forms a protein. When the ligand binds to the internal receptor, a conformational change is triggered that exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, then binds to specific regulatory regions of the chromosomal DNA and promotes the initiation of transcription (Figure 21.3). Transcription is the process of copying the information in a cells DNA into a special form of RNA called messenger RNA (mRNA); the cell uses information in the mRNA (which moves out into the cytoplasm and associates with ribosomes) to link specific amino acids in the correct order, producing a protein. Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers.

This illustration shows a hydrophobic signaling molecule that diffuses across the plasma membrane and binds an intracellular receptor in the cytoplasm. The intracellular receptor-signaling molecule complex then travels to the nucleus and binds DNA.
Figure 21.3 Hydrophobic signaling molecules typically diffuse across the plasma membrane and interact with intracellular receptors in the cytoplasm. Many intracellular receptors are transcription factors that interact with DNA in the nucleus and regulate gene expression.
Cell-Surface Receptors

Cell-surface receptors, also known as transmembrane receptors, are cell surface, membrane-anchored (integral) proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, in which an extracellular signal is converted into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

Because cell-surface receptor proteins are fundamental to normal cell functioning, it should come as no surprise that a malfunction in any one of these proteins could have severe consequences. Errors in the protein structures of certain receptor molecules have been shown to play a role in hypertension (high blood pressure), asthma, heart disease, and cancer.

Each cell-surface receptor has three main components: an external ligand-binding domain, a hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The ligand-binding domain is also called the extracellular domain. The size and extent of each of these domains vary widely, depending on the type of receptor.

Reading Check #2

Which type of receptor directly influences gene expression without the need for additional signaling molecules?

A) G-protein-linked receptors

B) Enzyme-linked receptors

C) Ion channel-linked receptors

D) Internal receptors


Evolution Connection

How Viruses Recognize a Host

Unlike living cells, many viruses do not have a plasma membrane or any of the structures necessary to sustain life. Some viruses are simply composed of an inert protein shell containing DNA or RNA. To reproduce, viruses must invade a living cell, which serves as a host, and then take over the hosts cellular apparatus. But how does a virus recognize its host?

Viruses often bind to cell-surface receptors on the host cell. For example, the virus that causes human influenza (flu) binds specifically to receptors on membranes of cells of the respiratory system. Chemical differences in the cell-surface receptors among hosts mean that a virus that infects a specific species (for example, humans) cannot infect another species (for example, chickens).

However, viruses have very small amounts of DNA or RNA compared to humans, and, as a result, viral reproduction can occur rapidly. Viral reproduction invariably produces errors that can lead to changes in newly produced viruses; these changes mean that the viral proteins that interact with cell-surface receptors may evolve in such a way that they can bind to receptors in a new host. Such changes happen randomly and quite often in the reproductive cycle of a virus, but the changes only matter if a virus with new binding properties comes into contact with a suitable host. In the case of influenza, this situation can occur in settings where animals and people are in close contact, such as poultry and swine farms. 1 Once a virus jumps to a new host, it can spread quickly. Scientists watch newly appearing viruses (called emerging viruses) closely in the hope that such monitoring can reduce the likelihood of global viral epidemics.

What requirements must be met for a new virus to emerge and spread?
  1. The virus must infect at least two different animals before infecting humans.
  2. The virus must come into contact with a new host so mutations will occur which allow the virus to bind to that host.
  3. A mutation must occur in the host allowing the virus to bind to the host.
  4. A mutation must occur in the virus allowing the virus to infect a new host, and the virus must come into contact with this host.

Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors.

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive membrane-spanning region. In order to interact with the phospholipid fatty acid tails that form the center of the plasma membrane, many of the amino acids in the membrane-spanning region are hydrophobic in nature. Conversely, the amino acids that line the inside of the channel are hydrophilic to allow for the passage of water or ions. When a ligand binds to the extracellular region of the channel, there is a conformational change in the proteins structure that allows ions such as sodium, calcium, magnesium, and hydrogen to pass through (Figure 21.4).

This illustration shows a gated ion channel that is closed in the absence of a signaling molecule. When a signaling molecule binds, a pore in the middle of the channel opens, allowing ions to enter the cell.
Figure 21.4 Gated ion channels form a pore through the plasma membrane that opens when the signaling molecule binds. The open pore then allows ions to flow into or out of the cell.
G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane (Figure 21.5). All G-protein-linked receptors have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-protein-binding site.

Cell signaling using G-protein-linked receptors occurs as a cyclic series of events. Before the ligand binds, the inactive G-protein can bind to a newly revealed site on the receptor specific for its binding. Once the G-protein binds to the receptor, the resultant shape change activates the G-protein, which releases GDP and picks up GTP. The subunits of the G-protein then split into the α subunit and the βγ subunit. One or both of these G-protein fragments may be able to activate other proteins as a result. After awhile, the GTP on the active α subunit of the G-protein is hydrolyzed to GDP and the βγ subunit is deactivated. The subunits reassociate to form the inactive G-protein and the cycle begins anew.

This illustration shows the activation pathway for a heterotrimeric G-protein, which has three subunits: alpha beta, and gamma, all associated with the inside of the plasma membrane. When a signaling molecule binds to a G-protein-coupled receptor in the plasma membrane, a GDP molecule associated with the alpha subunit is exchanged for GTP. The alpha subunit dissociates from the beta and gamma subunits and triggers a cellular response. Hydrolysis of GTP to GDP terminates the signal.
Figure 21.5 Heterotrimeric G proteins have three subunits: α, β, and γ. When a signaling molecule binds to a G-protein-coupled receptor in the plasma membrane, a GDP molecule associated with the α subunit is exchanged for GTP. The β and γ subunits dissociate from the α subunit, and a cellular response is triggered either by the α subunit or the dissociated βγ pair. Hydrolysis of GTP to GDP terminates the signal.

G-protein-linked receptors have been extensively studied and much has been learned about their roles in maintaining health. Bacteria that are pathogenic to humans can release poisons that interrupt specific G-protein-linked receptor function, leading to illnesses such as pertussis, botulism, and cholera. In cholera (Figure 21.6), for example, the water-borne bacterium Vibrio cholerae produces a toxin, choleragen, that binds to cells lining the small intestine. The toxin then enters these intestinal cells, where it modifies a G-protein that controls the opening of a chloride channel and causes it to remain continuously active, resulting in large losses of fluids from the body and potentially fatal dehydration as a result.

This 1866 poster warns people about a cholera epidemic and gives advice for preventing the disease.
Figure 21.6 Transmitted primarily through contaminated drinking water, cholera is a major cause of death in the developing world and in areas where natural disasters interrupt the availability of clean water. The cholera bacterium, Vibrio cholerae, creates a toxin that modifies G-protein-mediated cell signaling pathways in the intestines. Modern sanitation eliminates the threat of cholera outbreaks, such as the one that swept through New York City in 1866. This poster from that era shows how, at that time, the way that the disease was transmitted was not understood. (credit: New York City Sanitary Commission)

Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme. In some cases, the intracellular domain of the receptor itself is an enzyme. Other enzyme-linked receptors have a small intracellular domain that interacts directly with an enzyme. The enzyme-linked receptors normally have large extracellular and intracellular domains, but the membrane-spanning region consists of a single alpha-helical region of the peptide strand. When a ligand binds to the extracellular domain, a signal is transferred through the membrane, activating the enzyme. Activation of the enzyme sets off a chain of events within the cell that eventually leads to a response. One example of this type of enzyme-linked receptor is the tyrosine kinase receptor (Figure 21.7). A kinase is an enzyme that transfers phosphate groups from ATP to another protein. The tyrosine kinase receptor transfers phosphate groups to tyrosine molecules (tyrosine residues). First, signaling molecules bind to the extracellular domain of two nearby tyrosine kinase receptors. The two neighboring receptors then bond together, or dimerize. Phosphates are then added to tyrosine residues on the intracellular domain of the receptors (phosphorylation). The phosphorylated residues can then transmit the signal to the next messenger within the cytoplasm.

Reading Check #3

What is the primary function of G-protein-linked receptors in cell signaling?

A) Opening ion channels in the plasma membrane

B) Activating enzymes associated with the receptor

C) Directly influencing gene expression

D) Transferring phosphate groups to tyrosine residues


Visual Connection

This illustration shows two receptor tyrosine kinase monomers embedded in the plasma membrane. Upon binding of a signaling molecule to the extracellular domain, the receptors dimerize. Tyrosine residues on the intracellular surface are then phosphorylated, triggering a cellular response.
Figure 21.7 A receptor tyrosine kinase is an enzyme-linked receptor with a single transmembrane region, and extracellular and intracellular domains. Binding of a signaling molecule to the extracellular domain causes the receptor to dimerize. Tyrosine residues on the intracellular domain are then autophosphorylated, triggering a downstream cellular response. The signal is terminated by a phosphatase that removes the phosphates from the phosphotyrosine residues.
Refer to Figure 9.8
HER2 is a receptor tyrosine kinase. In 20 percent of human breast cancer cases, HER2 is permanently activated, resulting in unregulated cell division. Lapatinib, a drug used to treat breast cancer, inhibits HER2 receptor tyrosine kinase autophosphorylation, the process by which the receptor adds phosphates onto itself. This reduces tumor growth in patients by 50 percent. Besides autophosphorylation, predict which of the following steps would be inhibited by Lapatinib, and could likely be documented in its usage.
  1. dimerization and the downstream cellular response
  2. phosphatase activity, dimerization, and the downstream cellular response
  3. signaling molecule binding, dimerization, and the downstream cellular response
  4. the downstream cellular response

Signaling Molecules

Produced by signaling cells and the subsequent binding to receptors in target cells, ligands act as chemical signals that travel to the target cells to coordinate responses. The types of molecules that serve as ligands are incredibly varied and range from small proteins to small ions like calcium (Ca2+).

Small Hydrophobic Ligands

Small hydrophobic ligands can directly diffuse through the plasma membrane and interact with internal receptors. Important members of this class of ligands are the steroid hormones. Steroids are lipids that have a hydrocarbon skeleton with four fused rings; different steroids have different functional groups attached to the carbon skeleton. Steroid hormones include the female sex hormone, estradiol, which is a type of estrogen; the male sex hormone, testosterone; and cholesterol, which is an important structural component of biological membranes and a precursor of steroid hormones (Figure 21.8). Other hydrophobic hormones include thyroid hormones and vitamin D. In order to be soluble in blood, hydrophobic ligands must bind to carrier proteins while they are being transported through the bloodstream.

The molecular structures of estradiol, testosterone, and cholesterol are shown. All three molecules share a four-ring structure but differ in the types of functional groups attached to it.
Figure 21.8 Steroid hormones have similar chemical structures to their precursor, cholesterol. Because these molecules are small and hydrophobic, they can diffuse directly across the plasma membrane into the cell, where they interact with internal receptors.

Water-Soluble Ligands

Water-soluble ligands are polar and therefore cannot pass through the plasma membrane unaided; sometimes, they are too large to pass through the membrane at all. Instead, most water-soluble ligands bind to the extracellular domain of cell-surface receptors. This group of ligands is quite diverse and includes small molecules, peptides, and proteins.

Other Ligands

Nitric oxide (NO) is a gas that also acts as a ligand. It is able to diffuse directly across the plasma membrane, and one of its roles is to interact with receptors in smooth muscle and induce relaxation of the tissue. NO has a very short half-life and therefore only functions over short distances. Nitroglycerin, a treatment for heart disease, acts by triggering the release of NO, which causes blood vessels to dilate (expand), thus restoring blood flow to the heart.

Propagation of the Signal

During signal transduction, a series of relay proteins inside the cytoplasm of the target cell activate target proteins, resulting in a cellular response. These cascades are complex because of the interplay between proteins. A significant contributor to cell signaling cascades is the phosphorylation of molecules by enzymes known as kinases. (Substrate–level phosphorylation was studied when you learned about glycolysis.) By adding a phosphate group, phosphorylation changes the shapes of proteins. This change in shape activates or inactivates them. Second messengers, e.g., cAMP and Ca2+, are often used to transmit signals within a cell.

Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. Continuation of a signal in this manner is called signal transduction. Signal transduction only occurs with cell-surface receptors because internal receptors are able to interact directly with DNA in the nucleus to initiate protein synthesis.

When a ligand binds to its receptor, conformational changes occur that affect the receptor’s intracellular domain. Conformational changes of the extracellular domain upon ligand binding can propagate through the membrane region of the receptor and lead to activation of the intracellular domain or its associated proteins. In some cases, binding of the ligand causes dimerization of the receptor, which means that two receptors bind to each other to form a stable complex called a dimer. A dimer is a chemical compound formed when two molecules (often identical) join together. The binding of the receptors in this manner enables their intracellular domains to come into close contact and activate each other.

Binding Initiates a Signaling Pathway

After the ligand binds to the cell-surface receptor, the activation of the receptor’s intracellular components sets off a chain of events that is called a signaling pathway or a signaling cascade. In a signaling pathway, second messengers, enzymes, and activated proteins interact with specific proteins, which are in turn activated in a chain reaction that eventually leads to a change in the cell’s environment (Figure 21.9). The events in the cascade occur in a series, much like a current flows in a river. Interactions that occur before a certain point are defined as upstream events, and events after that point are called downstream events.


This illustration shows the epidermal growth factor receptor, which is embedded in the plasma membrane. Upon binding of a signaling molecule to the receptor’s extracellular domain, the receptor dimerizes, and intracellular residues are phosphorylated. Phosphorylation of the receptor triggers the phosphorylation of a protein called MEK by RAF. MEK, in turn, phosphorylates ERK. ERK stimulates protein translation in the cytoplasm, and transcription in the nucleus. Activation of ERK stimulates cell proliferation, cell migration and adhesion, and angiogenesis (growth of new blood vessels). ERK inhibits apoptosis.
Figure 21.9 The epidermal growth factor (EGF) receptor (EGFR) is a receptor tyrosine kinase involved in the regulation of cell growth, wound healing, and tissue repair. When EGF binds to the EGFR, a cascade of downstream events causes the cell to grow and divide. If EGFR is activated at inappropriate times, uncontrolled cell growth may occur.
In certain cancers, the GTPase activity of the RAS G-protein is inhibited. This means that the RAS protein can no longer hydrolyze GTP into GDP. What effect would this have on downstream cellular events?
  1. Cells will not proliferate.
  2. ERK is permanently inactivated.
  3. Regulated cell division.
  4. Uncontrolled cell proliferation.

Signaling pathways can get very complicated very quickly because most cellular proteins can affect different downstream events, depending on the conditions within the cell. A single pathway can branch off toward different endpoints based on the interplay between two or more signaling pathways, and the same ligands are often used to initiate different signals in different cell types. This variation in response is due to differences in protein expression in different cell types. Another complicating element is signal integration of the pathways, in which signals from two or more different cell-surface receptors merge to activate the same response in the cell. This process can ensure that multiple external requirements are met before a cell commits to a specific response.

The effects of extracellular signals can also be amplified by enzymatic cascades. At the initiation of the signal, a single ligand binds to a single receptor. However, activation of a receptor-linked enzyme can activate many copies of a component of the signaling cascade, which amplifies the signal.

Methods of Intracellular Signaling

The induction of a signaling pathway depends on the modification of a cellular component by an enzyme. There are numerous enzymatic modifications that can occur, and they are recognized in turn by the next component downstream. The following are some of the more common events in intracellular signaling.


Link to Learning

Observe an animation of cell signaling at this site.

Hemophilia is a rare condition in which the blood lacks sufficient clotting factors. These factors are required for the platelets to bind together and form clots. How does the absence of clotting interfere with the cell signals during wound healing?
  1. delay and prevention of the cell signal required for wound healing
  2. activate the cell signal required for wound healing
  3. activate and enhance the cell signals for wound healing
  4. cell signal will remain unaffected



One of the most common chemical modifications that occurs in signaling pathways is the addition of a phosphate group (PO4–3) to a molecule such as a protein in a process called phosphorylation. The phosphate can be added to a nucleotide such as GMP to form GDP or GTP. Phosphates are also often added to serine, threonine, and tyrosine residues of proteins, where they replace the hydroxyl group of the amino acid (Figure 21.10). The transfer of the phosphate is catalyzed by an enzyme called a kinase. Various kinases are named for the substrate they phosphorylate. Phosphorylation of serine and threonine residues often activates enzymes. Phosphorylation of tyrosine residues can either affect the activity of an enzyme or create a binding site that interacts with downstream components in the signaling cascade. Phosphorylation may activate or inactivate enzymes, and the reversal of phosphorylation, dephosphorylation by a phosphatase, will reverse the effect.

Molecular structures of phosphoserine, phosphothreonine and phosphotyrosine are shown. In each molecule, a phosphate is attached to an oxygen on the amino acid.
Figure 21.10 In protein phosphorylation, a phosphate group (PO4-3 ) is added to residues of the amino acids serine, threonine, and tyrosine.

Second Messengers

Second messengers are small molecules that propagate a signal after it has been initiated by the binding of the signaling molecule to the receptor. These molecules help to spread a signal through the cytoplasm by altering the behavior of certain cellular proteins.

Calcium ion is a widely used second messenger. The free concentration of calcium ions (Ca2+) within a cell is very low because ion pumps in the plasma membrane continuously use adenosine-5′-triphosphate (ATP) to remove it. For signaling purposes, Ca2+ is stored in cytoplasmic vesicles, such as the endoplasmic reticulum, or accessed from outside the cell. When signaling occurs, ligand-gated calcium ion channels allow the higher levels of Ca2+ that are present outside the cell (or in intracellular storage compartments) to flow into the cytoplasm, which raises the concentration of cytoplasmic Ca2+. The response to the increase in Ca2+ varies, depending on the cell type involved. For example, in the β-cells of the pancreas, Ca2+ signaling leads to the release of insulin, and in muscle cells, an increase in Ca2+ leads to muscle contractions.

Another second messenger utilized in many different cell types is cyclic AMP (cAMP). Cyclic AMP is synthesized by the enzyme adenylyl cyclase from ATP (Figure 21.11). The main role of cAMP in cells is to bind to and activate an enzyme called cAMP-dependent kinase (A-kinase). A-kinase regulates many vital metabolic pathways: It phosphorylates serine and threonine residues of its target proteins, activating them in the process. A-kinase is found in many different types of cells, and the target proteins in each kind of cell are different. Differences give rise to the variation of the responses to cAMP in different cells.

Cyclic AMP is made from ATP by the enzyme adenylyl cyclase. In the process, a pyrophosphate molecule composed of two phosphate residues is released. Cyclic AMP gets its name because the phosphate group is attached to the ribose ring in two places, forming a circle.
Figure 21.11 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. Termination of the signal occurs when an enzyme called phosphodiesterase converts cAMP into AMP.

Present in small concentrations in the plasma membrane, inositol phospholipids are lipids that can also be converted into second messengers. Because these molecules are membrane components, they are located near membrane-bound receptors and can easily interact with them. Phosphatidylinositol (PI) is the main phospholipid that plays a role in cellular signaling. Enzymes known as kinases phosphorylate PI to form PI-phosphate (PIP) and PI-bisphosphate (PIP2).

The enzyme phospholipase C cleaves PIP2 to form diacylglycerol (DAG) and inositol triphosphate (IP3) (Figure 21.12). These products of the cleavage of PIP2 serve as second messengers. Diacylglycerol (DAG) remains in the plasma membrane and activates protein kinase C (PKC), which then phosphorylates serine and threonine residues in its target proteins. IP3 diffuses into the cytoplasm and binds to ligand-gated calcium channels in the endoplasmic reticulum to release Ca2+ that continues the signal cascade.

The molecular structures of PIP_2, DAG, and IP_3 are shown. PIP_2 is a phospholipid that is cleaved by phospholipase C to form DAG, which has a long hydrophobic tail, and IP_3, a ring structure with three phosphates attached.
Figure 21.12 The enzyme phospholipase C breaks down PIP2 into IP3 and DAG, both of which serve as second messengers.

Response to the Signal

Inside the cell, ligands bind to their internal receptors, allowing them to directly affect the cell’s DNA and protein-producing machinery. Using signal transduction pathways, receptors in the plasma membrane produce a variety of effects on the cell. The results of signaling pathways are extremely varied and depend on the type of cell involved as well as the external and internal conditions. A small sampling of responses is described below.

Gene Expression

Some signal transduction pathways regulate the transcription of RNA. Others regulate the translation of proteins from mRNA. An example of a protein that regulates translation in the nucleus is the MAP kinase ERK. ERK is activated in a phosphorylation cascade when epidermal growth factor (EGF) binds the EGF receptor. Upon phosphorylation, ERK enters the nucleus and activates a protein kinase that, in turn, regulates protein translation (Figure 21.13).

This illustration shows the pathway by which ERK, a MAP kinase, activates protein synthesis. Phosphorylated ERK phosphorylates MNK1, which in turn phosphorylates eIF-4E, which is associated with mRNA. When eIF-4E is phosphorylated, the mRNA unfolds and protein synthesis begins.
Figure 21.13 ERK is a MAP kinase that activates translation when it is phosphorylated. ERK phosphorylates MNK1, which in turn phosphorylates eIF-4E, an elongation initiation factor that, with other initiation factors, is associated with mRNA. When eIF-4E becomes phosphorylated, the mRNA unfolds, allowing protein synthesis in the nucleus to begin.

The second kind of protein with which PKC can interact is a protein that acts as an inhibitor. An inhibitor is a molecule that binds to a protein and prevents it from functioning or reduces its function. In this case, the inhibitor is a protein called Iκ-B, which binds to the regulatory protein NF-κB. (The symbol κ represents the Greek letter kappa.) When Iκ-B is bound to NF-κB, the complex cannot enter the nucleus of the cell, but when Iκ-B is phosphorylated by PKC, it can no longer bind NF-κB, and NF-κB (a transcription factor) can enter the nucleus and initiate RNA transcription. In this case, the effect of phosphorylation is to inactivate an inhibitor and thereby activate the process of transcription.

Increase in Cellular Metabolism

The result of another signaling pathway affects muscle cells. The activation of β-adrenergic receptors in muscle cells by adrenaline leads to an increase in cyclic AMP (cAMP) inside the cell. Also known as epinephrine, adrenaline is a hormone (produced by the adrenal gland attached to the kidney) that readies 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) that 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.

Cell Growth

Cell signaling pathways also 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.


Reading Check #4

What is the primary function of second messengers in signal transduction?

A) To directly bind to internal receptors

B) To facilitate the diffusion of ligands across the plasma membrane

C) To propagate a signal initiated by the binding of a ligand to a receptor

D) To activate enzymes associated with cell-surface receptors


Career Connection

Cancer Biologist

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. As mentioned earlier, signaling pathways control cell growth. These signaling 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, which is 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 to 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). Herceptin is a monoclonal antibody that targets HER2 for removal by the immune system. Herceptin therapy helps to control signaling through HER2. The use of Herceptin in combination with chemotherapy has helped to increase the overall survival rate of patients with metastatic breast cancer.

More information on cancer biology research can be found at the National Cancer Institute website.

Cell Death

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. 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, the cell’s normal checks and balances fail. 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.

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, and target 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 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 (Figure 21.14). 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 photo shows a histological section of a foot of a 15-day-old mouse embryo. Tissue connects the space between the toes.
Figure 21.14 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. (credit: modification of work by Michal Mañas)

Termination of the Signal Cascade

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 stopping a specific signal is to degrade the ligand or remove it 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.


Reading Check #5

How does external signaling through the extracellular matrix contribute to apoptosis?

A) By promoting uncontrolled cell division.

B) By triggering a signaling cascade within the cell.

C) By preventing the release of potentially damaging molecules from inside the cell.

D) By ceasing signaling when cells move away from the extracellular matrix.





Adapted from Zedalis, J., & Eggebrecht. (2018). Biology for AP Courses. OpenStax. Retrieved from https://openstax.org/books/biology-ap-courses/pages/9-introduction

    • A. B. Sigalov, The School of Nature. IV. Learning from Viruses, Self/Nonself 1, no. 4 (2010): 282-298. Y. Cao, X. Koh, L. Dong, X. Du, A. Wu, X. Ding, H. Deng, Y. Shu, J. Chen, T. Jiang, Rapid Estimation of Binding Activity of Influenza Virus Hemagglutinin to Human and Avian Receptors, PLoS One 6, no. 4 (2011): e18664.













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