Signal transduction

SIGNIFICANCE: Signal transduction consists of all the molecular events that occur between the arrival of a signaling molecule at a target cell and its response. A significant proportion of the genome in animals consists of genes involved in cell signaling. The protein products of these genes allow cells to communicate with each other in order to coordinate their metabolism, movements, and reproduction. Failure of cells to communicate properly can lead to cancer, defects in embryological development, and many other disorders.

Signal Transduction Pathways

Signal can occur by a number of different, often complex sequences of molecular events called signal transduction pathways, which result in several kinds of target cell response: activating genes or metabolic pathways, affecting the cell cycle, etc. Among the signaling molecules found in higher organisms are hormones, local mediators that produce local physiological effects, growth factors that act locally to promote growth, and survival factors that act locally to repress cell suicide (apoptosis). Growth factors and survival factors are particularly important during embryological development, when they orchestrate the changes in cell types, positions, and numbers that give rise to the new organism.

Types of Receptors

Most signal transduction pathways begin with the binding of signaling molecules to specific in target cells. Signaling molecules are often referred to as receptor ligands. The binding of the ligand to its receptor initiates a signal transduction pathway. A cell can respond to a particular signaling molecule only if it possesses a receptor for it.

Receptors are protein molecules. There are two categories of them, based on location in the cell: receptors that are intracellular and receptors that are anchored in the cell’s surface membrane. The membrane-anchored receptors can be further divided based on the steps of the signal transduction pathway that they initiate: receptors that bind to and activate GTP-binding proteins (G proteins), receptors that are enzymes, and receptors that are ion channels. Ion-channel receptors bind neurotransmitters or hormones and increase or decrease the flow of specific ions into the cell, leading to a physiological response by the cell. These receptors generally do not have a direct effect on gene expression, although changes in a cell’s calcium-ion concentrations can influence gene expression. Each of the other receptor types stands at the head of a signal transduction pathway that is characteristic for each receptor type and can lead to gene expression.

Intracellular Receptors

Intracellular receptors include the receptors for lipid-soluble hormones such as steroid hormones. Some of these receptors are in the cell’s cytoplasm, and some are in the nucleus. Hormone molecules enter the cell by first diffusing across the membrane and then binding to the receptor. Before the hormones enter the cell, the receptors are attached to “chaperone” proteins, which hold the receptor in a configuration that allows hormone binding but prevents it from binding to DNA. Hormone molecules displace these chaperone molecules, enabling the receptor to bind to DNA. If the receptor is a cytoplasmic receptor, the hormone-receptor complex is first transported into the nucleus, where it binds to a specific DNA nucleotide sequence called a hormone response element (HRE) that is part of the of certain genes. In most cases the receptors bind as dimers; that is, two hormone-receptor complexes bind to the same HRE. The hormone-receptor complex functions as a transcription factor, promoting transcription of the gene and production of a protein that the cell was not previously producing. The hormone hydrocortisone, for example, triggers the synthesis of the enzymes aminotransferase and tryptophan oxygenase. A single hormone such as hydrocortisone can turn on synthesis of two or more proteins if each of the genes for the proteins contains an HRE. In some cases, when hormone-receptor complexes bind to an HRE, they suppress transcription rather than promote it.

G Protein-Coupled Receptors

Many hormones, growth factors, and other signaling molecules bind to membrane receptors that can associate with and activate heterotrimeric G proteins when a signaling molecule is bound to the receptor. Heterotrimeric G proteins are a family of proteins that are present on the cytoplasmic surface of the cell membrane. Many cell types in the body contain one or more of these family members, and different cell types contain different ones. All heterotrimeric G proteins are made up of three subunits, designated alpha, beta, and gamma. The alpha subunit has a binding site for GTP (guanosine triphosphate) or GDP (guanosine diphosphate)—hence the name "G proteins"—and is the principal part of the protein that differs from one heterotrimeric G protein family member to another. When the receptor is empty (no signal molecule attached), these G proteins have GDP bound to the alpha subunit, and the G protein is not bound to the receptor.

However, when a signaling molecule binds to the receptor, the cytoplasmic domain of the receptors changes shape so that it now binds to the G protein. In binding to the receptor, the G protein also changes shape, causing the GDP to leave and the GTP to bind instead. Simultaneously, the alpha subunit detaches from the beta-gamma subunit, and both the alpha subunit and the beta-gamma subunit detach from the receptor. Depending on the particular G protein family member involved and the cell type, either the alpha subunit or the beta-gamma subunit then activates (or, with some G protein family members, inhibits) one of several enzymes, most commonly adenylate cyclase or phospholipase C. Alternatively, they can open or close a membrane ion channel, altering the electrical properties of the cell; for example, potassium ion channels in heart muscle cells can be opened by G proteins in response to the acetylcholine.

In cases where adenylate cyclase or phospholipase C is activated, these enzymes catalyze reactions that produce molecules called second messengers, which, through a series of steps, activate proteins that may lead to a physiological response (such as contraction of smooth muscle), a biochemical response (such as glycogen synthesis), or a genetic response (such as activating a gene).

Activation of adenylate cyclase causes it to catalyze the conversion of adenosine triphosphate (ATP) to the second messenger cyclic adenosine monophosphate (cAMP), which in turn activates a protein called protein A, which, in some cells, moves into the nucleus and phosphorylates and activates transcription factors such as CREB (CRE-binding protein). CREB binds to a specific DNA sequence in the promoter of certain genes called the CRE (cAMP-response element), as well as to other transcription factors, to activate transcription of the gene. In other cells, protein kinase A activates enzymes or other proteins involved in physiological or metabolic responses.

Activation of phospholipase C catalyzes the breakdown of a glycolipid component of the cell membrane called phosphatidylinositol bisphosphate (PIP2) into two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG). DAG activates a protein called protein kinase C (PK-C), which in turn activates other proteins, leading to various cell responses, including, in certain cells of the immune system, activation of transcription factors that turn on genes involved in the body’s immune response to infection. IP3 causes the release of calcium ions stored in the endoplasmic reticulum. These ions bind and activate the protein calmodulin, which activates a variety of proteins, leading in most cases to a physiological response in the cell.

Catalytic Receptors

Catalytic receptors are receptors that function as enzymes, catalyzing specific reactions in the cell. The part of the receptor that is in the cytoplasm (the cytoplasmic domain) has catalytic capability. Binding of a signaling molecule to the external domain of the receptor activates the catalytic activity of the cytoplasmic domain. There are several kinds of catalytic receptors based on the type of reaction they catalyze; these include receptor tyrosine phosphatases, receptor guanylate cyclases, receptor serine/threonine kinases, and receptor tyrosine kinases. Receptor tyrosine kinases (RTKs) are the most common of these.

RTKs are the receptors for many growth factors and at least one hormone. For example, they are the receptors for fibroblast growth factor (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), and insulin. RTKs play a role in regulating many fundamental processes, such as cell metabolism, the cell cycle, cell proliferation, cell migration, and embryonic development. In most cases, when a ligand binds to this type of receptor, a conformational (shape) change occurs in the receptor so that it binds to another identical receptor-ligand complex to produce a double, or dimeric, receptor. The dimeric receptor then catalyzes a cytoplasmic reaction in which several tyrosine amino acids in the cytoplasmic domain of the receptor itself are phosphorylated. The phosphorylated tyrosines then function as docking sites for several other proteins, each of which can initiate one of the many branches of the RTK signal transduction pathway, leading to the various cell responses. One of the major branches of the RTK pathway that in many cases results in gene expression begins with the binding of the G protein Ras (which is not one of the trimeric G proteins discussed above) to the activated RTK receptor via adapter proteins. Binding Ras to the adapter proteins activates it by allowing it to bind GTP instead of GDP. Activated Ras then activates a mitogen-activated protein kinase kinase kinase (MAP3K, or MEKK) known as c-Raf, which phosphorylates the mitogen-activated protein kinase kinase (MAP2K, or MEK), which phosphorylates and activates a mitogen-activated protein kinase (MAPK), an enzyme of the MAP kinase family. This process is known as the MAP kinase cascade. In cases where the final MAPK enzyme is MAP kinase itself, the enzyme dimerizes, moves into the nucleus, and activates genes, usually many genes, by phosphorylating and activating their transcription factors.

Signal Transduction and the Cell Cycle

The biochemical machinery that produces the cell cycle consists of several whose concentrations rise and fall throughout the cycle. Cyclins activate cyclin-dependent kinases (CDKs), which activate the proteins that carry out the events of each stage of the cell cycle. In higher organisms, control of the is carried out primarily by growth factors. In the absence of growth factors, many cells will stop the cycle at a point known as the G₁ and cease dividing. The cell cycle is started when the cells are exposed to a growth factor. For example, some growth factors start cell division by binding to a membrane receptor and initiating the Ras/MAP kinase signal transduction pathway. The activated that results from this pathway activates a gene called MYC. The protein that is produced from this gene is itself a transcription factor that activates the cyclin D genes (CCND1, CCND2, and CCND3), which produce cyclin D, an important component of the cell cycle biochemical machinery. Cyclin D activates the enzyme cyclin-dependent kinase 4 (CDK4), which drives the cell into the G₁ phase of the cell cycle. CDK4 also causes an inhibiting molecule called retinoblastoma protein (pRB) to be removed from a transcription factor for the cyclin E gene. Cyclin E is then produced and activates cyclin-dependent kinase 2 (CDK2), which drives the cell into the S phase of the cell cycle, during which chromosomal DNA is replicated, leading to cell division by mitosis.

Signal Transduction and Cancer

Cancer is caused primarily by uncontrolled cell proliferation. Since many signal transduction pathways lead to cell proliferation, it is not surprising that defects in these pathways can lead to cancer. For example, as described above, many growth factors promote cell proliferation by activating the Ras/MAP kinase signal transduction pathway. In that pathway, a series of proteins is activated (Ras, MAP kinase, and so on). If a mutation occurred in the gene for one of these, ras for example, such that the mutant Ras protein is always activated rather than being activated only when it binds to the receptor, then the cell would always be dividing and cancerous growth could result. Another example would be if RB1, the gene that produces pRB, were mutated such that the pRB could never bind to and inhibit the cyclin E transcription factor; then the cell would divide continuously. Mutations in both the ras and RB1 genes are in fact known to cause cancer in humans.

Key Terms

• cell cyclethe orderly sequence of events by which a cell grows, duplicates its chromosomal DNA, and partitions the DNA into two new cells
• cell signalingcommunication between cells that occurs most commonly when one cell releases a specific signaling molecule that is received by another cell
• receptorsmolecules in target cells that bind specifically to a particular signaling molecule
• target cellthe cell that receives and responds to a signaling molecule

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