CELL SIGNALING

Converting the signals that carry that information from one form to another in order to induce a cellular response signal transduction.

The signaling cell produces a particular type of extracellular signal molecule that is detected by the target cell Ligand

Cells can act as can both signaling cells and target cells.

Target cells possess proteins called receptors that recognize and respond specifically to the signal molecule.

Signal transduction begins when the receptor on a target cell receives an incoming extracellular signal and converts it to the intracellular signaling molecules that alter cell behavior.

Extracellular signaling molecules are synthesized and released by signaling cells and produce a specific response only in target cells that have receptors for the signaling molecules.

In multicellular organisms, an enormous variety of chemicals, including small molecules (e.g., amino acid Ach), or peptides, and proteins, are used in this type of cell-to-cell communication.

Some signaling molecules, especially hydrophobic molecules such as steroids, retinoids, and thyroxine, spontaneously diffuse through the plasma membrane and bind to intracellular receptors.

The ligand binds to a structurally complementary site on the extracellular or membrane-spanning domains of the receptor.

Binding of a ligand to its receptor causes a conformational change in the cytosolic domain or domains of the receptor that ultimately induces specific cellular responses.

Communication by extracellular signals usually involves the following steps: (1) synthesis and (2) release of the signaling molecule by the signaling cell; (3)

transport of the signal to the target cell; (4) binding of the signal by a specific receptor protein leading to its activation; (5) initiation of one or more intracellular signal-transduction pathways by the activated receptor; (6) specific changes in cellular function, metabolism, or development; and (7) removal of the signal, which often terminates the cellular response.

The vast majority of receptors are activated by binding of secreted or membrane-bound molecules (e.g., hormones, growth factors, neurotransmitters, and pheromones).

Some receptors, however, are activated by changes in the concentration of a metabolite (e.g., oxygen or nutrients) or by physical stimuli (e.g., light, touch, heat). In E.coli, for instance, receptors in the cell-surface membrane trigger signaling pathways that help the cell respond to changes in the external level of phosphate and other nutrients.

Endocrine signaling broadcasting the signal throughout the whole body by secreting it into an animal’s bloodstream or a plant’s sap. (e.g. Hormones)

Paracrine signaling the signal molecules diffuse locally through the extracellular fluid, remaining in the neighborhood of the cell that secretes them. Thus, they act as local mediators on nearby cells. (e.g. Regulating inflammation, and many growth factors)

Autocrine signaling when the cells respond to the local mediators that they themselves produce. (e.g. growth factors of cancer cells)

Synaptic signaling electrical impulse stimulates the nerve terminal to release a pulse of an extracellular signal molecule called a neurotransmitter. The neurotransmitter then diffuses across the narrow (<100 nm) gap that separates the membrane of the axon terminal from that of the target cell, reaching its destination in less than 1 msec.

Contact-dependent signaling a cell-surface-bound signal molecule binds to a receptor protein on an adjacent cell. (e.g. differentiating of embryonic cells)

EI*>> Signaling molecules that are integral membrane proteins located on the cell surface also play an important role in development. In some cases, such membrane-bound signals on one cell bind receptors on the surface of an adjacent target cell to trigger its differentiation. In other cases, proteolytic cleavage of a membrane-bound signaling protein releases the exoplasmic region, which functions as a soluble signaling protein.

Some signaling molecules can act both short range and long range. Epinephrine, for example, functions as a neurotransmitter (paracrine signaling) and as a systemic hormone (endocrine signaling). Another example is epidermal growth factor (EGF), which is synthesized as an integral plasma membrane protein. Membrane-bound EGF can bind to and signal an adjacent cell by direct contact. Cleavage by an extracellular protease releases a soluble form of EGF, which can signal in either an autocrine or a paracrine manner.

External signals induce two major types of cellular responses: (1) changes in the activity or function of specific pre-existing proteins and (2) changes in the amounts of specific proteins produced by a cell.

Each produces only a limited set of receptors out of the thousands that are possible to restrict the types of signals that can affect it.

The signal from a cell- surface receptor is generally conveyed into the target cell interior via a set of intracellular signaling molecules. These molecules act in sequence and ultimately alter the activity of effector proteins, those that have some direct effect on the behavior of the target cell.

The intracellular relay system and the intracellular effector proteins on which it acts vary from one type of specialized cell to another, so that different types of cells respond to the same signal in different ways.

The information conveyed by the signal depends on how the target cell receives and interprets the signal.

A typical cell possesses many sorts of receptors—each present in tens to hundreds of thousands of copies. Such variety makes the cell simultaneously sensitive to many different extracellular signals and allows a relatively small number of signal molecules, used in different combinations, to exert subtle and complex control over cell behavior.

A combination of signals can evoke a response that is different from the sum of the effects that each signal would trigger on its own.

Rapid responses to signals are possible because, in each case, the signal affects the activity of proteins that are already present inside the target cell, awaiting their marching orders.

Some other responses are slow because they require changes in gene expression and the production of new proteins.

Most extracellular signal molecules are large and hydrophilic and are therefore unable to cross the plasma membrane directly; instead, they bind to cell-surface receptors, which in turn generate one or more intracellular signaling molecules in the target cell.

Some small, hydrophobic, extracellular signal molecules, by contrast, pass through the target cell’s plasma membrane and either activate intracellular enzymes directly or bind to intracellular receptors—in the cytosol or in the nucleus (as shown here)—that then regulate gene transcription or other functions.

One important category of signal molecules that rely on intracellular receptor proteins is the family of steroid hormones—including cortisol, estradiol, and testosterone—and the thyroid hormones such as thyroxine. All of these hydrophobic molecules pass through the plasma membrane of the target cell and bind to receptor proteins located in either the cytosol or the nucleus. Both the cytosolic and nuclear receptors are referred to as nuclear receptors, because, when activated by hormone binding, they act as transcription regulators in the nucleus.

The response of a cell or tissue to specific external signals is dictated by the particular receptors it possesses, by the signal-transduction pathways they activate, and by the intracellular processes ultimately affected.

Release of acetylcholine from a neuron adjacent to a striated muscle cell triggers contraction by activating a ligand-gated ion channel, whereas release adjacent to a heart muscle slows the rate of contraction via activation of a G protein–coupled receptor. Release adjacent to a pancreatic acinar cell triggers exocytosis of secretory granules that contain digestive enzymes.

Epinephrine binds to several different G protein–coupled receptors, each of which induces a distinct cellular response.

Each receptor protein is characterized by binding specificity for a particular ligand, and the resulting receptor-ligand complex exhibits effector specificity.

Different receptors of the same class that bind different ligands often induce the same cellular responses in a cell. In liver cells, for instance, the hormones epinephrine, glucagon, and ACTH bind to different members of the G protein–coupled receptor family, but all these receptors activate the same signal-transduction pathway, one that promotes synthesis of cyclic AMP (cAMP). This small signaling molecule in turn regulates various metabolic functions, including glycogen breakdown. As a result, all three hormones have the same effect on liver-cell metabolism.

Each receptor is anchored to the cell membrane by a hydrophobic membrane-spanning alpha helix.

The binding of a receptor to specific ligand depends on weak, noncovalent forces (i.e., ionic, van der Waals, and hydrophobic interactions) and molecular complementarity between the interacting surfaces of a receptor and ligand.

The specificity of a receptor refers to its ability to distinguish closely related substances. The insulin receptor, for example, binds insulin and a related hormone called insulinlike growth factor 1, but no other peptide hormones.

The fewer receptors present on the surface of a cell, the less sensitive the cell is to that ligand.

Cell-surface receptors often can be identified and followed through isolation procedures by affinity labeling. In this technique, cells are mixed with an excess of a radiolabeled ligand for the receptor of interest. After unbound ligand is washed away, the cells are treated with a chemical agent that covalently cross-links bound labeled ligand molecules and receptors on the cell surface. Once a radiolabeled ligand is covalently cross-linked to its receptor, it remains bound even in the presence of detergents and other denaturing agents that are used to solubilize receptor proteins from the cell membrane. The labeled ligand provides a means for detecting the receptor during purification procedures.

Another technique often used in purifying cell-surface receptors that retain their ligand-binding ability when solubilized by detergents is similar to affinity chromatography using antibodies. To purify a receptor by this technique, a ligand for the receptor of interest, rather than an antibody, is chemically linked to the beads used to form a column. A crude, detergent-solubilized preparation of membrane proteins is passed through the column; only the receptor binds, and other proteins are washed away. Passage of an excess of the soluble ligand through the column causes the bound receptor to be displaced from the beads and eluted from the column. In some cases, a receptor can be purified as much as 100,000-fold in a single affinity chromatographic step.

Following hormone binding, intracellular receptors act as transcription factors, binding to hormone response elements (HREs) on the 5’ flanking region of target genes.

Some dissolved gases can diffuse across the membrane to the cell interior and directly

regulate the activity of specific intracellular proteins. This direct approach allows such signals to alter a target cell within a few seconds or minutes.

NO is synthesized from the amino acid arginine and diffuses readily from its site of synthesis into neighboring cells. The gas acts only locally because it is quickly converted to nitrates and nitrites (with a half-life of about 5–10 seconds) by reacting with oxygen and water outside cells.

Endothelial cells—the flattened cells that line every blood vessel—release NO in response to neurotransmitters secreted by nearby nerve endings. This NO signal causes smooth muscle cells in the adjacent vessel wall to relax, allowing the vessel to dilate, so that blood flows through it more freely.

The neurotransmitter acetylcholine causes the blood vessel to dilate by binding to receptors on the surface of the endothelial cells, stimulating the cells to make and release NO. The NO then diffuses out of the endothelial cells and into adjacent smooth muscle cells, where it regulates the activity of specific proteins, causing the muscle cells to relax. One key target protein that can be activated by NO in smooth muscle cells is guanylyl cyclase, which catalyzes the production of cyclic GMP from GTP.

The effect of NO on blood vessels accounts for the action of nitroglycerine, which has been used for almost 100 years to treat patients with angina—pain caused by inadequate blood flow to the heart muscle. In the body, nitroglycerine is converted to NO, which rapidly relaxes blood vessels, thereby reducing the workload on the heart and decreasing the muscle’s need for oxygen-rich blood.

Many nerve cells also use NO to signal neighboring cells: NO released by nerve terminals in the penis, for instance, acts as a local mediator to trigger the blood-vessel dilation responsible for penile erection.

Inside many target cells, NO binds to and activates the enzyme guanylyl cyclase, stimulating the formation of cyclic GMP from the nucleotide GTP.

Cyclic GMP is a small intracellular signaling molecule that forms the next link in the NO signaling chain that leads to the cell’s ultimate response. It is very similar in its structure and mechanism of action to cyclic AMP, a much more commonly used intracellular signaling molecule.

The receptor protein performs the primary step in signal transduction: it recognizes the extracellular signal and generates new intracellular signals in response.

The resulting intracellular signaling process usually works like a molecular relay race, in which the message is passed “downstream” from one intracellular signaling molecule to another, each activating or generating the next signaling molecule in the pathway, until a metabolic enzyme is kicked into action, the cytoskeleton is tweaked into a new configuration, or a gene is switched on or off.

The components of these intracellular signaling pathways perform one or more crucial functions:

1. They can simply relay the signal onward and thereby help spread it through the cell. 2. They can amplify the signal received, making it stronger, so that a few extracellular

signal molecules are enough to evoke a large intracellular response. 3. They can detect signals from more than one intracellular signaling pathway and

integrate them before relaying a signal onward. 4. They can distribute the signal to more than one effector protein, creating branches in

the information flow diagram and evoking a complex response.

Many of the key intracellular signaling proteins behave as molecular switches: receipt of a signal causes them to toggle from an inactive to an active state. Once activated, these proteins can stimulate—or in other cases suppress—other proteins in the signaling pathway. They then persist in an active state until some other process switches them off again.

Many of the key intracellular signaling proteins behave as molecular switches: receipt of a signal causes them to toggle from an inactive to an active state.

Proteins that act as molecular switches fall mostly into one of two classes. The first—and by far the largest—class consists of proteins that are activated or inactivated by phosphorylation. For these molecules, the switch is thrown in one direction by a protein kinase, which covalently attaches a phosphate group onto the switch protein and in the other direction by a protein phosphatase, which takes the phosphate off again. The balance between the activities of the protein kinases that phosphorylate it and the protein phosphatases that dephosphorylate it is crucial.

Many of the switch proteins controlled by phosphorylation are themselves protein kinases and these are often organized into phosphorylation cascades: one protein kinase, activated by phosphorylation, phosphorylates the next protein kinase in the sequence, and so on, transmitting the signal onward and, in the process, amplifying, distributing, and regulating it.

Two main types of protein kinases operate in intracellular signaling pathways: the most common are serine/threonine kinases, which—as the name implies—phosphorylate proteins on serines or threonines; others are tyrosine kinases, which phosphorylate proteins on tyrosines.

The other class of switch proteins involved in intracellular signaling pathways are GTP-binding proteins. These toggle between an active and an inactive state depending on whether they have GTP or GDP bound to them, respectively. Once activated by GTP binding, these proteins have intrinsic GTP-hydrolyzing (GTPase) activity, and they shut themselves off by hydrolyzing their bound GTP to GDP.

Two main types of GTP-binding proteins participate in intracellular signaling pathways.

1. Large, trimeric GTP-binding proteins (also called G proteins) relay messages from G-protein-coupled receptors (GPCRs).

2. Other cell-surface receptors rely on small, monomeric GTPases to help relay their signals. These monomeric GTP-binding proteins are aided by two sets of regulatory proteins. Guanine nucleotide exchange factors (GEFs) activate the switch proteins by promoting the exchange of GDP for GTP, and GTPase-activating proteins (GAPs) turn them off by promoting GTP hydrolysis.

All cell-surface receptor proteins that bind to an extracellular signal molecule fall into three major classes:

1. Ion-channel-coupled receptors change the permeability of the plasma membrane to selected ions, thereby altering the membrane potential and, if the conditions are right, producing an electrical current.

2. G-protein-coupled receptors activate membrane-bound, trimeric GTP-binding proteins (G proteins), which then activate (or inhibit) an enzyme or an ion channel in the plasma membrane, initiating an intracellular signaling cascade.

3. Enzyme-coupled receptors either act as enzymes or associate with enzymes inside the cell; when stimulated, the enzymes can activate a wide variety of intracellular signaling pathways.

For many extracellular signal molecules there is more than one type of receptor, and these may belong to different receptor classes.

The neurotransmitter acetylcholine acts on skeletal muscle cells via an ion-channel-coupled receptor, whereas in heart cells it acts through a G-protein-coupled receptor.

These two types of receptors generate different intracellular signals and thus enable the two types of cells to react to acetylcholine in different ways, increasing contraction in skeletal muscle and decreasing the rate of contractions in heart.

The binding of ligands (“first messengers”) to many cell surface receptors leads to a short-lived increase (or decrease) in the concentration of certain low-molecular-weight intracellular signaling molecules termed second messengers. These molecules include 3,5-cyclic AMP (cAMP), 3,5cyclic GMP (cGMP), 1,2-diacylglycerol (DAG), and inositol 1,4,5-trisphosphate (IP3).

Calcium ion (Ca2+) and several membrane-bound phosphoinositides also act as second messengers.

The elevated intracellular concentration of one or more second messengers following binding of an external signaling molecule triggers a rapid alteration in the activity of one or more enzymes or non-enzymatic proteins.

In muscle, a signal-induced rise in cytosolic Ca2+ triggers contraction. a similar increase in Ca2+ induces exocytosis of secretory vesicles in endocrine cells and of neurotransmitter-containing vesicles in nerve cells.

REFERENCE// 1- MOLECULAR CELL BIOLOGY (5TH EDITION) –LODISH – BERK –

MATISUDAIRA – KAISER – KRIEGER – SCOTT – ZIPURSKY – DARNELL

2- ESSENTIAL CELL BIOLOGY (4th EDITION) ALBERTS • BRAY • HOPKIN • JOHNSON • LEWIS • RAFF • ROBERTS • WALTER

DONE BY: ALY AHMED BARAKAT - (MD STUDENT AT OMC).