Cell Signaling PDF - Lebanese University

1 Chapter 2: Cell Signaling Lebanese University Faculty of Medical Sciences Second year of General Medicine, 2024 – 2025 Cell Biology course, prepared by: Dr. Ghenwa NASR Outline 1. Cell Signaling 1.1. General principles of cell signaling 1.2. Forms of signaling 1.3. Type...

1 Chapter 2: Cell Signaling Lebanese University Faculty of Medical Sciences Second year of General Medicine, 2024 – 2025 Cell Biology course, prepared by: Dr. Ghenwa NASR Outline 1. Cell Signaling 1.1. General principles of cell signaling 1.2. Forms of signaling 1.3. Types of signals 1.4. Types of receptors 1.5. Types of signaling molecules 2. Stages of cell signaling 3. Mechanisms of signal transduction Ion-channel-linked receptors G-protein-coupled receptors Enzyme-bound receptors 4. Signal amplification and integration: the role of second messengers 5. Major cell signaling pathways 2 1. Cell Signaling ▪ In order to survive, a cell must be able to understand its environment and to respond to any occurring change. ▪ Cells communicate with their environment through a process called signaling. Cell signaling is how the cell collects information and then responds with an action at the correct time. ▪ Cell signaling and communication describe the ability of cells to respond to stimuli from their environment producing cellular responses. ▪ In biology, cell signaling is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in prokaryotes and eukaryotes. ▪ So many of the cellular events we explore in biology are dependent on signaling to happen correctly. ▪ Cell signaling is needed by multicellular organisms to coordinate a wide variety of functions. Nerve cells must communicate with muscle cells to create movement, immune cells must avoid destroying cells of the body, and cells must organize during the development of a baby. 3 1. Cell Signaling 1.1. General Principles of Cell Signaling ▪ In order to respond to changes in their immediate environment, cells must be able to receive and process signals that originate outside their borders. ▪ External signals are converted into responses within the cell. ▪ Individual cells often receive many signals simultaneously, and they then integrate the information they receive into a unified action plan. ▪ Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. ▪ The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis. ▪ Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. 4  1. Cell Signaling 1.1. General Principles of Cell Signaling ▪ Information can come in a variety of forms, and communication frequently involves converting the signals that carry that information from one form to another. ▪ When you receive a call from a friend on your mobile phone, for instance, the phone converts radio signals, which travel through the air, into sound waves, which you hear. This process of conversion is called signal transduction. ▪ In a typical communication between cells, the signaling cell produces a particular type of extracellular signal molecule that is detected by the target cell. ▪ Target cells possess proteins called receptors that recognize and respond specifically to the signal molecule. 5  1. Cell Signaling 1.1. General Principles of Cell Signaling ▪ Signal transduction is the process whereby one type of signal is converted into another. ❑ 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 then produces intracellular signaling molecules that alter cell A target cell converts an behavior. extracellular signal into an intracellular signal. 6  1. Cell Signaling 1.1. General Principles of Cell Signaling ▪ Typically, the signaling process involves three components: the signal, the receptor, and the effector. ▪ In this process, the signal interacts with the receptor; resulting in a series of molecular events within the cell leading to the final response of the signaling process. ▪ The effector component of the signaling pathway begins with signal transduction: the extracellular signal is converted into an intracellular signal that is relayed to different signaling proteins (following a specific signaling pathway) and finally affect the activity of effector proteins. 7  1. Cell Signaling 1.1. General Principles of Cell Signaling ▪ The principles of cell signaling can be summarized in three stages: 1. Binding of the signal molecule to the receptor. 2. Signal transduction, where the chemical signals activate signaling pathways involving many components such as enzymes. 3. Finally, the response is observed. 8  1. Cell Signaling 1.1. General Principles of Cell Signaling ▪ A simple intracellular signaling pathway activated by an extracellular signal molecule: ❑ The signal molecule usually binds to a receptor protein in the plasma membrane of the target cell. ❑ The receptor activates one or more intracellular signaling pathways, involving a series of signaling proteins. ❑ Finally, one or more of the intracellular signaling proteins alter the activity of effector proteins and thereby the behavior of the cell. 9 1. Cell Signaling 1.2. Forms of Cell Signaling ▪ There are two kinds of communication in the world of living cells: ❑ Intracellular communication: it refers to the communication within the cell. In other words, it describes how the cell react to an external stimulus and work independently. ❑ Intercellular communication: it refers to the communication between cells. In other words, it describes how a cell interacts with other cells; it is referred as “Cell Signaling”. 10 1. Cell Signaling 1.2. Forms of Cell Signaling ▪ Intercellular Communication: ❑ Direct Intercellular Communication: cells exchange chemicals through connections between the cytoplasm. ✓ Gap junctions ✓ Transient direct linkup of surface markers 11 1. Cell Signaling 1.2. Forms of Cell Signaling ▪ Intercellular Communication: ❑ Indirect Intercellular Communication through Chemical Messengers: the messenger must bind to a matching receptor and stimulate a response. 12 1. Cell Signaling 1.2. Forms of Cell Signaling ▪ Cell-cell signaling involves the transmission of a signal from a sending cell to a receiving cell. However, not all sending and receiving cells are next-door neighbors, nor do all cell pairs exchange signals in the same way. ▪ There are four basic categories of chemical signaling found in multicellular organisms: o paracrine signaling, o autocrine signaling, o endocrine signaling, o signaling by direct contact (juxtacrine signaling). o Another forms could be added to these four is the intracrine signaling that resembles to the autocrine signaling with some modifications. ▪ The main difference between the different categories of signaling is the distance that the signal travels through the organism to reach the target cell. 13 1. Cell Signaling 1.2. Forms of Cell Signaling ▪ In chemical signaling, a cell may target itself, a nearby cell, a distant cell, or a cell that it is connected to by a gap junction. 14 1. Cell Signaling 1.2. Forms of Cell Signaling ▪ Autocrine Signaling: ❑ Autocrine signaling involves a cell secreting a chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell itself. ▪ Intracrine Signaling: ❑ In intracrine signaling, the signaling chemicals are produced inside the cell and bind to cytosolic or nuclear receptors without being secreted from the cell. ❑ In intracrine signaling, signals are relayed without being secreted from the cell. ❑ In both autocrine and intracrine signaling, the signal has an effect on the cell that produced it. 15 1. Cell Signaling 1.2. Forms of Cell Signaling ▪ Juxtacrine Signaling: ❑ Juxtacrine signaling is a type of cell–cell or cell–extracellular matrix signaling in multicellular organisms that requires close contact. ▪ Paracrine Signaling: ❑ In paracrine signaling, a cell produces a signal to induce changes in nearby cells, altering the behavior of those cells. ❑ Signaling molecules known as paracrine factors diffuse over a relatively short distance (local action), as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system ❑ Neurotransmitters represent an example of a paracrine signal. ▪ Endocrine Signaling: ❑ Endocrine signals are called hormones. Hormones are produced by endocrine cells and they travel through the blood to reach target cells in different parts of the body. 16 1. Cell Signaling 1.3. Types of Signals ▪ Most cell signals are chemical in nature. ❑ Chemical signals are molecules with the ability to bind and activate a specific receptor. ❑ These molecules, also referred as ligands, are chemically diverse, including ions (Na+, K+, Ca++, etc.), lipids (steroid, prostaglandin), peptides (insulin, ACTH), carbohydrates, glycosylated proteins (proteoglycans), nucleic acids, etc. ❑ For example, prokaryotic organisms have sensors that detect nutrients and help them navigate toward food sources. ❑ In multicellular organisms, growth factors, hormones, neurotransmitters, and extracellular matrix components are some of the many types of chemical signals cells use. ❑ These substances can exert their effects locally, or they might travel over long distances. For instance, neurotransmitters are a class of short-range signaling molecules that travel across the tiny spaces between adjacent neurons or between neurons and muscle cells. Other signaling molecules must move much farther to reach their targets. One example is follicle-stimulating hormone, which travels from the mammalian brain to the ovary, where it triggers egg release. 17 1. Cell Signaling 1.3. Types of Signals ▪ Some cells also respond to mechanical stimuli. ❑ For example, sensory cells in the skin respond to the pressure of touch, whereas similar cells in the ear react to the movement of sound waves. ▪ Signals can also be physical cues such as voltage, temperature, or light. 18 1. Cell Signaling 1.4. Types of Receptors ▪ Receptors are complex proteins or tightly bound multimer of proteins, located in the plasma membrane or within the interior of the cell such as in the cytoplasm and nucleus. ▪ Receptors have the ability to detect a signal either by binding to a specific chemical or by undergoing a conformational change when interacting with physical agents. ▪ It is the specificity of the chemical interaction between a given ligand and its receptor that confers the ability to trigger a specific cellular response. ▪ Binding of signaling molecules to receptors induces a change in the cell behavior. ▪ Receptors can be broadly classified into two categories: cell membrane receptors (cell surface receptors) and intracellular receptors. 19 1. Cell Signaling 1.4. Types of Receptors ▪ Intracellular Receptors: ❑ Intracellular receptors are receptor proteins found on the inside of the cell, typically in the cytoplasm or nucleus. ❑ In most cases, the ligands of intracellular receptors are small, hydrophobic (water-hating) molecules, since they must be able to cross the plasma membrane in order to reach their receptors. ❑ Intracellular receptors possess regions that have DNA- binding activity, meaning that they can attach to specific sequences of DNA. ❑ Upon binding to a specific ligand, regions of the receptor having a DNA-binding site will be exposed. Consequently, the ligand-receptor complex can bind to the DNA sequence and regulate gene expression (mainly gene transcription). 20 1. Cell Signaling 1.4. Types of Receptors ▪ Intracellular Receptors: ❑ These receptors comprise three core domains: a ligand- binding domain, a DNA binding domain, and an amino terminus (which interacts with the gene transcription machinery). ❑ Once the ligands reach the cell interior, they bind to their specific intracellular receptor to form a ligand-receptor complex. Then it triggers a conformational change that exposes a DNA-binding site on the protein. The ligand- receptor complex moves into the nucleus, then bind to specific regulatory regions of the chromosomal DNA and promote transcription initiation, i.e., producing mRNA from DNA. ❑The intracellular receptors can directly influence gene expression without passing the signal to other receptors or messengers. 21 1. Cell Signaling 1.4. Types of Receptors ▪ Intracellular Receptors: ❑ For example, the primary receptors for hydrophobic steroid hormones, such as the sex hormones estradiol (an estrogen) and testosterone, are intracellular. ❑ When a hormone enters a cell and binds to its receptor, it causes the receptor to change shape, allowing the receptor- hormone complex to enter the nucleus (if it wasn’t there already) and regulate gene activity. ❑ Hormone binding exposes regions of the receptor that have DNA-binding activity, meaning they can attach to specific sequences of DNA. These sequences are found next to certain genes in the DNA of the cell, and when the receptor binds next to these genes, it alters their level of transcription. 22 1. Cell Signaling 1.4. Types of Receptors ▪ Intracellular Receptors: ❑ Effect of steroid hormone on gene expression. I 23 1. Cell Signaling 1.4. Types of Receptors ▪ Cell membrane Receptors: ❑ Cell-surface receptors, alternatively known as transmembrane receptors, are membrane-anchored or integral proteins found attached to the external or outer surface of the cell membrane. ❑ Most of the signaling in multicellular organisms is conducted by these receptors. ❑ The ligands are large, hydrophilic, and cannot pass through the cell membrane. So, they bind to these receptors. ❑ Cell-surface receptor spans the cell membrane and performs signal transduction by converting an extracellular signal into an intracellular one. 24 1. Cell Signaling 1.4. Types of Receptors ▪ Cell membrane Receptors: ❑ A typical cell-surface receptor contains three domains: an extracellular ligand-binding domain, a hydrophobic membrane-spanning domain, and a signal transmitting intracellular domain. ❑ The size and structure of these regions can vary depending on the type of receptor. ❑ The hydrophobic region may consist of multiple stretches of amino acids that traverse through the membrane. ❑ Cell-surface receptors are involved in most of the signaling in multicellular organisms. 25 1. Cell Signaling 1.4. Types of Receptors ▪ Cell membrane Receptors: ❑ There are three categories of cell-surface receptors: ✓ Enzyme-linked receptors, ✓ Ligand-gated Ion channel (or ion channel-linked receptors), ✓ G-protein-linked receptors 26 1. Cell Signaling 1.4. Types of Receptors ▪ Cell membrane Receptors types: ❑ Enzyme-linked Receptors: ✓ 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. ✓ Enzyme-linked receptors normally have large extracellular and intracellular domains, but the membrane-spanning region consists of a single alpha-helix in the peptide strand. 27 1. Cell Signaling 1.4. Types of Receptors ▪ Cell membrane Receptors types: ❑ Enzyme-linked Receptors: ✓ When a ligand binds to its extracellular domain, a signal is transferred through the membrane. ✓ The signal then activates the enzyme and sets off a series of events inside the cell. ✓ Receptor tyrosine kinases (RTKs) are a class of enzyme-linked receptors found in humans and many other species. 28 1. Cell Signaling 1.4. Types of Receptors ▪ Cell membrane Receptors types: ❑ Ligand-gated Ion Channels: ✓ A subtype of ion channels that can open in response to the binding of their respective ligand. ✓ When a ligand adheres to the extracellular region of the channel, a conformational change occurs in the protein’s structure, allowing ions such as sodium, calcium, magnesium, and hydrogen to pass through. ✓ This type of cell-surface receptor contains an extensive membrane-spanning region with a hydrophilic channel through its middle. The ions cross the membrane through this channel without touching the hydrophobic core of the phospholipid bilayer. ✓ The amino acids in the membrane-spanning region are mainly hydrophobic. Conversely, the amino acids lining the inside of the channel are hydrophilic, allowing water or ions to pass. ✓ Neurons, or nerve cells, have ligand-gated channels that are bound by neurotransmitters. 29 1. Cell Signaling 1.4. Types of Receptors ▪ Cell membrane Receptors types: ❑ Ligand-gated Ion Channels: ✓ When a ligand adheres to the extracellular region of the channel, a conformational change occurs in the protein’s structure, allowing ions such as sodium, calcium, magnesium, and hydrogen to pass through. ✓ The removal of the ligand results in the closure of the ligand. ✓ Ligand-gated ion channels found in neurons induce either a depolarization or hyperpolarization stimulating a cellular response inside the cell. 30 1. Cell Signaling 1.4. Types of Receptors ▪ Cell membrane Receptors types: ❑ G-proteins-linked Receptors: ✓ Also known as G-proteins-coupled receptors (GPCRs) ✓ A large family of cell surface receptors that share a common structure and method of signaling. ✓ They are found only in eukaryotes. ✓ All the family members possess seven transmembrane domains and transmit signals inside the cell through G protein. However, each receptor has its specific extracellular domain and G- protein-binding site. ✓ When its ligand is not present, a G protein-coupled receptor waits at the plasma membrane in an inactive state (G protein attached to GDP). Upon ligand binding, the G-protein is activated (attached to GTP) inducing a sequence of cellular events inside the cell. 31 1. Cell Signaling 1.3. Types of Receptors 32 1. Cell Signaling 1.5. Types of Signaling Molecules or Ligands ▪ Produced by signaling cells, ligands are chemical signals that travel to target cells and cause a sequence of events inside the cell resulting in a cellular response. ▪ The types of molecules that serve as ligands are varied and range from small proteins to small ions. ▪ Ligands are categorized as either small hydrophobic ligands, which can cross plasma membranes, or water-soluble (hydrophilic) ligands, which cannot. ▪ Small hydrophobic ligands: also called lipid-soluble ligands, can directly diffuse through the plasma membrane and interact with internal receptors. Important members of this class of ligands are the steroid hormones. Other hydrophobic hormones include thyroid hormones and vitamin D. ▪ Water-soluble ligands: these ligands cannot diffuse freely through the membrane. They interact with membrane surface receptors by binding to its extracellular domain. This group of ligands is quite diverse and includes small molecules, peptides, and proteins. 33 1. Cell Signaling 1.5. Types of Signaling Molecules or Ligands ▪ Extracellular signal molecules bind either to cell surface receptors or to intracellular receptors: o Most extracellular signal molecules are large o Some small, hydrophobic, extracellular signal and hydrophilic and are therefore unable to molecules pass through the target cell’s cross the plasma membrane directly; instead, plasma membrane and bind to intracellular they bind to cell-surface receptors, which in receptors—in the cytosol or in the nucleus turn generate one or more intracellular (as shown here)—that then regulate gene 34 signaling molecules in the target cell. transcription or other functions. 1. Cell Signaling 1.5. Types of Signaling Molecules or Ligands ▪ Signaling molecules are crucial for cellular communication and can be categorized based on their roles and chemical classes. They include: ❑ Intracrine ligands are produced by the target cell. Then, they bind to a receptor within the cell. ❑ Autocrine ligands are distinct in that they function internally and act on the cell that secretes them. ❑ Juxtacrine ligands target adjacent cells (involved in “contact-dependent” signaling). ❑ Paracrine ligands target cells only in the vicinity of the original emitting cell (ex. Neurotransmitters). ❑ Hormones: endocrine cells produce hormones that travel through the bloodstream to distant cells. 35 1. Cell Signaling 1.5. Types of Signaling Molecules or Ligands ▪ Characteristics of extracellular signals or signaling molecules: ❑ A typical cell in a multicellular organism is exposed to hundreds of different signal molecules in its environment. These may be free in the extracellular fluid, embedded in the extracellular matrix in which many cells reside, or bound to the surface of neighboring cells. ❑ Each cell must respond very selectively to this mixture of signals, disregarding some and reacting to others, according to the cell’s specialized function. ❑ Whether a cell responds to a signal molecule depends, first of all, on whether it possesses a receptor for that signal. Each receptor is usually activated by only one type of signal. Without the appropriate receptor, a cell will be deaf to the signal and will not respond to it. ❑ By producing only a limited set of receptors out of the thousands that are possible, a cell restricts the types of signals that can affect it. 36 1. Cell Signaling 1.5. Types of Signaling Molecules or Ligands ▪ Characteristics of extracellular signals or signaling molecules: ❑ The same signal molecule can induce different responses in different target cells. ✓ How a cell reacts to a signal depends on the set of intracellular signaling molecules each cell- surface receptor produces and how these molecules alter the activity of effector proteins, which have a direct effect on the behavior of the target cell. ✓ This 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. ✓ For example, when a heart pacemaker cell is exposed to the neurotransmitter acetylcholine, its rate of firing decreases. When a salivary gland cell is exposed to the same signal, it secretes components of saliva, even though the receptors on both cell types are the same. In skeletal muscle, acetylcholine binds to a different receptor protein, causing the muscle cell to contract (check figure, next slide). 37 1. Cell Signaling 1.5. Types of Signaling Molecules or Ligands ▪ Characteristics of extracellular signals or signaling molecules: ❑ The same signal molecule can induce different responses in different target cells. Different cell types are configured to respond to the neurotransmitter acetylcholine in different ways. Acetylcholine binds to similar receptor proteins on (A) heart pacemaker cells and (B) salivary gland cells, but it evokes different responses in each cell type. (C) Skeletal muscle cells produce a different type of receptor protein for the same signal molecule. 38 1. Cell Signaling 1.5. Types of Signaling Molecules or Ligands ▪ Characteristics of extracellular signals or signaling molecules: ❑ An animal cell behavior depends on multiple extracellular signals. ✓ 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. ✓ The cell’s response is mainly due to the intracellular relay systems activated by the different signals interacting with each other. Thus, the presence of one signal will often modify the effects of another. ✓ One combination of signals might enable a cell to survive; another might drive it to differentiate in some specialized way; and another might cause it to divide. ✓ In the absence of the proper signals, most animal cells are programmed to kill themselves. 39 1. Cell Signaling 1.5. Types of Signaling Molecules or Ligands ▪ Characteristics of extracellular signals or signaling molecules: ❑ An animal cell behavior depends on multiple extracellular signals. ✓ Every cell type displays a set of receptor proteins that enables it to respond to a specific set of extracellular signal molecules produced by other cells. ✓ These signal molecules work in combinations to regulate the behavior of the cell. ✓ As shown here, cells may require multiple signals (blue arrows) to survive, additional signals (red arrows) to grow and divide, and still other signals (green arrows) to differentiate. 40 1. Cell Signaling 1.5. Types of Signaling Molecules or Ligands ▪ Characteristics of extracellular signals or signaling molecules: > - gene transcription ❑ Extracellular signals can act slowly or rapidly. ✓ The length of time a cell takes to respond to an extracellular signal can vary greatly, depending on what needs to happen inside the cell once the message has been received. ✓ Some extracellular signals act quickly: acetylcholine can stimulate a skeletal muscle cell to contract within milliseconds and a salivary gland cell to secrete within a minute or so. ✓ Such rapid responses 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. ✓ Other responses take more time. Cell growth and cell division, when triggered by the appropriate signal molecules, can take many hours to execute. ✓ This is because the response to these extracellular signals requires changes in gene expression and the production of new proteins. - slow > ✓ Therefore, the cell’s response to a signal can be fast or slow. 41  1. Cell Signaling 1.5. Types of Signaling Molecules or Ligands ▪ Characteristics of extracellular signals or signaling molecules: ❑ Extracellular signals can act slowly or rapidly. ✓ Certain types of cell responses, such as cell differentiation or increased cell growth and division involve changes in gene expression and the synthesis of new proteins; they occur relatively slowly. ✓ Other responses, such as changes in cell movement, secretion, or metabolism, need not involve changes in gene expression and therefore, occur more quickly. 42 2. Stages of Cell Signaling ▪ Three main steps: 1. Reception 2. Transduction 3. Response 43 2. Stages of Cell Signaling ▪ Step 1: Reception Detection and Binding of the Signal to its Receptor Signals, also called ligands, are secreted from a cell (the secreting cell) and are released into the extracellular space. In order to receive the signal, the other cell, called the target cell, must have the proper receptors that can bind to the signal or ligand. ▪ Step 2: Signal Transduction Once the ligand is bound to its compatible receptor, the shape or activity of the receptor alters, triggering changes inside the cell. Signal transduction is usually a pathway of several steps. These signaling pathways inside the cell, also called signal transduction cascades, amplify the message, producing multiple intracellular signals. Each relay molecule changes the following molecule in the pathway somehow or the other. ▪ Step 3: Target-Cell Response Finally, the signal triggers a specific cellular response. 44 2. Stages of Cell Signaling ▪ Cell-Surface Receptors Relay Extracellular Signals via Intracellular Signaling Pathways ✓ Transmembrane receptors detect a signal on the outside and relay the message, in a new form, across the membrane into the interior of the cell. ✓ The receptor protein performs the primary step in signal transduction: it recognizes the extracellular signal and generates new intracellular signals in response. ✓ The message is the passed “downstream” from one intracellular signaling molecule to another, each activating or generating the next signaling molecule in the pathway, until the final outcome or cell response occurs. 45 2. Stages of Cell Signaling ▪ Cell-Surface Receptors Relay Extracellular Signals via Intracellular Signaling Pathways: ✓ A cell-surface receptor protein activates one or more intracellular signaling pathways, each mediated by a series of intracellular signaling molecules, which can be proteins or small messenger molecules; only one pathway is shown. ✓ Signaling molecules eventually interact with specific effector proteins, altering them to change the behavior of the cell in various ways. 46 2. Stages of Cell Signaling ▪ The components of these intracellular signaling pathways perform one or more crucial functions: 1. They can 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. 5. They can modulate the response to the signal by regulating the activity of components upstream in the signaling pathway, a process known as feedback. 47 2. Stages of Cell Signaling ▪ Intracellular signaling proteins can relay, amplify, integrate, distribute, and modulate via feedback an incoming signal. 48 2. Stages of Cell Signaling ▪ Feedback Regulation: ❑ Feedback regulation is a very important feature of cell signaling. ❑ It can occur anywhere in the signaling pathway and can either boost or weaken the response to the signal. ❑ In positive feedback, a component that lies downstream in the pathway acts on an earlier component in the same pathway to enhance the response to the initial signal; in negative feedback, a downstream component acts to inhibit an earlier component in the pathway to diminish the response to the initial signal. ❑ Such feedback regulation is very common in biological systems. 49 2. Stages of Cell Signaling ▪ Feedback regulation within an intracellular signaling pathway can adjust the response to an extracellular signal: (A) In this simple example, a downstream protein in a signaling pathway, protein Y, acts to increase the activity of the protein that activated it; a form of positive feedback. Positive feedback loops can ignite an explosive response, such as the activation of the proteins that trigger cell division. (B) In a simple example of negative feedback, protein Y inhibits the protein that activated it. 50