Cell Communication and Signaling PDF

Cell Biology Presented by Dr Ghada KHAWAJA Mechanisms of cell communication and signaling  Communication between cells is mediated mainly by extracellular signal molecules. Some of these operate over long distances, signaling to cells far away; others s...

Cell Biology Presented by Dr Ghada KHAWAJA Mechanisms of cell communication and signaling  Communication between cells is mediated mainly by extracellular signal molecules. Some of these operate over long distances, signaling to cells far away; others signal only to immediate neighbors.  Most cells in multicellular organisms both emit and receive signals. Reception of the signals depends on receptor proteins, usually (but not always) at the cell surface, which bind the signal molecule The binding activates the receptor, which in turn activates one or more intracellular signaling pathways. These relay chains of molecules—mainly intracellular signaling proteins—process the signal inside the receiving cell and distribute it to the appropriate intracellular targets. These targets are generally effector proteins, which are altered when the signaling pathway is activated and implement the appropriate change of cell behavior. Depending on the signal and the nature and state of the receiving cell, these effectors can be gene regulatory proteins, ion channels, components of a metabolic pathway, or parts of the cytoskeleton—among other things. Figure 15-1 Molecular Biology of the Cell (© Garland Science 2008) Cells in multicellular animals communicate by means of hundreds of kinds of signal molecules (proteins, small peptides, amino acids, nucleotides, steroids, retinoids, fatty acid derivatives, and even dissolved gases such as nitric oxide and carbon monoxide). Most of these signal molecules are released into the extracellular space by exocytosis from the signaling cell. Some, however, are emitted by diffusion through the signaling cell’s plasma membrane, whereas others are displayed on the external surface of the cell and remain attached to it, providing a signal to other cells only when they make contact. Transmembrane proteins may be used for signaling in this way; or their extracellular domains may be released from the signaling cell’s surface by proteolytic cleavage and then act at a distance. Regardless of the nature of the signal, the target cell responds by means of a receptor, which specifically binds the signal molecule and then initiates a response in the target cell. The extracellular signal molecules often act at very low concentrations, and the receptors that recognize them usually bind them with high affinity   In most cases, the receptors are transmembrane proteins on the target cell surface. When these proteins bind an extracellular signal molecule (a ligand), they become activated and generate various intracellular signals that alter the behavior of the cell.  In other cases, the receptor proteins are inside the target cell, and the signal molecule has to enter the cell to bind to them: this requires that the signal molecule be sufficiently small and hydrophobic to diffuse across the target cell’s plasma membrane Extracellular Signal Molecules Can Act Over Either Short or Long Distances: Four forms of intercellular signaling. (A) Contact-dependent signaling requires cells to be in direct membrane–membrane contact. (B) Paracrine signaling depends on signals that are released into the extracellular space and act locally on neighboring cells. (C) Synaptic signaling is performed by neurons that transmit signals electrically along their axons and release neurotransmitters at synapses, which are often located far away from the neuronal cell body. (D) Endocrine signaling depends on endocrine cells, which secrete hormones into the bloodstream for distribution throughout the body. Many of the same types of signaling molecules are used in paracrine, synaptic, and endocrine signaling; the crucial differences lie in the speed and selectivity with which the signals are delivered to their targets. The contrast between endocrine and neuronal strategies for long-range signaling. In complex animals, endocrine cells and nerve cells work together to coordinate the activities of cells in widely separated parts of the body. Whereas different endocrine cells must use different hormones to communicate specifically with their target cells, Different nerve cells can use the same neurotransmitter and still communicate in a highly specific manner. Endocrine cells secrete hormones into the blood, and these act only on those target cells that carry the appropriate receptors: the receptors bind the specific hormone, which the target cells thereby “pull” from the extracellular fluid. In synaptic signaling, by contrast, specificity arises from the synaptic contacts between a nerve cell and the specific target cells it signals. Usually, only a target cell that is in synaptic communication with a nerve cell is exposed to the neurotransmitter released from the nerve terminal (although some neurotransmitters act in a paracrine mode, serving as local mediators that influence multiple target cells in the area). The contrast between endocrine and neuronal strategies for long- range signaling.  The speed of a response to an extracellular signal depends not only on the mechanism of signal delivery but also on the nature of the target cell’s response. Other responses—such as changes in cell movement, secretion, or metabolism— need not involve changes in gene transcription and therefore occur much more quickly, often starting in seconds or Certain types of signaled minutes; they may involve the rapid responses, such as increased cell phosphorylation of effector proteins in the growth and division, involve cytoplasm, for example. Synaptic changes in gene expression and the responses mediated by changes in synthesis of new proteins; they membrane potential can occur in therefore occur slowly, often milliseconds (not shown). starting after an hour or more. Gap Junctions Allow Neighboring Cells to Share Signaling Information Gap junctions are narrow water-filled channels that directly connect the cytoplasms of adjacent epithelial cells, as well as of some other cell types. The channels allow the exchange of inorganic ions and other small water soluble molecules (including small intracellular signaling molecules such as cyclic AMP and Ca2+), but not of macromolecules such as proteins or nucleic acids. Thus, cells connected by gap junctions can communicate with each other directly, without having to surmount the barrier presented by the intervening plasma membranes. In this way, gap junctions provide for the most intimate of all forms of cell communication, short of cytoplasmic bridges or cell fusion and can therefore respond to extracellular signals in a coordinated way.  Each Cell Is Programmed to Respond to Specific Combinations of Extracellular Signal Molecules Each cell type displays a set of receptors that enables it to respond to a corresponding set of signal molecules produced by other cells. These signal molecules work in combinations to regulate the behavior of the cell. An individual cell often requires multiple signals to survive (blue arrows) and additional signals to grow and divide (red arrow) or differentiate (green arrows). If deprived of appropriate survival signals, a cell will undergo a form of cell suicide known as apoptosis. The actual situation is even more complex. Some extracellular signal molecules act to inhibit these and other cell behaviors, or even to induce apoptosis (not shown). Different Types of Cells Usually Respond Differently to the Same Extracellular Signal Molecule A cell’s response to extracellular signals depends not only on the receptor proteins it possesses but also on the intracellular machinery by which it integrates and interprets the signals it receives. Thus, a single signal molecule usually has different effects on different types of target cells. Different cell types are specialized to respond to acetylcholine in different ways. In some cases (B and C), the receptors for acetylcholine differ. In other cases (B and D), acetylcholine binds to similar receptor proteins, but the intracellular signals produced are interpreted differently in cells specialized for different functions.  The Fate of Some Developing Cells Depends on Their Position in Morphogen Gradients The same signal acting on the same cell type can have qualitatively different effects depending on the signal’s concentration. Such different responses of a cell to different concentrations of the same signal molecule are crucial in animal development, when cells are becoming different from one another. The extracellular signal molecule in these cases during development is called a morphogen, and, in the simplest cases, it diffuses out from a localized cellular source (a signaling center), generating a signal concentration gradient. The different concentrations of morphogen induce the expression of different sets of genes, resulting in different cell fates (indicated by different letters and colors). Nitric Oxide Gas Signals by Directly Regulating the Activity of Specific Proteins Inside the Target Cell Some important signal molecules that activate intracellular receptors include nitric oxide and steroid hormones. Although most extracellular signal molecules are hydrophilic and bind to receptors on the surface of the target cell, some are hydrophobic enough, small enough, or both, to pass readily across the target cell’s plasma membrane. Once inside, they directly regulate the activity of specific intracellular proteins. An important and remarkable example is the gas nitric oxide (NO), which acts as a signal molecule in both animals and plants. In mammals, one of NO’s many functions is to relax smooth muscle in the walls of blood vessels, for example. Autonomic nerves in the vessel wall release acetylcholine; the acetylcholine acts on the nearby endothelial cells that line the interior of the vessel; and the endothelial cells respond by releasing NO, which relaxes the smooth muscle cells in the wall, allowing the vessel to dilate.  Nuclear Receptors Are Ligand-Modulated Gene Regulatory Proteins Various small hydrophobic signal molecules diffuse directly across the plasma membrane of target cells and bind to intracellular receptors that are gene regulatory proteins. These signal molecules include steroid hormones, thyroid hormones, retinoids, and vitamin D. Although they differ greatly from one another in both chemical structure and function, they all act by a similar mechanism. They bind to their respective intracellular receptor proteins and alter the ability of these proteins to control the transcription of specific genes. Thus, these proteins serve both as intracellular receptors and as intracellular effectors for the signal. All nuclear receptors bind to DNA as either homodimers or heterodimers, but for simplicity we show them as monomers here. The nuclear receptors all have a related structure. the short DNA- binding domain in each receptor is indicated in light green. The Three Largest Classes of Cell-Surface Receptor Proteins Are Ion-Channel- Coupled, G-Protein-Coupled, and Enzyme-Coupled Receptors In contrast to the small hydrophobic signal molecules that bind to intracellular receptors, most extracellular signal molecules bind to specific receptor proteins on the surface of the target cells they influence and do not enter the cytosol or nucleus. These cell-surface receptors act as signal transducers by converting an extracellular ligand-binding event into intracellular signals that alter the behavior of the target cell. Most cell-surface receptor proteins belong to one of three classes, defined by their transduction mechanism. Ion-channel-coupled receptors, also known as transmitter-gated ion channels or ionotropic receptors, are involved in rapid synaptic signaling between nerve cells and other electrically excitable target cells such as nerve and muscle cells. This type of signaling is mediated by a small number of neurotransmitters that transiently open or close an ion channel formed by the protein to which they bind, briefly changing the ion permeability of the plasma membrane and thereby the excitability of the postsynaptic target cell. Most ion-channel-coupled receptors belong to a large family of homologous, multipass transmembrane proteins. G-protein-coupled receptors act by indirectly regulating the activity of a separate plasma-membrane- bound target protein, which is generally either an enzyme or an ion channel. A trimeric GTP-binding protein (G protein) mediates the interaction between the activated receptor and this target protein. The activation of the target protein can change the concentration of one or more small intracellular mediators (if the target protein is an enzyme), or it can change the ion permeability of the plasma membrane (if the target protein is an ion channel). The small intracellular mediators act in turn to alter the behavior of yet other signaling proteins in the cell. All of the G-protein-coupled receptors belong to a large family of homologous, multipass transmembrane proteins. Enzyme-coupled receptors either function directly as enzymes or associate directly with enzymes that they activate. They are usually singlepass transmembrane proteins that have their ligand-binding site outside the cell and their catalytic or enzyme-binding site inside. Enzyme-coupled receptors are heterogeneous in structure compared with the other two classes. The great majority, however, are either protein kinases or associate with protein kinases, which phosphorylate specific sets of proteins in the target cell when activated. A hypothetical intracellular signaling pathway from a cell-surface receptor to the nucleus. - Series of signaling proteins and small intracellular mediators relay the extracellular signal into the nucleus, causing a change in gene expression. -The signal is altered (transduced), amplified, distributed, and modulated en route. -Because many of the steps can be affected by other extracellular and intracellular signals, the final effect of one extracellular signal depends on multiple factors affecting the cell. -Ultimately, the signaling pathway activates (or inactivates) effector proteins that alter the cell’s behavior. - In this example, the effector is a gene regulatory protein that activates gene transcription. Although the figure shows individual signaling proteins performing a single function, in actuality they often have more than one function; scaffold proteins, for example, often also serve to anchor several signaling proteins to a particular intracellular structure. Most signaling pathways to the nucleus are more direct than this one, which is not based on a known pathway. Many Intracellular Signaling Proteins Function as Molecular Switches That Are Activated by Phosphorylation or GTP Binding -Many intracellular signaling proteins behave like molecular switches. -When they receive a signal, they switch from an inactive to an active conformation, until another process switches them off, returning them to their inactive conformation. -The switching off is just as important as the switching on. If a signaling pathway is to recover after transmitting a signal so that it can be ready to transmit another, every activated molecule in the pathway must return to its original, unactivated state. - Two important classes of molecular switches that operate in intracellular signaling pathways depend on the gain or loss of phosphate groups for their activation or inactivation, although the way in which the phosphate is gained and lost is very different in the two classes. Although one type is activated by phosphorylation and the other by GTP binding, in both cases the addition of a phosphate group switches the activation state of the protein and the removal of the phosphate switches it back again. Signaling by phosphorylation: A protein kinase covalently adds a phosphate from ATP to the signaling protein, and a protein phosphatase removes the phosphate. P.S: some signaling proteins are activated by dephosphorylation rather than by phosphorylation. Many signaling proteins controlled by phosphorylation are themselves protein kinases, and these are often organized into phosphorylation cascades. In such phosphorylation cascade, one protein kinase, activated by phosphorylation, phosphorylates the next protein kinase in the sequence, and so on, relaying the signal onward and, in the process, amplifying it and sometimes spreading it to other signaling pathways. Two main types of protein kinases operate as intracellular signaling proteins. The great majority are serine/threonine kinases, which phosphorylate proteins on serines and (less often) threonines. Others are tyrosine kinases, which phosphorylate proteins on tyrosines. An occasional kinase can do both. Signaling by GTP-Binding: A GTP binding protein is induced to exchange its bound GDP for GTP, which activates the protein; the protein then inactivates itself by hydrolyzing its bound GTP to GDP. Specific regulatory proteins control GTP-binding proteins. -GTPase-activating proteins (GAPs) drive the proteins into an “off” state by increasing the rate of hydrolysis of bound GTP; the GAPs that function in this way are also called regulators of G- protein signaling (RGS) proteins. - Conversely, G-protein-coupled receptors activate trimeric G proteins, and guanine nucleotide exchange factors (GEFs) activate monomeric GTPases, by promoting the release of bound GDP in exchange for binding of GTP. Signal integration: Extracellular signals A and B activate different intracellular signaling pathways, each of which leads to the phosphorylation of protein Y but at different sites on the protein. Protein Y is activated only when both of these sites are phosphorylated, and therefore it becomes active only when signals A and B are simultaneously present. Such proteins are often called coincidence detectors.  SIGNALING THROUGH G-PROTEIN-COUPLED CELL-SURFACE RECEPTORS (GPCRs) AND SMALL INTRACELLULAR MEDIATORS  All eucaryotes use GPCRs. These form the largest family of cell-surface receptors, and they mediate most responses to signals from the external world, as well as signals from other cells, including hormones, neurotransmitters, and local mediators.  Our senses of sight, smell, and taste (with the possible exceptions).  There are more than 700 GPCRs in humans, and in mice there are about 1000 concerned with the sense of smell alone.  The signal molecules that act on GPCRs are as varied in structure as they are in function and include proteins and small peptides, as well as derivatives of amino acids and fatty acids, not to mention photons of light and all the molecules that we can smell or taste.  The same signal molecule can activate many different GPCR family members; for example, adrenaline activates at least 9 distinct GPCRs, acetylcholine another 5, and the neurotransmitter serotonin at least 14.  The different receptors for the same signal are usually expressed in different cell types and elicit different responses.  Despite the chemical and functional diversity of the signal molecules that activate them, all GPCRs have a similar structure. They consist of a single polypeptide chain that threads back and forth across the lipid bilayer seven times. In addition to their characteristic orientation in the plasma membrane, they all use G proteins to relay the signal into the cell interior. When an extracellular signal molecule binds to a GPCR, the receptor undergoes a conformational change that enables it to activate a trimeric GTP-binding protein (G protein). G protein: -attached to the cytoplasmic face of the plasma membrane -functionally couples the receptor to either enzymes or ion channels in this membrane. - In some cases, G protein: physically associates with the receptor before the receptor is activated, whereas in others it binds only after receptor activation. Various types of G proteins, each specific for a particular set of GPCRs and for a particular set of target proteins (all have a similar structure, however, and operate similarly). G proteins: composed of three protein subunits—a, b, and g. In unstimulated state: alpha subunit has GDP bound and the G protein is inactive. When GPCR is activated, it acts like a guanine nucleotide exchange factor (GEF) and induces the alpha subunit to release its bound GDP, allowing GTP to bind in its place. This exchange causes a large conformational change in the G protein, which activates it.  Alpha subunit: GTPase, and once it hydrolyzes its bound GTP to GDP it becomes inactive. GTPase activity is greatly enhanced by the binding of the a subunit to a second protein, which can be either the target protein or a specific regulator of G protein signaling (RGS).  GPCRs Activation… A. Some G Proteins Regulate the Production of cAMP B. Some G Proteins Activate an Inositol Phospholipid Signaling Pathway by Activating Phospholipase C-β C. Some G Proteins Directly Regulate Ion Channels A. Some G Proteins Regulate the Production of cAMP GPCRs that act by increasing cyclic AMP are coupled to a stimulatory G protein (Gs), which activates adenylyl cyclase and thereby increases cyclic AMP concentration. Different cell types respond differently to an increase in cyclic AMP concentration, and one cell type often responds in the same way to such an increase, regardless of the extracellular signal that causes it. At least four hormones activate adenylyl cyclase in fat cells, for example, and all of them stimulate the breakdown of triglyceride to fatty acids In most animal cells, cyclic AMP exerts its effects mainly by activating cyclic-AMP-dependent protein kinase (PKA). This kinase phosphorylates specific serines or threonines on selected target proteins, including intracellular signaling proteins and effector proteins, thereby regulating their activity. The target proteins differ from one cell type to another, which explains why the effects of cyclic AMP vary so markedly depending on the cell type. Binding of cAMP to regulatory subunits of the PKA tetramer induces a conformational change, causing subunits to dissociate from catalytic subunits  activating kinase activity of the catalytic subunits. Release of catalytic subunits requires the binding of more than 2 cAMPs to regulatory subunits. This requirement greatly sharpens the response of the kinase to changes in cAMP concentration.  How a rise in intracellular cyclic AMP concentration can alter gene transcription? 1. Binding of a ligand to GPCR activates adenylyl cyclase via Gs and thereby increases [cAMP] in cytosol. 2. Rise in [cAMP] activates PKA, and the released catalytic subunits of PKA can then enter the nucleus, where they phosphorylate the gene regulatory protein called CREB. There are Short DNA sequences, called cyclic AMP response elements (CRE), found in the regulatory region of many other genes activated by cAMP. A specific gene regulatory protein called CRE-binding (CREB) protein recognizes this sequence. 3. When PKA is activated by cAMP, it phosphorylates CREB on a single serine; phosphorylated CREB then recruits a transcriptional coactivator called CREB- binding protein (CBP), which stimulates the transcription of the target genes This signaling pathway controls many processes in cells (e.g. hormone synthesis in endocrine cells) P.S.: CREB can also be activated by some other signaling pathways, independent of cAMP. B. Some G Proteins Activate an Inositol Phospholipid Signaling Pathway by Activating Phospholipase C-β Many GPCRs exert their effects mainly via G proteins that activate the plasma membrane- bound enzyme phospholipase C- β (PLC β) The phospholipase acts on a phosphorylated inositol phospholipid (a phosphoinositide) called phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2, or PIP2], which is present in small amounts in the inner half of the plasma membrane lipid bilayer. Receptors that activate this inositol phospholipid signaling pathway mainly do so via a G protein called Gq, which activates phospholipase C-β in much the same way that Gs activates adenylyl cyclase. The activated phospholipase then cleaves the PIP2 to generate two products: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol How GPCRs increase cytosolic Ca2+ and activate PKC ? The activated GPCR stimulates the plasma membrane-bound phospholipase PLCβ via a Gq protein. 2 small intracellular messengers are produced when PI(4,5)P2 is hydrolyzed by activated PLCβ. - Inositol 1,4,5-trisphosphate (IP3) diffuses through the cytosol and releases Ca2+ from the ER by binding to and opening IP3-gated Ca2+- release channels (IP3 receptors) in the ER membrane. The large electrochemical gradient for Ca2+ across this membrane causes Ca2+ to escape into the cytosol when the release channels are open. - Diacylglycerol remains in the plasma membrane and, together with phosphatidylserine (not shown) and Ca2+, helps to activate protein kinase C (PKC), which is recruited from the cytosol to the cytosolic face of the plasma membrane. Many effects of Ca2+ are mediated by protein phosphorylations catalyzed by a family of serine/threonine protein kinases called Ca2+/calmodulin-dependent kinases (CaM-kinases). Some CaM-kinases phosphorylate gene regulatory proteins, such as the CREB protein, and in this way activate or inhibit the transcription of specific genes. C. Some G Proteins Directly Regulate Ion Channels G proteins directly activate or inactivate ion channels in the plasma membrane of the target cell, thereby altering the ion permeability—and hence the electrical excitability—of the membrane. Ex: acetylcholine released by a nerve reduces both the rate and strength of heart muscle cell contraction. This effect is mediated by a special class of acetylcholine receptors that activate the Gi protein. Once activated, the a subunit of Gi inhibits adenylyl cyclase, while the βɣ subunits bind to K+ channels in the heart muscle cell plasma membrane and open them. The opening of these K+ channels makes it harder to depolarize the cell and thereby contributes to the inhibitory effect of acetylcholine on the heart. GPCR Desensitization Depends on Receptor Phosphorylation When target cells are exposed to a high concentration of a stimulating ligand for a prolonged period, they can become desensitized, or adapted, in several different ways. The GPCR kinases (GRKs) phosphorylates only activated receptors because it is the activated GPCR that activates the GRK. The binding of an arrestin to the phosphorylated receptor prevents the receptor from binding to its G protein and also directs its endocytosis (not shown). SIGNALING THROUGH ENZYME-COUPLED CELL-SURFACE RECEPTORS   Like GPCRs, enzyme-coupled receptors are transmembrane proteins with their ligand- binding domain on the outer surface of the plasma membrane.  Instead of having a cytosolic domain that associates with a trimeric G protein, however, their cytosolic domain either has intrinsic enzyme activity or associates directly with an enzyme. Whereas a GPCR has seven transmembrane segments, each subunit of an enzyme- coupled receptor usually has only one. GPCRs and enzyme-coupled receptors often activate some of the same signaling pathways, and there is usually no obvious reason why a particular extracellular signal utilizes one class of receptors rather than the other. Six principal classes of enzyme-coupled receptors: 1. Receptor tyrosine kinases directly phosphorylate specific tyrosines on themselves and on a small set of intracellular signaling proteins. 2. Tyrosine-kinase-associated receptors have no intrinsic enzyme activity but directly recruit cytoplasmic tyrosine kinases to relay the signal. 3. Receptor serine/threonine kinases directly phosphorylate specific serines or threonines on themselves and on latent gene regulatory proteins with which they are associated. 4. Histidine-kinase-associated receptors activate a two-component signaling pathway in which the kinase phosphorylates itself on histidine and then immediately transfers the phosphoryl group to a second intracellular signaling protein. 5. Receptor guanylyl cyclases directly catalyze the production of cyclic GMP in the cytosol, which acts as a small intracellular mediator in much the same way as cyclic AMP. 6. Receptorlike tyrosine phosphatases remove phosphate groups from tyrosines of specific intracellular signaling proteins. (They are called “receptorlike” because their presumptive ligands have not yet been identified, and so their receptor function is unproven.) 1. Activated Receptor Tyrosine Kinases (RTKs) Phosphorylate Themselves Some subfamilies of RTKs. Only one or two members of each subfamily are indicated. tyrosine kinase domain is interrupted by a “kinase insert region” in some of the Subfamilies. The functional roles of most of the cysteine-rich, immunoglobulin like, and fibronectin- type III-like domains are not known. Some of the ligands for the RTKs receptors Activation and inactivation of RTKs by dimerization The normal receptors dimerize in response to ligand binding. The two kinase domains cross- phosphorylate each other, increasing the activity of the kinase domains, which now phosphorylate other sites on the receptors. Ligand binding to RTKs induces the receptors to cross-phosphorylate their cytoplasmic domains on multiple tyrosines. This transautophosphorylation both stimulates the kinases and produces a set of phosphotyrosines that serve as docking sites for a set of intracellular signaling proteins, which bind via their SH2 (or PTB for “PhosphoTyrosine Binding”) domains.  Some of the docked proteins are enzymes, such as phospholipase C-ɣ (PLCɣ) Another dock protein or signaling protein serves as an adaptor to couple some activated receptors to a Ras-GEF (Ras guanine nucleotide exchange factors or Sos), which activates the monomeric GTPase Ras;  Ras, in turn, activates a three-component MAP kinase signaling module, which relays the signal to the nucleus by phosphorylating gene regulatory proteins there. Another important signaling protein that can dock on activated RTKs is PI 3-kinase The generation of phosphoinositide docking sites by PI 3-kinase. PI 3- kinase phosphorylates the inositol ring on carbon atom 3 to generate the phosphoinositides PI(3,4,5)P3 PI 3-kinase: important signaling protein that can dock on activated RTKs phosphorylates specific phosphoinositides to produce lipid docking sites in the plasma membrane for signaling proteins with phosphoinositide-binding PH domains, including the serine/threonine protein kinase Akt (PKB), which plays a key part in the control of cell survival and growth. Tyrosine-kinase-associated receptors depend on various cytoplasmic tyrosine kinases for their action. The largest family of receptors in this class is the cytokine receptor family. When stimulated by ligand binding, these receptors activate JAK cytoplasmic tyrosine kinases, which phosphorylate STATs. The STATs then dimerize, translocate to the nucleus, and activate the transcription of specific genes. Receptor serine/threonine kinases are activated by signal proteins of the TGFbeta superfamily: they directly phosphorylate and activate Smads, which then oligomerize with another Smad, translocate to the nucleus, and activate gene transcription.