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C H A P T E R •
Signal Transduction Pathways
Soluble Receptors
Transmembrane Receptors
Enzyme Coupled Receptors
G-Protein Coupled Receptors
Ion-Channel Coupled Receptors
Second Messengers
• • • • • • • • • • • • SIGNAL TRANSDUCTION PATHWAYS
Allow the cell to sense and respond to signals in the environment.
Signal Ǟ Receptor Ǟ Transducer Ǟ Effector Ǟ Response.
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Signal transduction pathways allow cells to respond to their environmentand to change their behavior accordingly. Signals are sensed by a recep-tor and changed in their form (transduced) so that they can exert theirfinal effect on the cell. In addition to the straightforward chain of eventsthat may lead from a signal to a final effect, there are components ofthese pathways that are designed to amplify and integrate various cellu-lar responses. This leads to a bewildering array of biochemical interac-tions with branches leading off in all directions, feedback loops (that usethe final effect to turn down the original response), and a series ofinhibitors and activators that may activate multiple pathways at the sametime.
The best approach for dealing with signal transduction pathways (as always, in my opinion) is to learn the various kinds of general pathwaysthat exist and then try to fit new pathways onto these types. There are afew general principles of signal transduction pathways that can be usedto organize your approach.
Components of signal transduction pathways are similar—what dif-fers is the details (Fig. 9-1).
Figure 9-1
Generalized Signal Transduction Pathway
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start the whole thing. They’re what the target cell senses.
sense the signal and are activated. Sensing the signal causes a change in the structure of the receptor. This structural change acti-vates the pathway.
receive the signal and then pass it on in a different form.
They can amplify the signal or integrate signals from multiple path-ways. Most components of signal transduction pathways can be con-sidered transducers.
Second messengers:
small molecules that are released in the cell in response to a signal. They can activate many other downstream com-ponents.
increase the strength of the signal. They turn one molecule of original signal into many, many molecules of second messengersor secondary signals.
allow multiple signals to converge on a single response.
the final step of the signaling pathway. Their activation results in the effect. Sometimes signals can activate multiple path-ways and have multiple effects.
turn off signaling pathways. Activating an inhibitor has the same effect as inactivating the signaling event.
Signals that enter the cell (steroids, vitamin D, thyroid hormone, Signals that exert their effects from outside the cell (everything The signal is what starts everything off. Signals take a variety of forms, but for our purposes there are only two. The first type are signalsthat go into the cell, bind to internal receptors, and exert their effects.
Steroid hormones, vitamin D, thyroid hormone, and retinoids are the onlymembers of this class. All of the intracellular receptors ultimately acti-vate the transcription of regulated genes. The common feature of signalsthat enter the cell is that they are all small lipophilic molecules that cancross the cell membrane.
All the other signals exert their effects by binding to an extracellu- lar receptor and initiating a cascade of signaling events. They work byactivating a phosphorylation cascade and/or the release of second mes-sengers in the cell.
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Steroids (cortisol, estrogen, testosterone) RECEPTORS
Receptors recognize a signal molecule and transmit the signal byactivating a downstream signaling pathway. The same signal oftenhas a different effect on different cell types. Cytosolic receptors aresoluble, cytoplasmic proteins (signal must get inside). Transmem-brane receptors span a membrane (i.e., signal outside, responseinside).
Receptors recognize the signal first. They also transmit the informa- tion that the signal has been received down the pathway. The pathway(and the receptor) is named for the signal that initiates it. Receptors arevery specific—they’re activated by only one signal (or some small vari-ations of it). Every cell type doesn’t respond to the same signal in thesame way. The easiest way to deal with this is to deal with it as youwould deal with metabolism: keep the function of the signal in mind andthe function of the tissue in mind, and it will help you sort through this.
Some cells may not respond to a particular signal because they don’t havethe receptor or they may have a different downstream response becauseof differences in the signaling pathway itself.
The signal crosses the membrane and activates gene transcription.
Signals for soluble receptors include steroid hormones, retinoicacid, thyroid hormone, and vitamin D.
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Soluble intracellular receptors include the steroid hormone recep- tors (estrogen, progesterone and cortisol), vitamin D receptor, thyroidhormone receptor, and retinoic acid receptor. Because of their insolu-bility in water, these hormones are transported in the blood by specificbinding proteins. They dissociate from the binding protein, cross themembrane, and find their receptor. Hormones that diffuse across themembrane and enter the cell bind to soluble intracellular receptors.
The central event for a receptor involves activation—getting some newactivity when the signal is present (Fig. 9-2). On binding the hormone,the soluble receptors change their conformation and gain the ability tobind to specific DNA sequences in the nucleus. The steroid hormonereceptors are transported to the nucleus only after they bind hormone,but the retinoid receptors are in the nucleus and bind to DNA evenwithout hormone present. They are both activated to start transcriptionwhen they bind hormone.
Figure 9-2
by soluble hormones. The hormone is
carried to its site of action by a carrier protein in the blood. The hormone crosses
the membrane (by itself) and binds to a soluble receptor. A conformation change
induced by hormone binding causes the receptor to expose its DNA binding site.
This site binds to a specific sequence in the DNA upstream of genes that are to
be activated for transcription. The transcription activation occurs through
another domain of the protein that binds to components of the RNA polymerase
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These receptors span the membrane. The signal activates a channel,an enzyme, or a G-protein cascade.
Enzyme coupled receptors:
of the receptor itself—tyrosine kinases, phospholipase C.
G-protein coupled receptors:
activates downstream enzymes—makes second messenger(cAMP or Ca2ϩ).
Ion-channel coupled receptors:
Signals that don’t enter the cell must be sensed by a receptor out- side that can send the signal inside. These signals are sensed by trans-membrane receptors. They have a protein domain that sticks outside thecell and binds an extracellular signal. This activates the part of the recep-tor that’s inside the cell. The signal molecule stays outside and the recep-tor transmits the signal inside. For enzyme coupled receptors, binding thesignal activates an intrinsic enzyme activity of the receptor itself. ForG-protein coupled receptors, an enzyme gets activated but the receptoractivates a G-protein first.
Tyrosine kinases phosphorylate protein tyrosine residues using ATP.
Phospholipase C cleaves PIP2 into IP3 and PAG.
For enzyme coupled receptors, activation of the receptor turns the receptor itself into an active enzyme. This activity may belong to thereceptor itself, but sometimes activation of the receptor recruits and acti-vates a separate enzyme through adaptor molecules (Fig. 9-3). A com-mon mechanism of activation of these receptors involves dimerization.
The signal molecule causes individual molecules of the receptor to asso-ciate with themselves in the membrane. Once dimerized, the receptorsbecome activated and gain enzyme activity.
There are basically two different enzyme activities that can be stim- ulated in enzyme-linked receptors. A receptor tyrosine kinase recognizesone or more specific tyrosines in the target and uses ATP to phosphory-late it. Often part of the activation involves the receptor phosphoryla- BG McGraw-Hill: Gilbert, Basic Concepts in Biochemistry, JN 5036 Signal Transduction Pathways
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Figure 9-3
Enzyme Coupled Receptors
Hormone binding (like growth factors) triggers a change in the receptor by caus-ing dimerization. This activates the receptor’s enzyme activity (tyrosine kinase).
ting its own tyrosine residues (called autophosphorylation). Receptorautophosphorylation can be a signal to recruit other activities (enzyme orG-protein) to the activated receptor.
The other activity associated with transmembrane receptors is phos- pholipase C. Phosphatidyl inositol is a membrane phospholipid that afterphosphorylation on the head group is found in the membrane as a phos-photidylinostitol bis phosphate. Phospholipase C cleaves this into a mem-brane associated diacylglycerol (the lipid part) and inositol trisphosphate(IP3, the soluble part). Both play a later role in elevating the level of thesecond messenger, Ca2ϩ.
C — O— CH2 Phospholipase C Diacylglycerol CH — BG McGraw-Hill: Gilbert, Basic Concepts in Biochemistry, JN 5036 • 130 •
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The functions of transmembrane receptors can be modified using adaptor molecules. Sometimes the adaptors bring in substrates to thereceptor’s enzyme activity, but other times they can bring in the activityitself. The best known adaptors have protein structural domains calledSH2 or SH3 domains. These adaptors couple various functions to recep-tor tyrosine kinases (Fig. 9-4). SH2 and SH3 stands for Src homologyregion 2 and 3 because they were discovered first in the oncogene, Src(see later). These adapters recognize specific phosphotyrosine residues inthe autophosphorylated receptor. Src itself is not a receptor, but it is atyrosine kinase. It has an SH2 and SH3 domain to link it to the receptorand, when this occurs, it becomes activated as a tyrosine kinase.
Figure 9-4
The SH2 DOMAIN links an activated (autophosphorylated) receptor to various
downstream pathways. Each of the proteins has a common SH2 adaptor domain
fused to another domain that performs the downstream function. The same sig-
nal can then activate multiple pathways. GNRP and GAP represent adaptors that
can affect G-protein signaling (see the following section “G-Protein Coupled
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These activate a G-protein that activates downstream signals. G-proteins are molecular timers. G-protein activation usually leadsto an increase in second messenger concentrations (Ca2ϩ orcAMP). GTPase activating protein (GAP) inactivates the G-proteinby increasing GTPase activity. Guanine nucleotide exchange fac-tors (GNEF) activate the G-protein by increasing the rate ofexchange of GDP for GTP.
G-proteins are molecular timers that couple transmembrane receptor activation to downstream members of the pathway (Fig. 9-5). They arecalled G-proteins because they are intimately involved with thenucleotide, GTP. Before activation, the G-protein is hanging around inits GDP form. When the activated receptor finds its G-protein it activatesit by increasing the rate of exchange between GTP and GDP. Once acti-vated, the G-protein interacts with downstream effectors and can activate Inactivated Ras
Activated Ras
Figure 9-5
G-protein Coupled Receptors
The Ras pathway is shown here. Ras is a G-protein that couples signaling fromgrowth factors. The activated receptor is a GNRP that increases the exchange ofGDP for GTP and activates the G-protein. Ras GAP inactivates the G-protein.
The downstream signal for activated Ras is eventually the mitogen-activatedprotein kinase pathway (MAPK).
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them or inhibit them (depending on what needs to be done). G-proteinshave an intrinsic enzyme activity that hydrolyzes the GTP. This is thetimer. When the timer runs down (GTP is hydrolyzed to GDP), the sig-nal goes away and the signaling is stopped.
There are two ways to affect the timing of G-proteins. Affector pro- teins can interact with the GDP form of the G-protein and make therelease of GDP and the binding of GTP faster. These proteins are calledguanine nucleotide exchange factors (GNEF), or guanine nucleotiderelease proteins (GNRP), depending on who is using the name (ratherthan any functional difference). Their effect is to help activate the sig-naling pathway. Other signaling molecules in the pathway can activatethe GTPase activity. They make the G-protein inactivate faster (speed upthe clock) and inactivate the signaling pathway. These are called GAPs(GTPase-activating proteins).
Most G proteins activate events that lead to an increase in sec- ond messenger concentrations (Ca2ϩ or cAMP); we’ll talk about thatlater.
There are different kinds of G-proteins. The trimeric G-proteins are used mainly with transmembrane receptors. They have three subunits, ␣, ␤, and ␥. The ␣ subunit is the GTPase part, but it’s kept in its GDP formwhen it is bound to the ␤-␥ subunits. When GTP is bound, the ␣-subunitis released as an activated G-protein. The activated G-proteins can stim-ulate some downstream enzyme (these are called stimulatory G-proteins,or Gs). However, some G-proteins may be inhibitory in their activeform—they’re called Gi. Whether the target protein is stimulated orinhibited will depend on the type of G-protein.
There are also monomeric G-proteins. Just like the trimeric G-pro- teins, they are involved as signal relays and timers. The Ras superfamilyrelays signals from receptor tyrosine kinases to downstream elements thateventually regulate transcription. Rho and Rac relay signals from cell-surface receptors to the cytoskeleton, while Rab regulates intracellulartransport of vesicles. Regardless of what they do, they use the timermechanism provided by the G-protein. Three-letter acronyms (TLA),such as Ras, Rho, and Rab, are difficult to remember, sometimes evenwhen you know what the letters stand for. Unfortunately, there’s nothingyou can do about this except to memorize them.
The signal activates the flow of ions across the membrane.
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The acetyl choline receptor is a ligand-gated ion channel that allows cations to flow out of the neuron to initiate an action potential duringneurotransmission (Fig. 9-6). When the receptor binds acetylcholine, aconformational change of the receptor opens a membrane channel thatconducts ions.
Figure 9-6
The binding of acetyl choline to the ACETYL CHOLINE RECEPTOR opens
a gate that allows cations to pass through the membrane. This is called a ligand-
gated channel
These are small signaling molecules generated in response to extra-cellular signals. They amplify and propagate the signal.
Second messengers relay the primary signal. The distinction between second messengers and normal transducers is that second messengers aresmall molecules. Extracellular signals of various kinds can activate intra-cellular pathways that cause an increase in the concentration of a smallmolecule messenger. All of these pathways involve G-protein coupledreceptors. There are two second messengers that you need to know about:cyclic nucleotides and calcium.
Cyclic nucleotides are like regular nucleotides (the things in DNA/RNA)except that the phosphate bridges the 3Ј and 5Ј hydroxyl group within BG McGraw-Hill: Gilbert, Basic Concepts in Biochemistry, JN 5036 • 134 •
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the same molecule. The enzymes that catalyze the formation of thesemessengers are called cyclases. Adenylyl cyclase makes cAMP, andguanylyl cyclase makes cGMP. The most used second messenger iscAMP, but cGMP is used in nitric oxide signaling and in vision.
Cyclic nucleotides are made in response to receptor activation. The receptor activates a G-protein that, in turn, activates adenylyl cyclase tomake the cyclic nucleotide. To complete the signaling, the increase incAMP concentration activates a specific protein kinase (serine/threo-nine), cAMP-dependent protein kinase (A kinase) (Fig. 9-7). To turn offthe signaling pathway, the cyclic nucleotides are destroyed by enzymescalled phosphodiesterases. These cleave cAMP to AMP.
Protein kinase A
Figure 9-7
Synthesis and Degradation of the Second Messenger, cAMP
Activation of adenylyl cyclase by an activated G-protein coupled receptor resultsin the synthesis of cAMP. The cAMP activates a downstream kinase, proteinkinase A. Phosphodiesterase hydrolyzes and inactivates the cAMP.
Increases in the concentration of calcium in the cytosol provides a signalthat can initiate muscle contraction, vision, and other signaling pathways.
The response depends on the cell type. In muscle, a transient rise in thecytosolic calcium levels (from opening calcium channels in the sar-coplasmic reticulum) causes contraction. This signaling in contractionis a direct consequence of electrical activation of the voltage-gatedchannel.
Calcium signaling is also involved in the response to growth factors.
Normally, cells maintain low calcium levels in the cytosol. A low cyto-solic calcium level is maintained by pumps that use ATP hydrolysisto move Ca2ϩ out of the cytosol. Ca2ϩ concentration in the cytosolincreases by activating a calcium channel that lets Ca2ϩ flow back intothe cytosol.
Calcium signaling can be activated directly by regulating Ca2ϩ chan- nels. However, there is an indirect way to cause cytosolic calcium to rise.
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The inositol phosphate signaling pathway can also activate calcium sig-naling in response to a number of hormones and effectors (see followingTable). Phosphatidyl inositol (PI) is a phospholipid found on the plasmamembrane. A kinase phosphorylates the head group leading to inositolbisphosphate (IP2). When an extracellular signal activates phospholipaseC (PLC), it cleaves the PIP2 into IP3 (inositol triphosphate) and diacyl-glycerol (DAG) (Fig. 9-8). IP3 activates a Ca2ϩ channel in the ER, andCa2ϩ comes rushing out. The increased calcium causes protein kinase C(PKC) to bind Ca2ϩ, move to the plasma membrane, and combine withDAG. The C kinase is responsible for activating the final effector—gen-erally activating transcription through transcription factors.
Calcium can also directly affect signaling through another pathway.
The major calcium binding protein in the cell is calmodulin (CAM).
CAM is not an enzyme, but it will activate some enzymes when it bindsto them. CAM binds to its target enzymes only when calcium is bound Ca2+

Figure 9-8
Inisitol Phosphate and Calcium Signaling
Increases in cytosolic calcium serves as a signal for a large number of finaleffectors, depending on the signal and the metabolic circumstances. Phospholi-pase C upon activation produces two signals, PIP3 and diacylglycerol (DAG).
The PIP3 activates a calcium channel of the endoplasmic reticulum (ER) result-ing in an increase in cytoplasmic calcium. The increased calcium binds to a sol-uble form of protein kinase C and translocates to the cell membrane where it isfurther activated by the second part of the pathway, diacylglycerol. Both theincreased calcium and activated protein kinase C make further downstream con-nections.
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so it propagates the calcium signal. You’ll see later that this can be usedto integrate signals in glycogen breakdown, but CAM can also activatea specific cellular kinase (serine/threonine), called CAM kinase (calmod-ulin-dependent kinase). This kinase then carries the signal.
Take one molecule of an incoming signal and make many mole-cules of an outgoing signal. Kinases, cyclases, and G-proteinsamplify the signal.
Many of the steps in signal transduction pathways makes the signal larger; they amplify it. All signal transduction pathways involve one ormore amplifiers. Amplification can occur by three mechanisms: produc-ing a second messenger, activating a G-protein, or activating a proteinkinase. The essence of amplification is that a single molecule binding toa transducer will result in the formation of many molecules of a down-stream signal. When there are multiple amplifications in a pathway, it canbe called a cascade.
G-proteins are easy. The GTP-bound form can interact successively withseveral molecules of its target before the GTP is hydrolyzed and the G-protein is inactivated. The synthesis of cyclic nucleotide second messen-gers by the cyclase is also an obvious amplification step.
There are huge numbers of protein kinases, but they come in two basicflavors. The transmembrane receptor kinases or others that are recruitedto a transmembrane receptor are usually tyrosine kinases. They use ATPto phosphorylate specific tyrosine residues in the target protein. Since it’senzymatic, it’s an amplification step. One activated receptor activatesmany downstream targets. The other class of protein kinases is the ser-ine/threonine protein kinases. They use ATP to phosphorylate specificserine or threonine residues in their targets. Not all serine or threonineresidues in a target protein get phosphorylated. For each target proteinthere will be a specific pattern of phosphorylation that leads to the effect.
Depending on the particular target, phosphorylation may activate or inac-tivate it. (The best way to make sense of whether activation or inactiva-tion occurs is to try to remember the purpose of the pathway.) BG McGraw-Hill: Gilbert, Basic Concepts in Biochemistry, JN 5036 Signal Transduction Pathways
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The kinases themselves can be arranged into phosphorylation cas- cades so that one kinase phosphorylates another, which, in turn, phos-phorylates another. This often leads to some funny names, such as MAPkinase kinase kinase. This means a mitogen-activated protein kinase thatphosphorylates MAP kinase kinase. The activated MAP kinase kinasethen phosphorylates and activates MAP kinase.
Integrators take signals from two signaling events and use them toactivate a single downstream effector.
Phosphorylase kinase provides one example of an integrator. Phos- phorylase kinase is activated by A kinase (cAMP-dependent proteinkinase) in response to increasing cAMP levels (Fig. 9-9). When calcium-signaling pathways are also turned on, the increased calcium will stimu-late phosphorylase kinase. Phosphorylase kinase is actually turned onwhen it binds a complex of Ca2ϩ with calmodulin. When phosphorylasekinase is phosphorylated, it takes less calcium to activate it. When youthink about the final role of phosphorylase kinase, which is to activateglycogen breakdown for energy, this makes sense. When either cAMP orCa2ϩ is high, you need energy. By integrating the two signals, you get asystem that will respond to each signal as well as to both signals.
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Figure 9-9
by phosphorylase kinase. Phosphorylase kinase
eventually phosphorylates and activates glycogen phosphorylase. Either (or
both) phosphorylation and calcium signaling pathways converge at phosphory-
lase kinase.
Inhibitors turn off signaling pathways.
Kinases are opposed by phosphatases.
Cyclic nucleotides are hydrolyzed by phosphodiesterases.
Ca2ϩ is pumped out of the cytoplasm.
Hormones and neurotransmitters are removed from circulationand/or degraded.
One of the principal rules of biochemical regulation is, “When you turn something on, be sure that you have a way to turn if off.” Signaltransduction pathways are no different. Kinases are opposed by phos-phatases. These enzymes simply hydrolyze the tyrosine or serine/threo-nine phosphate. Because they are in opposition, activation of thephosphatase (there are pathways for this too) is similar to inactivation ofthe opposing kinase. Often the two activities are coordinately regulated BG McGraw-Hill: Gilbert, Basic Concepts in Biochemistry, JN 5036 Signal Transduction Pathways
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so that when you activate the kinase you inactivate the phosphatase (orvice versa; Fig. 9-10).
Cyclic nucleotides (cAMP and cGMP) are hydrolyzed to destroy the signal. The enzyme that hydrolyzes them is called a phosphodiesterase(more formally, a cAMP or cGMP phosphodiesterase). The signal thatactivates the synthesis of the cyclic nucleotide will often inhibit the phos-phodiesterase.
Calcium is pumped out of the cytosol by Ca2ϩ pumps in the plasma membrane, endoplasmic reticulum, or mitochondria.
Hormone signals are turned off by degrading or excreting them so that the signal disappears. The same thing happens with neurotrans-mitters.
Figure 9-10
The phosphorylation state of a protein target is determined by the relative activ-
ities of the kinase that activates it and the phosphatase that inactivates it. When
the signaling event is over, the phosphatase returns the protein target to the inac-
tive state.
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Intracellular Receptor
Stimulates transcription of hormone-regu-lated genes General stimulation of metabolism: tran-scription Regulation of Ca2ϩ metabolism:transcription Regulation of vertebrate development:transcription G-protein Coupled Receptor
Gs–cAMP–A kinase: glycogen breakdown(muscle), gluconeogenesis (liver) Adrenaline Gs–cAMP–A kinase: glycogen (␤-adrenergic receptors) Adrenaline Gi–decrease cAMP: inhibits glycogen (␣-adrenergic receptors) Gs–cAMP–A kinase: water retention(kidney) G–cAMP–A kinase: synthesis of thyroid G–phospholipase C–IP3–Ȇ Ca2ϩ-DAG–C kinase Acetylcholine IP3–Ca2ϩ Ȇ contraction(smooth muscle) Receptor Tyrosine Kinases
Increase cell growth/mitogenic activity byactivating transcription Ligand-Gated Ion Channel
Nerve transmission (neuromuscular:activates cation channels BG McGraw-Hill: Gilbert, Basic Concepts in Biochemistry, JN 5036



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