Chapter 11: Signal Transduction Pathway

___ is absolutely essential for multicellular organisms such as humans and oak trees.
The trillions of cells in a multicellular organism must communicate with each other to ___ their activities in a way that enables the organism to develop from a ___, then __ and ___ in turn.
__ between cells is also important for many unicellular organisms.

The __ received by cells, whether orinating from other cells or from changes in the physical environment, take various forms, including __ and __.
However, cells often communicate with each other by __.

In studying how cells signal to each other and how they interpret the signals they receive, biologists have discovered some universal mechanisms of __, additional evidence for the evolutionary relatedness of all life.

One topic of cell "conversation" is __- at least for the yeast Saccaromyces cerevisiao, which people have used for millenia to make bread, wine and beer. Researchers have learned that cells of this yeast identify their mates by __. There are two sexes, or mating types, called __ and __.
-Cells of mating type __ secrete a signaling molecule call __, which can bind to specific receptor proteins on nearby __ cells.
- At the same time, _ cells secrete _, which binds to receptors on __ cells.
W/o actually entering teh cells, the two mating factors cause the cells to grow toward each other and also bring about other cellular changes. The result is the __, or mating, of two cells of opposite type. The new __ cell contains all the genes of both original cells, a combination of ___ that provides advantages to the cell's descendants, which arise by subsequent __.

How is the mating signal at the yeast cell surface changed, or transduced, into a form that brings about the cellular response of mating?

changed

a series of steps linking a mechanical or chemical stimulus to a specific cellular response

Many such pathways have been extensively studied in both yeast and animal cells. Amazingly, the molecular details of __ in yeast and mammals are strikingly similar, even though thelast common ancestor of these two groups of organisms lived over a billion years ago.
- These similarities- and others more recently uncovered between __ in bacteria and plants- suggest that early versions of the __ used today evolved well before the first multicellular creatures appeared on Earth.

__ has remained important in the microbial world. Cells of many bacterial species secrete small molecules that can be detected by other bacterial cells. The concentration of such __ molecules allows bacteria to sense the local __ of bacterial cells, a phenomenon called __.

Furthermore, signaling among members of a bacterial population can lead to __ of their activities.

In response to the signal, bacterial cells are able to come together and form __, aggregations of bacteria that often form recognizable structures containing regions of specialized function.

Cells in a multicellular organism usually communicate via __ targeted for cells that may or may not be immediately adjacent.

Cells may communicate by __. Both animals and plants have __ that, where present, directly connect the cytoplasms of adjacent cells. In these cases, signaling substances dissolved in the __ can pass freely between adjacent cells.

Moreover, animal cells may communicate via direct contact betewen membrane-bound __ molecules, which occurs during a process called __. This sort of signaling is important in such processes as __ and __.

In many other cases, messenger molecules are secreted by the signaling cell. Some of these travel only short distances; such ___ influence cells in the vicinity. One class of __ in animals, __, consists of coompounds that stimulate nearby target cells to grow and divide. Numerous cells can simltaneously receive and respond to the molecules of growth factor produced by a single cell in their vicinity. This type of ___ in animals is called __.

a secreted molecule that influences cells near where it is secreted

Another, more specialized type of lcoal signaling called __ occurs in the animal nervous system. An __ along a nerve cell triggers the secretion of a chemical signal carried by __ molecules. These diffuse across the __, the narrow space between the nerve cell and its __ cell (often another nerve cell). The __ stimulates the __ cell.

__ in plants is not as well understood. Because of their __, plants use mechanisms somewhat different from those operating locally in animals.

Both animals and plants use chemicals called __ for __. In __ in animals, also known as __, specialized cells release hormone molecules, which travel via the __ to target cells in other parts of the body.

Plant hormones (often called __) sometimes travel in vessels but more often reach their targets by moving through cells or by diffusing through the air as a __. __ vary widely in molecular size and type, as do __. For instance, the plant hormone __, a gas that promotes fruit ripening and helps regulate growth, is a __ of only six atoms (C2H4), small enough to pass through cell walls. In contrast, the __, which regulates sugar levels in the blodd, is a protein with thousands of atoms.

What can also be considered an example of long-distance signaling?
- An __ travels the length of a nerve cell and is then converted back to a __ when a signaling molecule is released and crosses the __ to another nerve cell. Here it is converted back to an __. In this way, a __ can travel along a series of nerve cells. Beacue some nerve cells are quite long, the __ can quickly travel great distances.

What happens when a cell encounters a signaling molecule?

Our current understanding of how chemical messengers act via __ had its origins in the pioneering- work of __and his colleagues at Vanderbilt U were investigating how the animal hormone __ stimulates the breakdown of the storage __ within liver cells and skeletal muscle cells. __ breakdown releases the sugar glucose-1-phosphate, which the cell converts to glucose-6-phosphate. The cell can thesn use this compound, an early intermediate in glycolysis, for __. Alternatively, the compound can be stripped of __ and released from the liver cell into the blood as __, which can fuel cells throughout the body. Thus, one effect of _, which is secreted from the __ during times of physical or mental stress, is the mobilization of __.

What did Sutherland's research team discover?
-However, when epinephrine was added to a test-tube mixture containing the enzyme and its substrate, __, no breakdown occurred. Epinephrine could activate __ only when the hormone was added to a solution containing __ cells.

This result told Sutherland two things. What were they?

What are the three stages of cell signaling?

__: is the target's cell detection of a signaling molecule coming from outside the cell. A chemical signal is "detected" when the signaling molecule binds to a receptor protein at the cell's surface or inside the cell

__: the signaling molecule changes the receptor protein in some way, initiating this process; this stage converts the signal to a form that can bring about a specific cellular response. In Sutherland's system, the binding of epinephrine to a receptor protein in a liver cell's plasma membrane leads to activation of glycogen phosphorylase. This step sometimes occurs in a single step but more often requires a sequence of changes in a series of different molecules- a ___. The molecules in the pathway are often called __ molecules.

: In the third stage of cell signaling, the transduced signal finally triggers a specific cellular response. The response may be almost any imaginable cellular activity- such as catalysis by an enzyme, rearrangement of the cytoskeleton, or activation of specific genes in the nucleus. The cell-signaling process helps ensure that crucial activities like these occur in the right cells, at the right time, and in proper coordination with the other cells of the organism.

TRUE OR FALSE:
Although epinephrine encounters many types of cells as it circulates in the blood, only certain target cell detect and react to the hormone.
True False

A __ on or n the target cell allows the cell to "hear" the signal and respond to it.

The __ is complementary in shape to a __ site on the receptor and attaches there, like a key in a lock or a substrate in the catalytic site of an enzyme. The signaling molecule behaves as a __, the term for a molecule that specifically binds to another molecule, often a larger one.

__ binding generaly causes a __ protein to undergo a change in shape. For many __, this shape change directly activates the receptor, enabling it to interact with other cellular molecules. FOr other kinds of __, the immediate effect of __ binding is to cause the aggregation of two or more receptor molecules, which leads to further molecular events inside the cell.

In a general way, __ is similar to the binding of an __ to an enzyme, causing a shape change that either promotes or inhibits enzyme activity. In the case of __, binding of the __ alters the ability of the __ to __ the signal.

Most __ are plasma membrane proteins. Their __ are water-soluble and generally too large to pass freely through the plasma membrane. Other signal receptors, however, are located inside the cell.

Most __ signaling molecules bind to specific sites on __ proteins embedded in the cell's plasma membrane. Such a receptor transmits info from the __ to the inside of the cell by __ or __ when a specific __ binds to it.

What are three types of membrane receptors?

___ are found in either the __ or __ of target cells. To reach such a receptor, a chemical messenger passes through the target cell's plasma membrane. A # of important signaling molecules can do this because they are either __ enough or small enough to cross the __ interior of the membrane. Such __ chem. messengers include the __ and __ of animals. Another chemical signaling molecule with an __ is nitric oxide (NO), a gas; its very small molecules readily pass between the membrane __.

The behavior of __ is representative of __. Secreted by cells of the testis, the hormone travels through the blood and enters cells all over the body. In the cytoplasm of target cells, the only cells that contain __ molecules for testosterone, the hormone binds to the __ protein, activating it. With the hormone attached, the __ form of the receptor protein then enters the __ and turns on specific genes that control male sex characteristics.

How does the activated hromone-receptor complex turn on genes?

By acting as a __, the testosterone receptor itself carries out the complete __ of the signal. Most other ___ function in the same way, although many of them are already in the nucleus before the ___ molecule reaches them. Interestingly, many of these ___ are structurally similar, suggesting an evolutionary kinship.

A ___ is a plasma membrane receptor that works with the help of a __, a protein that binds the energy-rich molecule __. Many different signaling molecuels, including yeat mating factors, epinephrine and many other hormones, and neurotransmitters, use __. These receptors vary in the binding sites for both their signaling molecules (also called their __) and for different __ inside the cell. Nevertheless, __ are all remarkably similar in structure. They each have seven alpha helices spanning the membrane.

A large family of eukaryotic receptor proteins has this __ structure, where the single polypeptide, represented here as a ribbon, has __ transmembrane __ helices, represented as cylinders and depicted in a row for clarity. Specific loops between the helices form binding sites for __ and __.

___ are extremely widespread and diverse in their functions, including roles in __ and __. In humans, for example, both vision and smell depend on such proteins. Similarities in structure among __ and __ in diverse organisms suggest that __ and associated receptors evolved very early.

__ are involved in many human diseases, including bacterial infections. The bacteria that cause cholera, pertussis (whooping cough), and botulism, among others make their victims ill by producing toxins that interfere with __. Pharmacologists now realize that up to 60% of all meds used today exert their effects by influencing __.

__ belong to a major class of plasma membrane receptors characterized by having enzymatic activity. A __ is an enzyme that catalyzes the transfer of __ groups. The part of the receptor protein extending into the cytoplasm functions as a __, an enzyme that catalyzes the transfer of a phosphate group from ATP to the amino acid __ on a substrate protein. Thus, __ are membrane recepotrs that attach phosphates to __.

One __ may activate ten or more dif. __ and __. Often, more than one __ can be triggered at once, helping the cell regulate and coordinate many aspects of cell growth and cell reprodcution.

What is a main difference between receptor tyrosine kinases and G protein- coupld receptors?

Abnormal___ that function even in the absence of signaling molecules may contribute to some kinds of cancer.

A __ is a type of membrane receptor containing a region that can act as a "gate" when the receptor changes shape. When a signaling molecule binds as a __ to the receptor protein, the gate opens or closes, allowing or blocking the flow of specific ions through a channel in the receptor. Like the other receptors we have discussed, these proteins bind the __ as a specific site on their __ sides.

__ are very important in the nervous system. For example, the __ molecules released at a __ between two nerve cells bind as __ to __ on the receiving cell, causing the channels to open. Ions flow in (or out) triggering an __ that propagates down the length of the receiving cell. Some __ are controlled by __ instead of ligands; these __ are also crucial to the functioning of the nervous system.

When receptors for signaling molecules are __ proteins, the __ is usually a multistep pathway. Steps often include _ of proteins by addition orremoval of phosphate groups, or release of other small molecules or ions that act as messengers.

One benefit of multiple steps is the possiblity of greatly amplifying a signal. If some of the molecules in a pathway transmit the signal to mumerous molecules at the next step in the series, the result can be a large # of __ molecules at the end of the pathway. Moreover, __ pathways provide more opportunities for __ and __ than simpler systems do. This allows fine-tuning of the response in both uni- and multicellular organisms.

What triggers the first step in the chain of molecular interactions-the signal transduction pathway- that leads to a particular response within the cell?

The __ activates another molecule, which activates yet another molecule and so on until the protein that produces the final cellular response is activated. The molecules that relay a signal from receptor to _, which we call __molecules, are often proteins. The interaction of proteins is a major theme of __. Indeed, __ interactions is a unifying theme of all __ at the cellular level.

TRUE OR FALSE:
In most cases, the original signaling molecules never even enters the cell
True False

What do we mean when we say that the signal is relayed along a pathway?

At each step, what is happening to the signal?

The __ and __ of proteins is a widespread cellular mechanism for regulation protein activity.

The general name for an enzyme that transfers phosphate groups from ATP to a protein is __.

A __ phosphorylates tyrosines on the other receptor receptor __ in a dimer.

Most cytoplasmic protein __ act on proteins different from themselves.

Another distinction is that most cytoplansmic protein __ phosphorylate either the amino acid serine or threonine, rather than tyrosine. SUch serine/ threonine __ are widely involved in signaling pathways in animals, plants and fungi.

Many of the relay molecules in __ are protein kinases, and they often act on other protein kinases in the pathway.
The signal is transmitted by a cascade of protein __, each bringing with it a shape change. Each such shape change results from the interaction of the newly added __ groups with charged or polar amiino acids. THe addition of __ groups often changes a protein from an __ form to an __ form.

True or False:
In some cases phosphorylation decreases the activity of a protein.
True False

enzymes that can rapidly remove phosphate groups from proteins, a process called dephosphorylation

By __ and thus inactivating protein kinases, __ provide the mechanism for turning off the __ when the initial signal is no longer present.

__ also make the protein kinases available for reuse, enabling the cell to respond again to an extracellular signal.

At any given moment, the activity of a protein regulated by phosphorylation depends on what?
-The ___ system acts as a molecular switch in the cell, turning activities on or off as required.

a small, nonprotein water-soluble molecule or ion, such as a calcium ion, or cyclic AMP, that relays a signal to a cell's interior in response to a signaling molecule bound by a signal receptor protein

The extracellular signaling molecule that binds to the membrane receptor is a pathway's __.

__ participate in pathways initiated by both G protein- coupled receptors and receptor tyrosine kinases. A large variety of relay proteins are sensitive to the cytosolic concentration of one or the other of these __.

Sutherland found that the binding of epinephrine to the plasma membrane of a liver cell elevates the cytosolic concentration of a compound called __

An enzyme embedded in the plasma membrane ___converts ATP to __ in response to an extracellular signal. But epinephrine doesn't stimulate __ directly. When epi. outside the cell binds to a specific receptor protein, the protein activates __, which in turn can catalyze the synthesis of many moecules of __. In this way, the normal cellular concen. of __ can be boostd 20- fold in a matter of seconds.

The __ broadcasts the signal to the cytoplasm. It does not persist for long in the absence of the hormone because another enzyme, called phosphodiesterase, converts __ to __. ANother surge of epinephrine is needed to boost the cytosolic concentration of __ again.

cAMP pathways include __, __, and __. The immediate effect of cAMP is usually the activation of a serine/threonine kinase called __. THe activated kinase then phosphorylates various other proteins, depending on the cell type.

Further regulation of cell metabolism is provided by other G- protein systems that __ adenylyl cyclase. In these systems, a different signaling molecule activates a dif. receptor, which activiates an __ G protein.

In one pathway __ acts as a signaling molecule whose effects include relaxation of smooth muscle cells in artery walls.

A compound that inhibits the hydrolysis of __ to __ prolongs the signal.
---It increases blood flow to the heart muscle.

__ is even more widely used that cAMP as a second messenger.
Cells use __ as a second messenger in both __ and __ pathways.

Where is the Ca²⁺ concentration lower?
Calcium ions are actively transported out of the cell and are actively imported from the __ into the __ by various protein pumps. As a result, the calcium concen. in the ER is usually much higher than in the cytosol.

In respnse to a signal relayed by a signal transduction pathway, the cytosolic calcium level may rise, usually by a mechanism that releases Ca²⁺ from the cell's __. THe pathways leading to calcium release involve still other second messengers, __ and __. These two messengers are produced by cleaveage of a certain kind of phospholipid in the plasma membrane.

Because __ acts before calcium in these pathways, calcium can be considered a __. However, scientists use the term __ for all small, nonprotein components of signal transduction pathways.

Like an activated __, the final activated molecule in a signaling pathway may function as a __.
In some cases, the __ might regulate the gene by turning it off. Often a __ regulates several different genes.

SOmetimes a signaling pathway may regulate the __ of proteins rather than their __, directly affcting proteins that function outside the nucleus.

Regardless of whether the response occurs in the nucleus or in the cytoplasm, it is __ at multiple points.

What are the two benefits of a signaling pathway with numerous steps between a signaling event at the cell surface and teh cell's response?
-This allows __ of signaling pathways and also contributes to the specificity of the respnse. The overall efficiency of the respnse is also enhanced by __ proteins.

A crucial point in fine-tuning the response is what?

Elaborate __ amplify the cell's response to a signal. At each catalytic step in the cascade, the number of activated products is much greater than in the preceding step.
-The __ stems from the fact that these proteins persist in the active form long enough to process numerous molecules of sbustrate before they become __ again.

What is the explanation for the specificity exhibited in cellular responses to signals?

The response of a particular cell to a signal depends on its part. collection of __, __, and proteins needed to carry out the response.

Thus, what is the difference in two cells tha causes them to respond differently to the same signal?

__ and __ between pathways are important in regulating and coordiating a cell's responses to information coming in from dif. sources in the body.
--> Moreover, the use of some of the same proteins in more than one pathway allows the cell to __ on the number of dif. proteins it must make.

THe efficiency of signal transduction may in many cases be increased by the presence of __, large relay proteins to which several other relay proteins are simultaneiously attached.

Researchers are finding __ in brain cells that permanently hold together networks of signaling- pathway proteins at synapses. This hardwiring enhances the speen and accuracy of __ between cells, because the rate of protein-protein interaction is not limited by diffusion.

true or false:
Some proteins may participate in more than one pathway, either in dif. cell types or in the same cell at dif. times or under dif. conditions.
True False

The importance of the relay proteins that serve as points of branching or intersection in signailing pathways is highlighted when?

What is an essential aspect of cell signaling?
- For a cell of a multicellular organism to remain alert and capable of responding to incoming signals, what must happen?
Thus, a key to acell's continuing receptiveness to regulation by signaling is what?

The binding of signaling molecules to receptors is __; the lower the concentration of signaling molecules is, the __ (phrase)

What happens when signaling molecules leave the receptor?

Cells that are infected or damaged or that have simply reached the end of their functional ife span often enter a progam of controlled cell suicide called __. During this process, cellular agents chop up the DNA and fragment the organelles and other cytoplasmic components. The cell shrinks and becomes lobed, and the cell's parts are packaged up in vesicles that are engulfed and digested by specialized scavenger cells, leaving no trace.

__ protects neighboring cells from damage that they would otherwise suffer if a dying cell merely leaked out all its contents, including its many digestive and other enzymes.

__ is a preiod during which apotptosis is widespread and palys a crucial role.
-What are two key apoptosis genes?
-- What do they do?
---- How are these and other proteins involved in apoptosis present in cells?
----- Thus, protein activity is regulated rather than protein synthesis (by way of gene activity)

When a death signal is received by the cell, it overrides the brake, and the apoptotic pathways activates __ and __, enzymes that cut up the proteins and DNA of the cell.
--The main proteases of apoptosis are called __.

In humans and other mammals, several different pathways, involving about 15 different __, can carry out apoptosis.
-The pathway that is used depends on what?
- One major pathway involves __.

How does apoptosis go about in the mitochondria?

At key points in the apoptotic program, proteins integrate signals from several different sources and can send a cell down an __.

(Outside signal) When a death-signaling __ occupies a cell-surface receptor, this binding leads to activation of __ and other enzymes that carry out apoptosis, w/o involving the mito. pathway.

Two other types of alarm signals originate from inside the cell; one from the __, generated when the DNA has suffered irreparable damage, and a second comes from the __ when excessive protein misfolding occurs.

In vertebrates, what is apoptosis essential for?

What does a lower level of apoptosis account for in developing limbs?

In the case of humans, the failure of appropriate apoptosis can result in __.