Information About Plasma Membrane

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Amplification

Outside of cell

Signal (Cortisol)

Outside of cell

Signal (Cortisol)

|1| The receptor chaperone complex cannot enter the nucleus

Cortisol receptor

|1| The receptor chaperone complex cannot enter the nucleus

Cortisol receptor

Cortisol enters the cytoplasm and binds to the receptor.

Signal Transduction For Cortisol

15.8 A Cytoplasmic Receptor The receptor for cortisol is bound to a chaperone protein. Binding of the signal releases the chaperone and allows the receptor protein to enter the cell's nucleus, where it functions as a transcription factor.

Cortisol enters the cytoplasm and binds to the receptor.

|3| .causing the receptor to change ^^ shape and release \ the chaperone.

14 .exposing a site that allows the receptor to enter the nucleus.

subunit separates from the effector protein. The G protein subunit must form a complex with other subunits before binding to yet another activated receptor. When an activated receptor is bound, the G protein exchanges its GDP for GTP, and the cycle begins again.

By means of their diffusing subunits, G proteins can either activate or inhibit an effector. An example of an activating response involves the receptor for epinephrine (adrenaline), hormone made by the adrenal gland in response to stress or heavy exercise. In heart muscle, this hormone binds to its G protein-linked receptor, activating a G protein . The GTP-bound subunit then activates a membrane-bound enzyme to produce a small molecule, cyclic AMP (see below), that has many effects on the cell, including glucose mobilization for energy and muscle contraction.

G protein-mediated inhibition occurs when the same hormone, epinephrine, binds to its receptor in the smooth muscle cells surrounding blood vessels lining the digestive tract. Again, the epinephrine-bound receptor changes its shape and activates a G protein, and the GTP-bound subunit binds to a target enzyme. But in this case, the enzyme is inhibited instead of being activated. As a result, the muscles relax and the blood vessel diameter increases, allowing more nutrients to be carried away from the digestive system to the rest of the body. Thus the same signal and initial signaling mechanism can have different consequences in different cells, depending on the nature of the responding cell.

cytoplasmic receptors. Receptors for signals that can diffuse across the plasma membrane are located inside the cell. Binding to the ligand causes the receptor to change its shape so that it can enter the cell nucleus, where it acts as a transcription factor (Figure 15.8). But this general view is somewhat simplified. The receptor for the hormone cortisol, for example, is normally bound to a chaperone protein, which blocks it from entering the nucleus. Binding of the hormone causes the receptor to change its shape so that the chaperone is released. This allows the receptor, which is a transcription factor, to fold into an appropriate conformation for entering the nucleus and initiating transcription.

Having discussed signals and receptors, we now turn our attention to the characteristics of transducers.

Signal Transduction

As we have just seen, the same signal may produce different responses in different tissues. When epinephrine, for example, binds to receptors on heart muscle cells, it stimulates muscle contraction, but when it binds to receptors on smooth muscle cells in the blood vessels of the digestive system, it slows muscle contraction. These different responses to the same signal-receptor complex are mediated by the events of

15.8 A Cytoplasmic Receptor The receptor for cortisol is bound to a chaperone protein. Binding of the signal releases the chaperone and allows the receptor protein to enter the cell's nucleus, where it functions as a transcription factor.

signal transduction. These events, which are critical to the cell's response, may be either direct or indirect.

► Direct transduction is a function of the receptor itself and occurs at the plasma membrane.

► In indirect transduction, which is more common, another molecule, termed a second messenger, mediates the interaction between receptor binding and cellular response.

In neither case is transduction a single event. Rather, the signal initiates a cascade of events, in which proteins interact with other proteins until the final responses are achieved. Through such a cascade, a weak initial signal can be both amplified and distributed to cause several different responses in the target cell.

Protein kinase cascades amplify a response to receptor binding

We have seen that when a signal binds to a protein kinase receptor, the receptor changes its conformation to expose a protein kinase active site, which catalyzes the phosphorylation of target proteins. This process is an example of direct signal transduction. Protein kinase receptors are important in binding ligands that stimulate cell division in both plants and animals. In Chapter 9, we described growth factors that serve as external inducers of the cell cycle. These growth factors work by binding to protein kinase receptors.

The complete signal transduction pathway that occurs after a protein kinase receptor binds a growth factor was worked out through studies on a cell that went wrong. Many human bladder cancers contain an abnormal form of a protein called Ras (so named because it was first isolated from a rat sarcoma tumor). Investigations of these bladder cancers showed that this Ras protein was a G protein, but was always active because it was permanently bound to GTP. So the abnormal Ras protein caused continuous cell division. If the cancer cells' Ras protein was inhibited, they stopped dividing. This discovery has led to a major effort to develop specific Ras inhibitors for cancer treatment.

What does Ras do in normal, noncancerous cells? Researchers knew that cells must be stimulated by growth factors (signals) in order to enter the cell cycle and divide. One hypothesis was that Ras was an intermediary between the binding of a growth factor to its receptor and the ultimate response of cell division. To investigate this hypothesis, the re searchers treated cells in a culture dish with both a Ras inhibitor and a growth factor. Cell division did not occur, confirming their hypothesis.

After this discovery, the next step was to work out what the activated growth factor receptor did to Ras, and what Ras did to stimulate further events in signal transduction. This signaling pathway has been worked out, and it is an example of a more general phenomenon, called a protein kinase cascade (Figure 15.9). Such cascades are key to the external regulation of many cellular activities. Indeed, the eukaryotic genome codes for hundreds, even thousands, of such kinases.

The unbound receptors for growth factors exist in the plasma membrane as separate polypeptide chains (subunits). When the growth factor signal binds to a subunit, it associates with another subunit to form a dimer, which changes its shape to expose a protein kinase active site. The kinase activity sets off a series of events, activating several other pro-

15.9 A Protein Kinase Cascade In a protein kinase cascade, a series of proteins are sequentially activated. In this example, the growth factor receptor protein stimulates the G protein Ras, which mediates a cascading series of reactions.The final product of the cascade, MAP kinase (MAPk), enters the nucleus and causes changes in transcription. Inactive forms of the proteins are on the left, activated forms are on the right.

Outside of cell

IA growth factor binds its receptor...

Growth factor

.which auto-phosphorylates.

Activated receptor acts as a protein kinase and binds adaptor proteins.

Outside of cell

IA growth factor binds its receptor...

Growth factor

.which auto-phosphorylates.

Activated receptor acts as a protein kinase and binds adaptor proteins.

These events occur at I the membrane.

Plasma Membrane And Cytoplasm

These events occur in the cytoplasm.

|4l Adaptor protein binding

|4l Adaptor protein binding rn allows Ras to bind GTP and become activated.

Activated Ras recruits Raf.

These events occur at I the membrane.

6) Activated Raf is a protein kinase that phosphorylates many molecules of MEK.

These events occur in the cytoplasm.

allows Ras to bind GTP and become activated.

Activated Ras recruits Raf.

6) Activated Raf is a protein kinase that phosphorylates many molecules of MEK.

Activated MEK is a protein kinase that phosphorylates many molecules of MAP kinase.

MAP kinase, when activated by phosphorylation, can enter the nucleus.

Cellular responses

Activated MEK is a protein kinase that phosphorylates many molecules of MAP kinase.

MAP kinase, when activated by phosphorylation, can enter the nucleus.

Cellular responses tein kinases in turn. The final phosphorylated, activated protein—MAP kinase—moves into the nucleus and phosphory-lates target proteins that are necessary for cell division.

Protein kinase cascades are useful signal transducers for three reasons:

► At each step in the cascade of events, the signal is amplified, because each newly activated protein kinase is an enzyme, which can catalyze the phosphorylation of many target proteins.

► The information from a signal that originally arrived at the plasma membrane is communicated to the nucleus.

► The multitude of steps provides some specificity to the process. As we have seen with epinephrine, signal binding and receptor activation do not result in the same response in all cells. Different target proteins at each step in the cascade can provide variation in the response.

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