In humans and other mammals, several different pathways, involving about 15 different caspases, can carry out apopto-sis. The pathway that is used depends on the type of cell and on the particular signal that initiates apoptosis. One major pathway involves certain mitochondrial proteins that are triggered to form molecular pores in the mitochondrial outer membrane, causing it to leak and release other proteins that promote apoptosis. Surprisingly, these latter include cy-tochrome c, which functions in mitochondrial electron transport in healthy cells (see Figure 9.15) but acts as a cell death factor when released from mitochondria. The process of mitochondrial apoptosis in mammals uses proteins similar to the nematode proteins Ced-3, Ced-4, and Ced-9. These can be thought of as relay proteins capable of transducing the apoptotic signal.
At key gateways into the apoptotic program, relay proteins integrate signals from several different sources and can send a cell down an apoptotic pathway. Often, the signal originates outside the cell, like the death-signaling molecule depicted in
Figure 11.21b, which presumably was released by a neighbor-ing cell. When a death-signalneighbor-ing ligand occupies a cell-surface receptor, this binding leads to activation of caspases and other enzymes that carry out apoptosis, without involving the mi-tochondrial pathway. This process of signal reception, trans-duction, and response is similar to what we discussed earlier in this chapter. In a twist on the classic scenario, two other types of alarm signals that can lead to apoptosis originate from inside the cell rather than from a cell-surface receptor.
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One signal comes from the nucleus, generated when the DNA has suffered irreparable damage, and a second comes from the endoplasmic reticulum when excessive protein misfolding oc-curs. Mammalian cells make life-or-death decisions by somehow integrating the death signals and life signals they receive from these external and internal sources.
A built-in cell suicide mechanism is essential to develop-ment and maintenance in all animals. The similarities be-tween apoptosis genes in nematodes and mammals, as well as the observation that apoptosis occurs in multicellular fungi and even in single-celled yeasts, indicate that the basic mechanism evolved early in the evolution of eukaryotes. In vertebrates, apoptosis is essential for normal development of the nervous system, for normal operation of the immune system, and for normal morphogenesis of hands and feet in humans and paws in other mammals (Figure 11.22). The level of apoptosis between the developing digits is lower in the webbed feet of ducks and other water birds than in the nonwebbed feet of land birds, such as chickens. In the case of humans, the failure of appropriate apoptosis can result in webbed ngers and toes.
Signi cant evidence points to the involvement of apoptosis in certain degenerative diseases of the nervous system, such as Parkinson s disease and Alzheimer s disease. Also, cancer can
result from a failure of cell suicide; some cases of human melanoma, for example, have been linked to faulty forms of the human version of the C. elegans Ced-4 protein. It is not surprising, therefore, that the signaling pathways feeding into apoptosis are quite elaborate. After all, the life-or-death ques-tion is the most fundamental one imaginable for a cell.
This chapter has introduced you to many of the general mechanisms of cell communication, such as ligand binding, protein-protein interactions and shape changes, cascades of interactions, and protein phosphorylation. As you continue through the text, you will encounter numerous examples of cell signaling.
* Figure 11.22 Effect of apoptosis during paw development in the mouse.
In mice, humans, other mammals, and land birds, the embryonic region that develops into feet or hands initially has a solid, platelike
structure. Apoptosis eliminates the cells in the interdigital regions, thus forming the digits. The embryonic mouse paws shown in these
uorescence light micrographs are stained so that cells undergoing apoptosis appear a bright
yellowish green. Apoptosis of cells begins at the margin of each interdigital region (left), peaks as the tissue in these regions is reduced (middle), and is no longer visible when the interdigital tissue has been eliminated (right).
Interdigital tissue Cells undergoing apoptosis 1 mm Space between digits
C O N C E P T C H E C K
11.5
1.Give an example of apoptosis during embryonic de-velopment, and explain its function in the develop-ing embryo.
2. What types of protein defects could re-sult in apoptosis occurring when it should not? What types could result in apoptosis not occurring when it should?
For suggested answers, see Appendix A.
WHAT IF?
lar organisms, suggesting an early evolutionary origin of signal-ing mechanisms. Bacterial cells can sense the local density of bacterial cells (quorum sensing) by binding molecules secreted by other cells. In some cases, such signals lead to aggregation of these cells into bio lms.
In local signaling, animal cells may communicate by direct con-tact or by secreting local regulators, such as growth factors or neurotransmitters. For long-distance signaling, both animals and plants use hormones; animals also pass signals electrically.
11 C H A P T E R R E V I E W
SUMMARY OF KEY CONCEPTS
C O N C E P T
11.1
External signals are converted to responses within the cell (pp. 206 210)
Signal transduction pathwaysare crucial for many processes, including the mating of yeast cells. In fact, signaling in microbes has much in common with processes in
multicellu-Relay molecules
Activation of cellular response Reception
Signaling molecule Receptor
1 2 Transduction 3 Response
Earl Sutherland discovered how the hormone epinephrine acts on cells. Like other hormones that bind to membrane receptors, it triggers a three-stage cell-signaling pathway:
Ca2*as a second messenger in both G protein and tyrosine ki-nase pathways. The tyrosine kiki-nase pathways can also involve two other second messengers, diacylglycerol (DAG)and inositol trisphosphate (IP3). IP3can trigger a subsequent in-crease in Ca2*levels.
What is the difference between a protein kinase and a second messenger? Can both types of molecules operate in the same signal transduction pathway?
C O N C E P T
11.4
Response: Cell signaling leads to regulation of transcription or cytoplasmic activities (pp. 219 223)
Some pathways lead to a nuclear response: Speci c genes are turned on or off by activation of proteins called transcription factors. In other pathways, the response involves cytoplasmic regulation, including cytoskeletal rearrangement (which can lead to cell shape changes) or changes in enzyme activity.
Cellular responses are not simply on or off; they are ne-tuned at many steps in the process. Each catalytic protein in a signal-ing pathway ampli es the signal by activatsignal-ing multiple copies of the next component of the pathway; for long pathways, the total ampli cation may be a millionfold or more. The particular combination of proteins in a cell gives the cell great speci city in both the signals it detects and the responses it carries out.
Scaffolding proteinscan increase signal transduction ef -ciency. Pathway branching and cross-talk further help the cell coordinate incoming signals and responses. Signal response is terminated quickly by the reversal of ligand binding.
What mechanisms in the cell terminate its response to a signal and maintain its ability to respond to new signals?
C O N C E P T
11.5
Apoptosis integrates multiple cell-signaling pathways (pp. 223 225)
Apoptosisis a type of programmed cell death in which cell components are disposed of in an orderly fashion, without damage to neighboring cells. Studies of the soil worm Caenorhabditis elegansshowed that apoptosis occurs at de ned times during embryonic development and clari ed molecular details of the signaling pathway involved in the process. A pro-tein (Ced-9) in the mitochondrial membrane acts as a brake;
when released by a death signal, it allows activation of caspases, the main proteases that carry out apoptosis, and nucleases.
Several apoptotic signaling pathways exist in the cells of hu-mans and other mammals, and these pathways may be trig-gered in several ways. A major pathway involves pore formation in the outer mitochondrial membrane, which leads to release of factors that activate caspases. Signals eliciting this response can originate from outside or inside the cell.
What is an explanation for the similarities between genes in yeasts, nematodes, and mammals that control apoptosis?
TEST YOUR UNDERSTANDING
LEVEL 1: KNOWLEDGE/COMPREHENSION
1.Phosphorylation cascades involving a series of protein kinases are useful for cellular signal transduction because
a. they are species speci c.
b. they always lead to the same cellular response.
c. they amplify the original signal manyfold.
d. they counter the harmful effects of phosphatases.
e. the number of molecules used is small and xed.
?
?
?
What determineswhethera cell responds to a hormone such as epi-nephrine? What determineshowa cell responds to such a hormone?
C O N C E P T
11.2
Reception: A signaling molecule binds to a receptor protein, causing it to change shape (pp. 210 214)
The binding between signaling molecule (ligand) and receptor is highly speci c. A speci c shape change in a receptor is often the initial transduction of the signal.
There are three major types of cell-surface transmembrane recep-tors: (1) G protein-coupled receptors (GPCRs)work with the help of cytoplasmic G proteins. Ligand binding activates the receptor, which then activates a speci c G protein, which ac-tivates yet another protein, thus propagating the signal along a signal transduction pathway. (2) Receptor tyrosine kinases (RTKs)react to the binding of signaling molecules by forming dimers and then adding phosphate groups to tyrosines on the cytoplasmic part of the other monomer making up the dimer.
Relay proteins in the cell can then be activated by binding to dif-ferent phosphorylated tyrosines, allowing this receptor to trigger several pathways at once. (3) Ligand-gated ion channels open or close in response to binding by speci c signaling mole-cules, regulating the ow of speci c ions across the membrane.
The activity of all three types of receptors is crucial to proper cell functioning, and abnormal GPCRs and RTKs are associated with many human diseases.
Intracellular receptors are cytoplasmic or nuclear proteins. Signal-ing molecules that are hydrophobic or small enough to cross the plasma membrane bind to these receptors inside the cell.
How are the structures of a G protein-coupled receptor and a receptor tyrosine kinase similar? In what key way does the triggering of sig-nal transduction pathways differ for these two types of receptors?
C O N C E P T
11.3
Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell (pp. 214 219)
At each step in a signal transduction pathway, the signal is transduced into a different form, which commonly involves a shape change in a protein. Many signal transduction pathways include phosphorylation cascades, in which a series of protein kinaseseach add a phosphate group to the next one in line, activating it. Enzymes called protein phosphatasesremove the phosphate groups. The balance between phosphorylation and dephosphorylation regulates the activity of proteins in-volved in the sequential steps of a signal transduction pathway.
Second messengers, such as the small molecule cyclic AMP (cAMP)and the ion Ca2*, diffuse readily through the cytosol and thus help broadcast signals quickly. Many G proteins acti-vate adenylyl cyclase, which makes cAMP from ATP. Cells use
?
?
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2.Binding of a signaling molecule to which type of receptor leads directly to a change in the distribution of ions on opposite sides of the membrane?
a. receptor tyrosine kinase b. G protein-coupled receptor
c. phosphorylated receptor tyrosine kinase dimer d. ligand-gated ion channel
e. intracellular receptor
3.The activation of receptor tyrosine kinases is character-ized by
a. dimerization and phosphorylation.
b. dimerization and IP3binding.
c. a phosphorylation cascade.
d. GTP hydrolysis.
e. channel protein shape change.
4.Lipid-soluble signaling molecules, such as testosterone, cross the membranes of all cells but affect only target cells because
a. only target cells retain the appropriate DNA segments.
b. intracellular receptors are present only in target cells.
c. most cells lack the Y chromosome required.
d. only target cells possess the cytosolic enzymes that trans-duce the testosterone.
e. only in target cells is testosterone able to initiate the phosphorylation cascade leading to activated transcription factor.
5.Consider this pathway: epinephrine *G protein-coupled receptor *G protein *adenylyl cyclase *cAMP.
Identify the second messenger.
a. cAMP b. G protein c. GTP
d. adenylyl cyclase
e. G protein-coupled receptor
6.Apoptosis involves all but which of the following?
a. fragmentation of the DNA b. cell-signaling pathways c. activation of cellular enzymes d. lysis of the cell
e. digestion of cellular contents by scavenger cells
LEVEL 2: APPLICATION/ANALYSIS
7.Which observation suggested to Sutherland the involve-ment of a second messenger in epinephrine s effect on liver cells?
a. Enzymatic activity was proportional to the amount of calcium added to a cell-free extract.
b. Receptor studies indicated that epinephrine was a ligand.
c. Glycogen breakdown was observed only when epinephrine was administered to intact cells.
d. Glycogen breakdown was observed when epinephrine and glycogen phosphorylase were combined.
e. Epinephrine was known to have different effects on differ-ent types of cells.
8.Protein phosphorylation is commonly involved with all of the following except
a. regulation of transcription by extracellular signaling molecules.
b. enzyme activation.
c. activation of G protein-coupled receptors.
d. activation of receptor tyrosine kinases.
e. activation of protein kinase molecules.
LEVEL 3: SYNTHESIS/EVALUATION
9. Draw the following apoptotic pathway, which op-erates in human immune cells. A death signal is received when a molecule called Fas binds its cell-surface receptor. The binding of many Fas molecules to receptors causes receptor clustering.
The intracellular regions of the receptors, when together, bind proteins called adaptor proteins. These in turn bind to inactive molecules of caspase-8, which become activated and then acti-vate caspase-3. Once actiacti-vated, caspase-3 initiates apoptosis.
10.EV OLUT ION CONNECTION
What evolutionary mechanisms might account for the origin and persistence of cell-to-cell signaling systems in unicellular prokaryotes?
11.SC IENTIFI C INQUIRY
Epinephrine initiates a signal transduction pathway that in-volves production of cyclic AMP (cAMP) and leads to the break-down of glycogen to glucose, a major energy source for cells.
But glycogen breakdown is actually only part of the ght-or-ight response that epinephrine brings about; the overall effect on the body includes increased heart rate and alertness, as well as a burst of energy. Given that caffeine blocks the activity of cAMP phosphodiesterase, propose a mechanism by which caf-feine ingestion leads to heightened alertness and sleeplessness.
12.SC IENCE, TECHNOLOGY, AND SOCIETY
The aging process is thought to be initiated at the cellular level. Among the changes that can occur after a certain num-ber of cell divisions is the loss of a cell s ability to respond to growth factors and other chemical signals. Much research into aging is aimed at understanding such losses, with the ultimate goal of signi cantly extending the human life span. Not everyone, however, agrees that this is a desirable goal. If life expectancy were greatly increased, what might be the social and ecological consequences?
13.
Emergent Properties The property of life emerges at the bio-logical level of the cell. The highly regulated process of apop-tosis is not simply the destruction of a cell; it is also an emergent property. Write a short essay (about 100 150 words) that brie y explains the role of apoptosis in the development and proper functioning of an animal and then describes how this form of programmed cell death is a process that emerges from the orderly integration of signaling pathways.
For selected answers, see Appendix A.
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K E Y C O N C E P T S
12.1
Most cell division results in genetically identical daughter cells12.2
The mitotic phase alternates with interphase in the cell cycle12.3
The eukaryotic cell cycle is regulated by a molecular control systemO V E R V I E W