KEY CONCEPTS 11.1 External signals are converted to responses within the cell 11.2 Reception: A signaling molecule binds to a receptor protein, causing it to change shape 11.3 Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell 11.4 Response: Cell signaling leads to regulation of transcription or cytoplasmic activities 11.5 Apoptosis integrates multiple cell-signaling pathways

1. Chapter 11. Cell Communication
• Cell-to-cell communication is essential for
multicellular organisms
• Biologists have discovered some universal
mechanisms of cellular regulation

2. Evolution of Cell Signaling
• A signal-transduction pathway is a series of steps
by which a signal on a cell’s surface is converted
into a specific cellular response
• Signal transduction pathways convert signals on a
cell’s surface into cellular responses
• Pathway similarities suggest that ancestral
signaling molecules evolved in prokaryotes and
have since been adopted by eukaryotes
Video: Common signaling mechanisms
• Microbes are a window on the role of cell
signaling in the evolution of life

3. Figure 11.2-3
Yeast cell,
mating type a
Exchange
of mating
factors
Receptor
a factor Yeast cell,
mating type α
a α
1
a α
2 Mating
3 New a/α cell
a/ α
α factor
The molecular details of signal
transduction in yeast and
mammals are strikingly similar

4. Local and Long-Distance Signaling
• Cells in a multicellular organisms communicate
by chemical messengers.
• Animal and plant cells have cell junctions that
directly connect the cytoplasm of adjacent cells.
• In local signaling, animal cells may communicate
by direct contact.
• Cell signaling is also critical in the microbial
world. A concentration of signaling molecules
allows bacteria to sense local population density
in a process called quorum sensing.

5. Figure 11.4
Plasma membranes Cell wall
(a) Cell junctions
(b) Cell-cell recognition
Gap junctions
between animal cells
Plasmodesmata
between plant cells

6. Figure 11.5
Local signaling
Target cells
Secreting
cell
Secretory
vesicles
Local regulator Target cell
(b) Synaptic signaling(a) Paracrine signaling
(c) Endocrine (hormonal) signaling
Electrical signal triggers
release of neurotransmitter.
Neurotransmitter
diffuses across
synapse.
Long-distance signaling
Endocrine cell Target cell
specifically
binds
hormone.
Hormone
travels in
bloodstream.
Blood
vessel
•In many other
cases, animal cells
communicate using
local regulators,
messenger
molecules that
travel only short
distances:
paracrine
signaling
•In long-distance
signaling, plants
and animals use
chemicals called
hormones

7. Regional specificity of induction in the chick
Instructive mesenchyme

8. The Three Stages of Cell Signaling: A
Preview
• Earl W. Sutherland discovered how the
hormone epinephrine acts on cells
• Sutherland suggested that cells receiving signals
went through three processes:
– Reception
– Transduction
– Response

9. Figure 11.6-1
CYTOPLASM
Plasma membrane
EXTRACELLULAR
FLUID
Receptor
Signaling
molecule
Reception1

10. Figure 11.6-2
CYTOPLASM
Plasma membrane
EXTRACELLULAR
FLUID
Receptor
Signaling
molecule
Reception1 Transduction2
Relay molecules
1 2 3

11. Figure 11.6-3
CYTOPLASM
Plasma membrane
EXTRACELLULAR
FLUID
Receptor
Signaling
molecule
Reception1 Transduction2
Relay molecules
1 2 3
Response3
Activation
of cellular
response
GAME TIME

12. Reception: A signal molecule binds to a
receptor protein, causing it to change shape
• The binding between a signal molecule (ligand)
and receptor is highly specific
• A conformational change in a receptor is often
the initial transduction of the signal
• Most signal receptors are plasma membrane
proteins

13. Intracellular Receptors
• Some receptor proteins are intracellular, found in
the cytosol or nucleus of target cells
• Small or hydrophobic chemical messengers can
readily cross the membrane and activate receptors
• Examples of hydrophobic messengers are the
steroid and thyroid hormones of animals
• An activated hormone-receptor complex can act as
a transcription factor, turning on specific genes

14. LE 11-6
EXTRACELLULAR
FLUID
Plasma
membrane
The steroid
hormone testosterone
passes through the
plasma membrane.
Testosterone binds
to a receptor protein
in the cytoplasm,
activating it.
The hormone-
receptor complex
enters the nucleus
and binds to specific
genes.
The bound protein
stimulates the
transcription of
the gene into mRNA.
The mRNA is
translated into a
specific protein.
CYTOPLASM
NUCLEUS
DNA
Hormone
(testosterone)
Receptor
protein
Hormone-
receptor
complex
mRNA
New protein

15. Receptors in the Plasma Membrane
• Most water-soluble signal molecules bind to
specific sites on receptor proteins in the plasma
membrane
• There are three main types of membrane
receptors:
– G-protein-linked receptors
– Receptor tyrosine kinases
– Ion channel receptors

16. Segment that
interacts with
G proteins
Signal-binding site
G-protein-linked receptor
•A G-protein-linked
receptor is a plasma
membrane receptor
that works with the
help of a G protein
•The G-protein acts
as an on/off switch:
If GDP is bound to
the G protein, the G
protein is inactive

17. Figure 11.8b
Activated
enzyme
Enzyme
G protein
(inactive)CYTOPLASM
G protein-coupled
receptor
Plasma membrane Activated
receptor
Signaling
molecule
GDP
GTP
GDP
GTP
GDP
Inactive
enzyme
Cellular
response
P i
GTP
GDP
1 2
43

18. •Receptor tyrosine kinases are membrane receptors that attach phosphates to
tyrosines
•A receptor tyrosine kinase can trigger multiple signal transduction pathways at once
Tyrosines
CYTOPLASM
Receptor tyrosine
kinase proteins
(inactive monomers)
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Ligand-binding site
α helix in the
membrane
Signaling molecule
(ligand)
Signaling molecule
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Dimer
Activated relay
proteins
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Inactive
relay proteins
Cellular
response 1
Cellular
response 2
P
P
P
P
P
P
P
P
P
P
P
P
Tyr
Tyr
Tyr
Fully activated
receptor tyrosine
kinase (phos-
phorylated dimer)
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
6 6 ADPATP
Activated tyrosine
kinase regions
(unphosphorylated
dimer)
1 2
43

19. Structure and function of a receptor tyrosine kinase

20. Activation of the Mitf transcription factor through the binding
of stem cell factor by the Kit RTK protein (Part 2)
2nd
example of RTK(Kit)

21. Two signals
(juxtacrine) are
needed to effect the
differentiation of the
T lymphocyte

22. Signal
molecule
(ligand)
Gate
closed Ions
Ligand-gated
ion channel receptor
Plasma
membrane
Gate closed
Gate open
Cellular
response
An ion channel receptor acts
as a gate when the receptor
changes shape
When a signal molecule binds
as a ligand to the receptor, the
gate allows specific ions, such
as Na+
or Ca2+
, through a
channel in the receptor

23. 1. Which choice CORRECTLY describes what happens
during the transduction part of a signal transduction
response pathway?
a. Some fraction of the original signal is converted into
something else and passed through the cell.
b. Changes in protein activities and in other items
in the cell are induced by an activated receptor.
c. The original signal is amplified as it is passed
through the cell.
d. Energy from the signal is used to power the
changes needed in the cell for a response.
e. Some phenotypic feature of the cell is altered.

24. 1. Which choice CORRECTLY describes what happens
during the transduction part of a signal transduction
response pathway?
a. Some fraction of the original signal is converted into
something else and passed through the cell.
b. Changes in protein activities and in other items
in the cell are induced by an activated receptor.
c. The original signal is amplified as it is passed
through the cell.
d. Energy from the signal is used to power the
changes needed in the cell for a response.
e. Some phenotypic feature of the cell is altered.

25. 2. Of the following events, which might typically occur
THIRD in the course of a cell’s receiving and responding to a
signal?
a. An enzyme cascade occurs, increasing the number of
activated proteins.
b. A signal molecule is bound by a transmembrane tyrosine
kinase receptor protein.
c. The receptor protein complex phosphorylates other
proteins.
d. A reconfigured protein binds
to DNA, altering gene
expression.
e. Tyrosine kinase receptor
subunits dimerize.

26. 2. Of the following events, which might typically occur
THIRD in the course of a cell’s receiving and responding to a
signal?
a. An enzyme cascade occurs, increasing the number of
activated proteins.
b. A signal molecule is bound by a transmembrane tyrosine
kinase receptor protein.
c. The receptor protein complex phosphorylates other
proteins.
d. A reconfigured protein binds
to DNA, altering gene
expression.
e. Tyrosine kinase receptor
subunits dimerize.
f. B->e->c->a->d

27. Transduction: Cascades of molecular interactions
relay signals from receptors to target molecules in
the cell
• Transduction usually involves multiple steps
• Multistep pathways can amplify a signal: A few
molecules can produce a large cellular response
• Multistep pathways provide more opportunities
for coordination and regulation

28. Signal Transduction Pathways
• The molecules that relay a signal from receptor
to response are mostly proteins
• Like falling dominoes, the receptor activates
another protein, which activates another, and
so on, until the protein producing the response
is activated
• At each step, the signal is transduced into a
different form, usually a conformational change

29. Protein Phosphorylation and
Dephosphorylation
• In many pathways, the signal is transmitted by a
cascade of protein phosphorylations (protein
kinases transfer PO4 from ATP to protein)
• Phosphatase enzymes remove the phosphates
• This phosphorylation and dephosphorylation
system acts as a molecular switch, turning
activities on and off

30. Figure 11.10
Signaling molecule
Activated relay
molecule
Receptor
Inactive
protein kinase
1
Inactive
protein kinase
2
Inactive
protein kinase
3
Active
protein
kinase
1
Active
protein
kinase
2
Active
protein
kinase
3
Active
protein
Inactive
protein
Phosphorylation
cascade
ATP
ADP
PP
ATP
ADP
P i
P
P
P i
ATP
ADP
PP
PP
P i
P
Cellular
response

31. Small Molecules and Ions as Second
Messengers
• Second messengers are small, nonprotein,
water-soluble molecules or ions; Calcium ions
and cyclic AMP are common second messengers
• The extracellular signal molecule that binds to
the membrane is a pathway’s “first messenger”
• Second messengers can readily spread
throughout cells by diffusion
• Second messengers participate in pathways
initiated by G-protein-linked receptors and
receptor tyrosine kinases

32. ATP Cyclic AMP AMP
Adenylyl cyclase
Pyrophosphate
P P i
Phosphodiesterase
H2O
Cyclic AMP
•Cyclic AMP (cAMP) is one of the most widely
used second messengers
•Adenylyl cyclase, an enzyme in the plasma
membrane, converts ATP to cAMP in response to
an extracellular signal

33. • Many signal molecules trigger formation of cAMP
• Other components of cAMP pathways are G
proteins, G-protein-linked receptors, and protein
kinases
• cAMP usually activates protein kinase A, which
phosphorylates various other proteins
• Further regulation of cell metabolism is provided
by G-protein systems that inhibit adenylyl cyclase

34. Figure 11.12
First messenger
(signaling molecule
such as epinephrine)
G protein
Adenylyl
cyclase
G protein-coupled
receptor
Second
messenger
Cellular responses
Protein
kinase A
GTP
ATP
cAMP

35. • Understanding of the role of cAMP in G protein
signaling pathways helps explain how certain
microbes cause disease
• The cholera bacterium, Vibrio cholerae,
produces a toxin that modifies a G protein so
that it is stuck in its active form
• This modified G protein continually makes
cAMP, causing intestinal cells to secrete large
amounts of salt into the intestines
• Water follows by osmosis and an untreated
person can soon die from loss of water and salt

36. Calcium ions and Inositol Triphosphate
(IP3)
• Calcium ions (Ca2+
) act as a second messenger in
many pathways
• Calcium is an important second messenger
because cells can regulate its concentration

37. Figure 11.13
Endoplasmic
reticulum (ER)
Plasma
membrane
Mitochondrion
ATP
ATP
ATPCYTOSOL
Nucleus
Ca2+
pump
EXTRACELLULAR
FLUID
Key High [Ca2+
] Low [Ca2+
]

38. • A signal relayed by a signal transduction
pathway may trigger an increase in calcium in
the cytosol
• Pathways leading to the release of calcium
involve inositol triphosphate (IP3) and
diacylglycerol (DAG) as additional second
messengers
• These two are produced by cleavage of a
certain phospholipid in the plasma membrane

39. Figure 11.14-1
EXTRA-
CELLULAR
FLUID
Signaling molecule
(first messenger)
G protein
GTP
CYTOSOL
G protein-coupled
receptor Phospholipase C
DAG
PIP2
IP3
(second messenger)
IP3-gated
calcium channel
Ca2+
Nucleus
Endoplasmic
reticulum (ER)
lumen

40. Figure 11.14-2
EXTRA-
CELLULAR
FLUID
Signaling molecule
(first messenger)
G protein
GTP
CYTOSOL
G protein-coupled
receptor Phospholipase C
DAG
PIP2
IP3
(second messenger)
IP3-gated
calcium channel
Ca2+
Nucleus
Endoplasmic
reticulum (ER)
lumen
Ca2+
(second
messenger)

41. Figure 11.14-3
EXTRA-
CELLULAR
FLUID
Signaling molecule
(first messenger)
G protein
GTP
CYTOSOL
G protein-coupled
receptor Phospholipase C
DAG
PIP2
IP3
(second messenger)
IP3-gated
calcium channel
Ca2+
Nucleus
Endoplasmic
reticulum (ER)
lumen
Ca2+
(second
messenger)
Various
proteins
activated
Cellular
responses

42. Cytoplasmic and Nuclear Responses
• Ultimately, a signal transduction pathway leads
to regulation of one or more cellular activities
• The response may occur in the cytoplasm or
may involve action in the nucleus
• Many pathways regulate the activity of enzymes
via gene expression control

43. Figure 11.16
Reception Transduction
Inactive
G protein
Active G protein (102
molecules)
Inactive
adenylyl cyclase
Active adenylyl cyclase (102
)
ATP
Cyclic AMP (104
)
Inactive
protein kinase A
Active protein kinase A (104
)
Inactive
phosphorylase kinase
Active phosphorylase kinase (105
)
Active glycogen phosphorylase (106
)
Inactive
glycogen phosphorylase
Glycogen
Response
Glucose 1-phosphate
(108
molecules)
Binding of epinephrine to G protein-coupled
receptor
(1 molecule)

44. • Many other signaling pathways regulate the
synthesis of enzymes or other proteins, usually
by turning genes on or off in the nucleus
• The final activated molecule may function as a
transcription factor

45. Figure 11.15
Growth factor
Receptor
Phospho-
rylation
cascade
Reception
Transduction
CYTOPLASM
Inactive
transcription
factor
Active
transcription
factor
DNA
Response
P
Gene
mRNANUCLEUS

46. Fine-Tuning of the Response
• Multistep pathways have two important
benefits:
– Amplifying the signal (and thus the response)
– Contributing to the specificity of the response
Signal Amplification
• Enzyme cascades amplify the cell’s response
• At each step, the number of activated products
is much greater than in the preceding step

47. The Specificity of Cell Signaling
• Different kinds of cells have different collections
of proteins
• These differences in proteins give each kind of
cell specificity in detecting and responding to
signals
• The response of a cell to a signal depends on
the cell’s particular collection of proteins
• Pathway branching and “cross-talk” further help
the cell coordinate incoming signals

48. Figure 11.17
Signaling
molecule
Receptor
Relay
mole-
cules
Response 1 Response 2 Response 3 Response 4 Response 5
Cell A: Pathway leads
to a single response.
Cell B: Pathway
branches, leading to
two responses.
Cell C: Cross-talk
occurs between two
pathways.
Cell D: Different
receptor leads to a
different response.
Activation
or inhibition

49. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings
Signaling Efficiency: Scaffolding Proteins and
Signaling Complexes
• Scaffolding proteins are large relay proteins to which other
relay proteins are attached
• Scaffolding proteins can increase the signal transduction
efficiency
Signaling
molecule
Receptor
Scaffolding
protein
Plasma
membrane
Three
different
protein
kinases

50. Termination of the Signal
• Inactivation mechanisms are an essential aspect
of cell signaling
• When signal molecules leave the receptor, the
receptor reverts to its inactive state

51. 3. Which of the following INCORRECTLY describes an aspect of
the use of a second messenger in a typical signal transduction
pathway?
a. The second messenger can diffuse rapidly through the
cytosol.
b. After the rise in the concentration of the second messenger,
it is often removed quickly by degradation or export from
the cytosol.
c. The proteins that will bind the second messenger are already
present before there is a rise in its concentration.
d. Synthesis of the enzyme that creates the second
messenger occurs right after the signal is received, and not
before.
e. When the cell does not receive the signal, the second
messenger is kept at a low concentration.

52. 3. Which of the following INCORRECTLY describes an aspect of
the use of a second messenger in a typical signal transduction
pathway?
a. The second messenger can diffuse rapidly through the
cytosol.
b. After the rise in the concentration of the second messenger,
it is often removed quickly by degradation or export from
the cytosol.
c. The proteins that will bind the second messenger are already
present before there is a rise in its concentration.
d. Synthesis of the enzyme that creates the second
messenger occurs right after the signal is received, and not
before.
e. When the cell does not receive the signal, the second
messenger is kept at a low concentration.

53. Concept 11.5: Apoptosis integrates
multiple cell-signaling pathways
• Cells that are infected or damaged or have
reached the end of their functional lives often
undergo “programmed cell death”
• Apoptosis is the best understood type
• Components of the cell are chopped up and
packaged into vesicles that are digested by
scavenger cells
• Apoptosis prevents enzymes from leaking out
of a dying cell and damaging neighboring cells

54. Figure 11.19
2 µm

55. Apoptosis in the Soil Worm
Caenorhabditis elegans
• In worms and other organisms, apoptosis is
triggered by signals that activate a cascade of
“suicide” proteins in the cells programmed to
die
• When the death signal is received, an
apoptosis inhibiting protein (Ced-9) is
inactivated, triggering a cascade of caspase
proteins that promote apoptosis
• The chief caspase in the nematode is called
Ced-3

56. Figure 11.20
Ced-9 protein (active)
inhibits Ced-4 activity
Mitochondrion
Receptor
for death-
signaling
molecule
(a) No death signal (b) Death signal
Ced-4 Ced-3
Inactive proteins
Death-
signaling
molecule
Ced-9 (inactive)
Active
Ced-4
Active
Ced-3
Cell
forms
blebs
Other
proteases
Nucleases
Activation
cascade

57. Apoptotic Pathways and the
Signals That Trigger Them
• In humans and other mammals, several
different pathways, including about 15
caspases, can carry out apoptosis
• Apoptosis can be triggered by signals from
outside the cell or inside it
• Internal signals can result from irreparable
DNA damage or excessive protein misfolding

58. • Apoptosis evolved early in animal evolution
and is essential for the development and
maintenance of all animals
• For example, apoptosis is a normal part of
development of hands and feet in humans
(and paws in other mammals)
• Apoptosis may be involved in some diseases
(for example, Parkinson’s and Alzheimer’s);
interference with apoptosis may contribute to
some cancers

59. Figure 11.21
Interdigital
tissue 1 mm
Cells
undergoing
apoptosis
Space
between
digits