09 ge lecture presentation

BIOLOGYA Global Approach

Campbell • Reece • Urry • Cain • Wasserman • Minorsky • Jackson

© 2015 Pearson Education Ltd

TENTH EDITION

Global Edition

Lecture Presentation by Nicole Tunbridge andKathleen Fitzpatrick

9Cellular Signaling


Cellular Messaging

a) Cells can signal to each other and interpret the signals they receive from other cells and the environment

b) Signals are most often chemicals

c) The same small set of cell signaling mechanisms shows up in diverse species and processes


Figure 9.1a

Epinephrine


Concept 9.1: External signals are converted to responses within the cell

a) Communication among microorganisms provides some insight into how cells send, receive, and respond to signals


Local and Long-Distance Signaling

a) Cells in a multicellular organism communicate via signaling molecules

b) In local signaling, animal cells may communicate by direct contact

c) Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells

d) Signaling substances in the cytosol can pass freely between adjacent cells


Figure 9.4Plasma membranes Cell wall

(a) Cell junctions

(b) Cell-cell recognition

Gap junctionsbetween animal cells

Plasmodesmatabetween plant cells


a) In many other cases, animal cells communicate using secreted messenger molecules that travel only short distances

b) Growth factors, which stimulate nearby target cells to grow and divide, are one class of such local regulators in animals

c) This type of local signaling in animals is called paracrine signaling


a) Synaptic signaling occurs in the animal nervous system when a neurotransmitter is released in response to an electric signal

b) Local signaling in plants is not well understood beyond communication between plasmodesmata


a) In long-distance signaling, plants and animals use chemicals called hormones

b) Hormonal signaling in animals is called endocrine signaling; specialized cells release hormones, which travel to target cells via the circulatory system

c) The ability of a cell to respond to a signal depends on whether or not it has a receptor specific to that signal


Figure 9.5 Local signaling

Target cells

Secreting cell

Secretoryvesicles

Local regulator Target cell

(b) Synaptic signaling(a) Paracrine signaling

(c) Endocrine (hormonal) signaling

Electrical signal triggersrelease of neurotransmitter.

Neurotransmitterdiffuses acrosssynapse.

Long-distance signalingEndocrine cell Target cell

specificallybindshormone.

Hormonetravels inbloodstream.

Bloodvessel


Figure 9.5a

Local signaling

Target cells

Secreting cell

Secretoryvesicles

Local regulator(a) Paracrine signaling


Figure 9.5b

Target cell

(b) Synaptic signaling

Electrical signal triggersrelease of neurotransmitter.

Neurotransmitterdiffuses acrosssynapse.

Local signaling


Figure 9.5c

(c) Endocrine (hormonal) signaling

Long-distance signalingEndocrine cell Target cell

specificallybindshormone.

Hormonetravels inbloodstream.

Bloodvessel


The Three Stages of Cell Signaling: A Preview

a) Earl W. Sutherland discovered how the hormone epinephrine acts on cells

b) Sutherland suggested that cells receiving signals went through three processes

a)Reception

b)Transduction

c)Response


a) In reception, the target cell detects a signaling molecule that binds to a receptor protein on the cell surface

b) In transduction, the binding of the signaling molecule alters the receptor and initiates a signal transduction pathway; transduction often occurs in a series of steps

c) In response, the transduced signal triggers a specific response in the target cell


Figure 9.6-1

CYTOPLASMPlasma membrane

EXTRACELLULARFLUID

Receptor

Signalingmolecule

Reception1


Figure 9.6-2


EXTRACELLULARFLUID

Receptor

Signalingmolecule

Reception1 Transduction2

Relay molecules

1 2 3


Figure 9.6-3


EXTRACELLULARFLUID

Receptor

Signalingmolecule

Reception1 Transduction2

Relay molecules

1 2 3

Response3

Activationof cellularresponse


Animation: Overview of Cell Signaling


Concept 9.2: Reception: A signaling molecule binds to a receptor protein, causing it to change shape

a) The binding between a signal molecule (ligand) and receptor is highly specific

b) A shape change in a receptor is often the initial transduction of the signal

c) Most signal receptors are plasma membrane proteins


Receptors in the Plasma Membrane

a) G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors

b) Most water-soluble signal molecules bind to specific sites on receptor proteins that span the plasma membrane


Figure 9.7

Plasmamembrane

Cholesterol

Moleculemimickingligand

β2-adrenergicreceptors


a) There are three main types of membrane receptors

a)G protein-coupled receptors

b)Receptor tyrosine kinases

c)Ion channel receptors


a) G protein-coupled receptors (GPCRs) are cell surface transmembrane receptors that work with the help of a G protein

b) G proteins bind the energy-rich GTP

c) G proteins are all very similar in structure

d) GPCR systems are extremely widespread and diverse in their functions


a) Receptor tyrosine kinases (RTKs) are membrane receptors that attach phosphates to tyrosines

b) A receptor tyrosine kinase can trigger multiple signal transduction pathways at once

c) Abnormal functioning of RTKs is associated with many types of cancers


a) A ligand-gated ion channel receptor acts as a gate when the receptor changes shape

b) 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


Figure 9.8a

Signaling molecule binding site

Segment thatinteracts withG proteins

G protein-coupled receptor


Figure 9.8b

Activatedenzyme

EnzymeG protein(inactive)CYTOPLASM

G protein-coupledreceptor

Plasma membrane Activatedreceptor

Signalingmolecule

GDP

GTPGDP

GTPGDP

Inactiveenzyme

Cellularresponse

P i

GTP

GDP

1 2

43


Figure 9.8ba

EnzymeG protein(inactive)CYTOPLASM


Plasma membrane

GDP

Activatedreceptor

Signalingmolecule

Inactiveenzyme

GTP

GDP

GDP

GTP

1

2


Figure 9.8bb Activatedenzyme

Cellularresponse

3

GTP

GDP

P i

4


Figure 9.8c

Tyrosines

CYTOPLASMReceptor tyrosinekinase proteins(inactive monomers)

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Ligand-binding site helix in themembrane

Signaling molecule(ligand)

Signaling molecule

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Dimer

Activated relayproteins

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Inactiverelay proteins

Cellularresponse 1

Cellularresponse 2

PPP

PPP

PPP

PPP

Tyr

Tyr

Tyr

Fully activatedreceptor tyrosinekinase (phos-phorylated dimer)

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr 6 6 ADPATP

Activated tyrosinekinase regions(unphosphorylateddimer)

1 2

43


Figure 9.8ca

Tyrosines

CYTOPLASMReceptor tyrosinekinase proteins(inactive monomers)

Ligand-binding site helix in themembrane

Signaling molecule(ligand)

TyrTyr

Tyr

TyrTyr

Tyr

1


Figure 9.8cb

Signaling molecule

Dimer

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

2

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr


Figure 9.8cc

3

Fully activatedreceptor tyrosinekinase (phos-phorylated dimer)

6 6 ADPATP

Activated tyrosinekinase regions(unphosphorylateddimer)

TyrTyr

Tyr

TyrTyr

Tyr

TyrTyr

Tyr

TyrTyr

Tyr

PPP

PPP


Figure 9.8cd

4

TyrTyr

Tyr

PPP

TyrTyr

Tyr

PPP

Activated relayproteins

Inactiverelay proteins

Cellularresponse 1

Cellularresponse 2


Figure 9.8d-1

1Ions

PlasmamembraneLigand-gated

ion channel receptor

GateclosedSignaling

molecule(ligand)


Figure 9.8d-2

1Ions



GateclosedSignaling

molecule(ligand)

Gate open2

Cellularresponse


Figure 9.8d-3

1Ions



GateclosedSignaling

molecule(ligand)

Gate open2

Cellularresponse

Gate closed3


Intracellular Receptors

a) Intracellular receptor proteins are found in the cytoplasm or nucleus of target cells

b) Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors

c) Examples of hydrophobic messengers are the steroid and thyroid hormones of animals

d) An activated hormone-receptor complex can act as a transcription factor, turning on specific genes


Figure 9.9Hormone(aldosterone)

Receptorprotein

Plasmamembrane

Hormone-receptorcomplex

EXTRA-CELLULARFLUID

DNA

mRNA

NUCLEUS

Newprotein

CYTOPLASM


Figure 9.9a

Hormone(aldosterone)

Receptorprotein

PlasmamembraneHormone-receptorcomplex

EXTRA-CELLULARFLUID

NUCLEUS CYTOPLASM


Figure 9.9b

Hormone-receptorcomplex

DNA

mRNA

NUCLEUS

Newprotein

CYTOPLASM

Concept 9.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell

a) Signal transduction usually involves multiple steps

b) Multistep pathways can greatly amplify a signal

c) Multistep pathways provide more opportunities for coordination and regulation of the cellular response



Signal Transduction Pathways

a) The binding of a signaling molecule to a receptor triggers the first step in a chain of molecular interactions

b) Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated

c) At each step, the signal is transduced into a different form, usually a shape change in a protein


Protein Phosphorylation and Dephosphorylation

a) Phosphorylation and dephosphorylation of proteins is a widespread cellular mechanism for regulating protein activity

b)Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation

c) Many relay molecules in signal transduction pathways are protein kinases, creating a phosphorylation cascade


Figure 9.10

Signaling molecule

Activated relaymolecule

Receptor

Inactiveprotein kinase

1


2


3

Activeprotein kinase

1


2


3

Activeprotein

Inactiveprotein

Phosphorylation cascade

ATPADP

PP

ATPADP

P i

P

P

P i

ATPADP

PP

PPP i

P

Cellularresponse


Figure 9.10a

Signaling molecule

Activated relaymolecule

Receptor


1 Activeprotein kinase

1


Figure 9.10b


1


2


3


1


2


3

ATPADP

PPP i

ATPADP

PPP i

Phosphorylationcascade

P

P


Figure 9.10c


3 Activeprotein kinase

3

ATPADP

PPP i

P i

P

P

ATPADP

PP

Inactiveprotein

Activeprotein

Cellularresponse


a) Protein phosphatases rapidly remove the phosphates from proteins, a process called dephosphorylation

b) This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off or up or down, as required


Small Molecules and Ions as Second Messengers

a) Many signaling pathways involve second messengers

b)Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion

c) Second messengers participate in pathways initiated by GPCRs and RTKs

d) Cyclic AMP and calcium ions are common second messengers


Cyclic AMP

a) Cyclic AMP (cAMP) is one of the most widely used second messengers

b)Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal


Figure 9.11

ATP cAMP AMP

PhosphodiesteraseAdenylyl cyclase

Pyrophosphate H2O


Figure 9.11a

ATP cAMP

Adenylyl cyclase

Pyrophosphate


Figure 9.11b

cAMP AMP

H2O

Phosphodiesterase


a) Many signal molecules trigger formation of cAMP

b) Other components of cAMP pathways are G proteins, G protein-coupled receptors, and protein kinases

c) cAMP usually activates protein kinase A, which phosphorylates various other proteins

d) Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl cyclase


Figure 9.12

First messenger(signaling moleculesuch as epinephrine)

G protein

Adenylylcyclase


Secondmessenger

Cellular responses

Proteinkinase A

GTP

ATP

cAMP


a) Understanding of the role of cAMP in G protein signaling pathways helps explain how certain microbes cause disease

b) The cholera bacterium, Vibrio cholerae, produces a toxin that modifies a G protein so that it is stuck in its active form

c) This modified G protein continually makes cAMP, causing intestinal cells to secrete large amounts of salt into the intestines

d) Water follows by osmosis and an untreated person can soon die from loss of water and salt


Calcium Ions and Inositol Triphosphate (IP3)

a) Calcium ions (Ca2+) act as a second messenger in

many pathways

b) Ca2+ can function as a second messenger because

its concentration in the cytosol is normally much lower than the concentration outside the cell

c) A small change in number of calcium ions thus represents a relatively large percentage change in calcium concentration


Figure 9.13

Endoplasmicreticulum (ER)

Plasmamembrane

Mitochondrion

ATP

ATP

ATPCYTOSOL

Nucleus

Ca2+

pump

EXTRACELLULARFLUID

Key High [Ca2+] Low [Ca2+]


a) A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol

b) Pathways leading to the release of calcium involve inositol triphosphate (IP3) and diacylglycerol (DAG) as additional second messengers

c) These two are produced by cleavage of a certain phospholipid in the plasma membrane


Figure 9.14-1

EXTRA-CELLULARFLUID

Signaling molecule(first messenger)

G protein

GTP

CYTOSOL G protein-coupledreceptor Phospholipase C

DAG

PIP2

IP3(second messenger)

IP3-gatedcalcium channel

Ca2+

Nucleus

Endoplasmicreticulum (ER)lumen


Figure 9.14-2

EXTRA-CELLULARFLUID


G protein

GTP


DAG

PIP2



Ca2+

Nucleus


Ca2+

(secondmessenger)


Figure 9.14-3

EXTRA-CELLULARFLUID


G protein

GTP


DAG

PIP2



Ca2+

Nucleus


Ca2+

(secondmessenger)

Variousproteinsactivated

Cellularresponses


Animation: Signal Transduction Pathways

Concept 9.4: Response: Cell signaling leads to regulation of transcription or cytoplasmic activities

a) The cell’s response to an extracellular signal is called the “output response”



Nuclear and Cytoplasmic Responses

a) Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities

b) The response may occur in the cytoplasm or in the nucleus

c) Many signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus

d) The final activated molecule in the signaling pathway may function as a transcription factor


Figure 9.15

Growth factorReceptor

Phospho-rylation

cascade

Reception

Transduction

CYTOPLASM

Inactivetranscriptionfactor

Activetranscriptionfactor

DNA

ResponseP

Gene

mRNANUCLEUS


Figure 9.15a

Growth factorReceptor

Phospho-rylation

cascade

Reception

Transduction

NUCLEUS

CYTOPLASM



Figure 9.15b

NUCLEUS

CYTOPLASM

Phospho-rylation

cascade Transduction


Activetranscriptionfactor Response

DNA

P

Gene

mRNA


a) Other pathways regulate the activity of enzymes rather than their synthesis

b) For example, a signal could cause opening or closing of an ion channel in the plasma membrane, or a change in cell metabolism


Figure 9.16

Reception Transduction

InactiveG protein

Active G protein (102 molecules)

Inactiveadenylyl cyclase

Active adenylyl cyclase (102)

ATP

Cyclic AMP (104)Inactiveprotein kinase A

Active protein kinase A (104)

Inactivephosphorylase kinase

Active phosphorylase kinase (105)

Active glycogen phosphorylase (106)

Inactiveglycogen phosphorylaseGlycogen

Response

Glucose 1-phosphate(108 molecules)

Binding of epinephrine to G protein-coupledreceptor(1 molecule)


Figure 9.16a

Reception

Glycogen

Response

Glucose 1-phosphate(108 molecules)

Binding of epinephrine to G protein-coupledreceptor(1 molecule)


Figure 9.16b

Transduction

InactiveG protein

Active G protein (102 molecules)

Inactiveadenylyl cyclase

Active adenylyl cyclase (102)

ATP




Figure 9.16c

Inactivephosphorylase kinase

Active phosphorylase kinase (105)

Active glycogen phosphorylase (106)

Inactiveglycogen phosphorylase



Transduction


a) Signaling pathways can also affect the overall behavior of a cell, for example, a signal could lead to cell division


Regulation of the Response

a) A response to a signal may not be simply “on” or “off”

b) There are four aspects of signal regulation to consider

a)Amplification of the signal (and thus the response)

b)Specificity of the response

c)Overall efficiency of response, enhanced by scaffolding proteins

d)Termination of the signal


Signal Amplification

a) Enzyme cascades amplify the cell’s response to the signal

b) At each step, the number of activated products is much greater than in the preceding step


The Specificity of Cell Signaling and Coordination of the Response

a) Different kinds of cells have different collections of proteins

b) These different proteins allow cells to detect and respond to different signals

c) The same signal can have different effects in cells with different proteins and pathways

d) Pathway branching and “cross-talk” further help the cell coordinate incoming signals


Figure 9.17

Signalingmolecule

Receptor

Relaymole-cules

Response 1 Response 2 Response 3 Response 4 Response 5

Cell A: Pathway leadsto a single response.

Cell B: Pathway branches, leading totwo responses.

Cell C: Cross-talkoccurs between twopathways.

Cell D: Differentreceptor leads to a different response.

Activationor inhibition


Figure 9.17a

Signalingmolecule

Receptor

Relaymole-cules

Response 1 Response 2 Response 3

Cell A: Pathway leadsto a single response.

Cell B: Pathway branches, leading totwo responses.


Figure 9.17b

Response 4 Response 5

Cell C: Cross-talkoccurs between twopathways.

Cell D: Differentreceptor leads to a different response.

Activationor inhibition


Signaling Efficiency: Scaffolding Proteins and Signaling Complexes

a) Scaffolding proteins are large relay proteins to which other relay proteins are attached

b) Scaffolding proteins can increase the signal transduction efficiency by grouping together different proteins involved in the same pathway

c) In some cases, scaffolding proteins may also help activate some of the relay proteins


Figure 9.18

Signalingmolecule

Receptor

Scaffoldingprotein

Plasmamembrane

Threedifferentproteinkinases


Termination of the Signal

a) Inactivation mechanisms are an essential aspect of cell signaling

b) If ligand concentration falls, fewer receptors will be bound

c) Unbound receptors revert to an inactive state


Concept 9.5: Apoptosis integrates multiple cell-signaling pathways

a) Cells that are infected or damaged or have reached the end of their functional lives often undergo “programmed cell death”

b)Apoptosis is the best understood type

c) Components of the cell are chopped up and packaged into vesicles that are digested by scavenger cells

d) Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells


Figure 9.19

2 µm


Apoptosis in the Soil Worm Caenorhabditis elegans

a) In worms and other organisms, apoptosis is triggered by signals that activate a cascade of “suicide” proteins in the cells programmed to die

b) When the death signal is received, an apoptosis inhibiting protein (Ced-9) is inactivated, triggering a cascade of caspase proteins that promote apoptosis

c) The chief caspase in the nematode is called Ced-3


Figure 9.20

Ced-9 protein (active)inhibits Ced-4 activity

Mitochondrion

Receptorfor death-signalingmolecule

(a) No death signal (b) Death signal

Ced-4 Ced-3

Inactive proteins

Death-signalingmolecule

Ced-9 (inactive)

ActiveCed-4

ActiveCed-3

Cellformsblebs

Otherproteases

NucleasesActivationcascade


Figure 9.20a

Ced-9 protein (active)inhibits Ced-4 activity

Mitochondrion

Receptorfor death-signalingmolecule

(a) No death signal

Ced-4 Ced-3

Inactive proteins


Figure 9.20b

(b) Death signal

Death-signalingmolecule

Ced-9 (inactive)

ActiveCed-4

ActiveCed-3

Cellformsblebs

OtherproteasesNucleases

Activationcascade


Apoptotic Pathways and the Signals That Trigger Them

a) In humans and other mammals, several different pathways, including about 15 caspases, can carry out apoptosis

b) Apoptosis can be triggered by signals from outside the cell or inside it

c) Internal signals can result from irreparable DNA damage or excessive protein misfolding


a) Apoptosis evolved early in animal evolution and is essential for the development and maintenance of all animals

b) For example, apoptosis is a normal part of development of hands and feet in humans (and paws in other mammals)

c) Apoptosis may be involved in some diseases (for example, Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers


Figure 9.21

Interdigitaltissue 1 mm

Cellsundergoingapoptosis

Spacebetweendigits


Figure 9.21a

Interdigitaltissue1 mm


Figure 9.21b

1 mm

Cellsundergoingapoptosis


Figure 9.21c

Spacebetweendigits1 mm


Figure 9.UN01a

Matingfactor

Mating factoractivatesreceptor.

GDPG protein binds GTPand becomes activated.

GTP

Fus3 Fus3P

Phosphoryl- ation cascade

Phosphorylation cascadeactivates Fus3, which movesto plasma membrane.

Formin ForminP

Fus3 phos-phorylatesformin,activating it.

Formin initiates growth ofmicrofilaments that formthe shmoo projections.

Microfilament

P

P

Fus3Actinsubunit

Formin

Shmoo projectionformingG protein-coupled

receptor

1

2

5

4

3


Figure 9.UN01aa

Matingfactor

Mating factoractivatesreceptor.

GDPG protein binds GTPand becomes activated.

GTP

Fus3 Fus3P

Phosphoryl- ation cascade

Phosphorylation cascadeactivates Fus3, which movesto plasma membrane.


1

2

3


Figure 9.UN01ab

Formin ForminP

Fus3 phos-phorylatesformin,activating it.

Formin initiates growth ofmicrofilaments that formthe shmoo projections.

Microfilament

P

P

Fus3Actinsubunit

Formin

Shmoo projectionforming

4

5


Figure 9.UN01b

Wild type


Figure 9.UN01c

Fus3


Figure 9.UN01d

formin


Figure 9.UN02

Reception Transduction Response

Relay molecules

Signalingmolecule

Receptor

Activationof cellularresponse

1 2 3

1 2 3


Figure 9.UN03

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