Lecture: Cell SignalingI. Introduction / Overview of Cell Communication

II. Local vs. Long Distance Signaling Cell to Cell Contact (ex: cell junctions & cell-cell recognition) Secretion of Local Regulators (local) Neurotransmitters and Neurons (local) Hormones traveling in blood (long distance)

III. 3 Stages of Cell Signaling #1 - Reception (of signal = ligand) & Receptors

* 3 receptors: (1) G-protein couple receptors (2) Receptor Tyrosine Kinases (3) Ion Channel Receptors

#2 – Transduction (a multistep pathway)* Phospholylation by Kinases* 2nd messengers – ex: cyclic AMP (cAMP) and Calcium & IP3

#3 – Cellular Response* Cytoplasmic* Nuclear

Overview: The Cellular Internet

• Cell-to-cell communication is essential for life of unicellular and multicellular organisms

• Cells can communicate to the cell(s) next to them or cells from much further away in another part of the body

• How do cells receive a signal? • Once cells receive the signal, how does this lead to changes

inside the cell (response)?• Biologists have discovered some universal mechanisms of

cellular regulation• The combined effects of multiple signals determine cell

response• For example, the dilation of blood vessels is controlled by

multiple moleculesCopyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

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

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Local and Long-Distance Signaling

• Cells in a multicellular organism communicate by chemical messengers

• Local = factors (ex: growth factors), neurotransmitters• Long Distance = hormones

• 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, or cell-cell recognition

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Fig. 11-4Plasma membranes

Gap junctionsbetween animal cells

(a) Cell junctions

Plasmodesmatabetween plant cells

(b) Cell-cell recognition

Fig. 11-5ab

Local signaling

Target cell

Secretoryvesicle

Secretingcell

Local regulatordiffuses throughextracellular fluid

(a) Paracrine signaling (b) Synaptic signaling

Target cellis stimulated

Neurotransmitter diffuses across synapse

Electrical signalalong nerve celltriggers release ofneurotransmitter

Fig. 11-5c

Long-distance signaling

Endocrine cell Bloodvessel

Hormone travelsin bloodstreamto target cells

Targetcell

(c) Hormonal signaling

The Three Stages of Cell Signaling: A Preview

• The first research into cell signaling involved how the hormone epinephrine acts on cells

• Research suggested that cells receiving signals went through three processes:– Reception– Transduction– Response

Animation: Overview of Cell Signaling

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Fig. 11-6-1

Reception1

EXTRACELLULARFLUID

Signalingmolecule

Plasma membrane

CYTOPLASM

1

Receptor

Fig. 11-6-2

1

EXTRACELLULARFLUID

Signalingmolecule

Plasma membrane

CYTOPLASM

Transduction2

Relay molecules in a signal transduction pathway

Reception1

Receptor

Fig. 11-6-3

EXTRACELLULARFLUID

Plasma membrane

CYTOPLASM

Receptor

Signalingmolecule

Relay molecules in a signal transduction pathway

Activationof cellularresponse

Transduction Response2 3Reception1

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

• Most signal receptors are plasma membrane proteins

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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-coupled receptors– Receptor tyrosine kinases– Ion channel receptors

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• A G protein-coupled 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

Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Fig. 11-7a

Signaling-molecule binding site

Segment thatinteracts withG proteins

G protein-coupled receptor

Fig. 11-7b

G protein-coupledreceptor

Plasmamembrane

EnzymeG protein(inactive)

GDP

CYTOPLASM

Activatedenzyme

GTP

Cellular response

GDP

P i

Activatedreceptor

GDP GTP

Signaling moleculeInactiveenzyme

1 2

3 4

• Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines

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

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Fig. 11-7c

Signalingmolecule (ligand)

Ligand-binding site

Helix

TyrosinesTyr

Tyr

Tyr

Tyr

Tyr

Tyr

Receptor tyrosinekinase proteins

CYTOPLASM

Signalingmolecule

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Dimer

Activated relayproteins

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

PPP

P

PP

Cellularresponse 1

Cellularresponse 2

Inactiverelay proteins

Activated tyrosinekinase regions

Fully activated receptortyrosine kinase

6 6 ADPATP

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

PPP

PPP

1 2

3 4

• A ligand-gated 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

Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Fig. 11-7dSignalingmolecule(ligand)

Gateclosed Ions

Ligand-gatedion channel receptor

Plasmamembrane

Gate open

Cellularresponse

Gate closed3

2

1

Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target

molecules in the cell

• Signal 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 of the cellular response

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Protein Phosphorylation and Dephosphorylation

• In many pathways, the signal is transmitted by a cascade of protein phosphorylations

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

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Fig. 11-9

Signaling molecule

ReceptorActivated relaymolecule

Inactiveprotein kinase

1 Activeproteinkinase

1

Inactiveprotein kinase

2

ATPADP Active

proteinkinase

2

P

PPP

Inactiveprotein kinase

3

ATPADP Active

proteinkinase

3

P

PPP

i

ATPADP P

ActiveproteinPP

P i

Inactiveprotein

Cellularresponse

Phosphorylation cascadei

Small Molecules and Ions as Second Messengers

• The extracellular signal molecule that binds to the receptor is a pathway’s “first messenger”

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

• Cyclic AMP and calcium ions are common second messengers

• Second messengers participate in pathways initiated by G protein-coupled receptors and receptor tyrosine kinases

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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

• Many signal molecules trigger formation of cAMP• Other components of cAMP pathways are G proteins,

G protein-coupled receptors, and protein kinases• cAMP usually activates protein kinase A, which

phosphorylates various other proteins

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Adenylyl cyclase

Fig. 11-10

Pyrophosphate

P P i

ATP cAMP

Phosphodiesterase

AMP

First messengerFig. 11-11

G proteinAdenylylcyclase

GTP

ATPcAMP

Secondmessenger

Proteinkinase A

G protein-coupledreceptor

Cellular responses

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

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EXTRACELLULARFLUID

Fig. 11-12

ATP

Nucleus

Mitochondrion

Ca2+ pump

Plasmamembrane

CYTOSOL

Ca2+

pumpEndoplasmicreticulum (ER)

Ca2+

pumpATP

Key

High [Ca2+]Low [Ca2+]

• 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

Animation: Signal Transduction Pathways

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Fig. 11-13-1

EXTRA-CELLULARFLUID

Signaling molecule(first messenger)

G protein

GTP

G protein-coupledreceptor Phospholipase C PIP2

IP3

DAG

(second messenger)

IP3-gatedcalcium channel

Endoplasmicreticulum (ER) Ca2+

CYTOSOL

Fig. 11-13-2

G protein

EXTRA-CELLULARFLUID

Signaling molecule(first messenger)

G protein-coupledreceptor Phospholipase C PIP2

DAG

IP3(second messenger)

IP3-gatedcalcium channel

Endoplasmicreticulum (ER) Ca2+

CYTOSOL

Ca2+

(secondmessenger)

GTP

Fig. 11-13-3

G protein

EXTRA-CELLULARFLUID

Signaling molecule(first messenger)

G protein-coupledreceptor Phospholipase C PIP2

DAG

IP3(second messenger)

IP3-gatedcalcium channel

Endoplasmicreticulum (ER) Ca2+

CYTOSOL

Variousproteinsactivated

Cellularresponses

Ca2+

(secondmessenger)

GTP

Concept 11.4: Response: Cell signaling leads to regulation of transcription or cytoplasmic activities

• The cell’s response to an extracellular signal is sometimes called the “output response”

• 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

• Signaling pathways can also affect the physical characteristics of a cell, for example, cell shape

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Nuclear and Cytoplasmic Responses

• Many 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

• Other pathways regulate the activity of enzymes

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Fig. 11-14Growth factor

Receptor

Phosphorylationcascade

Reception

Transduction

Activetranscriptionfactor

ResponseP

Inactivetranscriptionfactor

CYTOPLASM

DNA

NUCLEUS mRNA

Gene

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

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Fig. 11-15

Reception

Transduction

Response

Binding of epinephrine to G protein-coupled receptor (1 molecule)

Inactive G protein

Active G protein (102 molecules)

Inactive adenylyl cyclaseActive adenylyl cyclase (102)

ATPCyclic AMP (104)

Inactive protein kinase AActive protein kinase A (104)

Inactive phosphorylase kinaseActive phosphorylase kinase (105)

Inactive glycogen phosphorylase

Active glycogen phosphorylase (106)

GlycogenGlucose-1-phosphate

(108 molecules)