Cell Signaling

AP Chapter 11

Evolution of cell signaling

• Similarities in pathways in bacteria, protists, fungi, plants, and animals suggest an early evolution of signaling pathways

Bacteria communication“bacteria talking to each other”

• Quorum sensing- concentration of signaling molecules allows bacteria to sense their local density

• Ex- Vibrio – glowing bacteria (luciferase enzyme) give off auto inducers into their environment

autoinducers

Quorum sensing can lead to the formation of biofilms

Slime molds – chemical signaling

• Slime molds live as solitary amoebae.• When slime mold cells begin to starve or dehydrate,

they release a pheromone-like chemical called cyclic AMP.  This messenger molecule alerts other slime mold amoebae. They detect the cAMP and follow the scent to join forces with the troubled amoebae forming a large mass of cells.

Other slime mold amoebae detect the cAMP and   follow the scent to join forces with the troubled amoebae.

cAMP is an important chemical word in the language of cells and seems to be understood and made by all cells, even our own. 

Fruiting body formation in fungichemical signaling

Local and long-distance signaling

Direct cytoplasmic connections:

- gap junctions or plasmodesmata in plant cells

- contact of surface molecules (cell-to- cell recognition via receptors

Plasmodesmata in plant cells

Gap junctions in animal cells

Immune cells – direct contact

Local regulators – nearby cells • paracrine signaling – only includes cells

of a particular organ• synaptic signaling – between neurons

• Long distance

• endocrine signaling

• nerve transmission

3 stages of cell signaling

1. Reception

2. Transduction

3. Response

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

• Ligand – the signal molecule, fits like a lock and key to receptor

• Most ligands bind to cell surface receptors; some bind to intracellular receptors

• Usually induces a shape change in receptor protein’s shape

Types of receptorsBind with water-soluble molecules on

membrane:

• G-Protein-linked Receptor

• Tyrosine Kinase Receptor

• Ligand-gated Ion Channel

Bind with hydrophobic receptors:

• Intracellular Receptors

G- Protein-Linked Receptors

• 7 protein helices that span the membrane

• Binding of the ligand to the G-protein receptor, activates a specific G protein located on the cytoplasm side. How - GDP becomes GTP.

• The activated G-protein activates a membrane-bound enzyme which continues on its pathway.

• The GTP goes back to GDP.Animation: Membrane-Bound Receptors that Activate G Proteins

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

How important is the G-protein system?

• Used by hormones, neurotransmitters, sensory reception, development….

• Many bacteria produce toxins that interfere with with G-protein systems

• Up to 60% of medicines influence G-protein pathways

Tyrosine kinase receptors• Receptor tyrosine kinases are membrane receptors that attach

phosphates from ATP to tyrosines (Remember kinase…ATP.)

• Once the receptors are activated, relay proteins bind to them and become activated themselves.

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

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

P

P

P

P

P

P

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

P

P

P

P

P

P

1 2

3 4

Tyrosine Kinase Receptors

• Binding of the signal molecules causes the two polypeptides to join.

They are activated and act as enzymes to phosphorylate the

tyrosines in the tails.

The receptor protein is now recognized by relay proteins,

triggering different effects.

Ligand-gated ion channel

• A ligand-gated ion channel receptor acts as a gate

• 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

• Ex- in neurotransmitters and nervous signal transmission

Fig. 11-7d

Signalingmolecule(ligand)

Gateclosed Ions

Ligand-gatedion channel receptor

Plasmamembrane

Gate open

Cellularresponse

Gate closed3

2

1

Ligand-Gated Ion Channels

http://msjensen.cehd.umn.edu/1135/Links/Animations/Flash/0003-swf_receptors_link.swf

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

Fig. 11-8-5

Hormone(testosterone)

EXTRACELLULARFLUID

Receptorprotein

Plasmamembrane

Hormone-receptorcomplex

DNA

mRNA

NUCLEUS New protein

CYTOPLASM

Intracellular Receptors

http://highered.mcgraw-hill.com/olc/dl/120109/bio46.swf

Signal Transduction

• Allow for amplification of signals

• Signal coordination and regulation

• Involves

1) second messengers (cAMP and Ca+2)

2) relay proteins such as protein kinases

How does epinephrine work?...an example of cAMP messenging

• Epinephrine acts via cyclic AMP (cAMP) as a second messenger.

• An activated G protein activates the enzyme adenylyl cyclase (THINK CYCLING!) which turns ATP to cAMP.

• Then cAMP can activate other inactive molecules to reach the desired product.

action of epinephrine Video | DnaTube.com - Scientific Video Site

Adenylyl cyclase

Fig. 11-10

Pyrophosphate

P P i

ATP cAMP

Phosphodiesterase

AMP

First messengerFig. 11-11

G protein

Adenylylcyclase

GTP

ATP

cAMPSecondmessenger

Proteinkinase A

G protein-coupledreceptor

Cellular responses

cAMP second messenger systems

Membrane Structure

• Calcium ions also act as second messengers.

One example is activating an enzyme phospholipase C to produce two more messengers which will open Ca channels.

The signal receptor may be a G protein or a tyrosine kinase receptor.

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

RELAY PROTEINS

• Enzymes called protein kinases are also important links in transduction.

• A protein kinase catalyzes the transfer of PHOSPHATE GROUPS from ATP to another protein to activate it.

• Amplification is possible in these type of pathways.

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

This can get pretty complicated!

Cell Responses

• Alteration of metabolism

• Rearrangement of cytoskeleton

• Modulation of gene activity

Fig. 11-14

Growth factor

Receptor

Phosphorylationcascade

Reception

Transduction

Activetranscriptionfactor

ResponseP

Inactivetranscriptionfactor

CYTOPLASM

DNA

NUCLEUS mRNA

Gene

ModulatingGeneActivity

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 kinase

Active phosphorylase kinase (105)

Inactive glycogen phosphorylase

Active glycogen phosphorylase (106)

GlycogenGlucose-1-phosphate

(108 molecules)

Alteration ofMetabolism

Fig. 11-16RESULTS

CONCLUSION

Wild-type (shmoos) ∆Fus3 ∆formin

Shmoo projection forming

ForminP

ActinsubunitP

PForminFormin

Fus3

Phosphory- lation cascade

GTP

G protein-coupledreceptor

Matingfactor

GDP

Fus3 Fus3

P

Microfilament

1

2

3

4

5

RearrangementOf cytoskeleton

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

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

The Specificity of Cell Signaling and Coordination of the Response

• Different kinds of cells have different collections of proteins which allow cells to detect and respond to different signals.

• Even the same signal can have different effects in cells with different proteins and pathways

Fig. 11-17

Signalingmolecule

Receptor

Relaymolecules

Response 1

Cell A. Pathway leadsto a single response.

Response 2 Response 3

Cell B. Pathway branches,leading to two responses.

Response 4 Response 5

Activationor inhibition

Cell C. Cross-talk occursbetween two pathways.

Cell D. Different receptorleads to a different response.

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

Same signal - different effects in cells with different proteins and pathways

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 by grouping together different proteins involved in the same pathway

Fig. 11-18

Signalingmolecule

Receptor

Scaffoldingprotein

Plasmamembrane

Threedifferentproteinkinases

Apoptosis (programmed cell death) integrates multiple cell-signaling pathways

• Apoptosis is programmed or controlled cell suicide

• A cell is chopped and packaged into vesicles that are digested by scavenger cells

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

• Apoptosis is important in shaping an organism during embryonic development

Fig. 11-20b

(b) Death signal

Death-signalingmolecule

Ced-9(inactive)

Cellformsblebs

ActiveCed-4

ActiveCed-3

Activationcascade

Otherproteases

Nucleases

Apoptotic Pathways and the Signals That Trigger Them

• Caspases are the main proteases (enzymes that cut up proteins) that carry out apoptosis

• Apoptosis can be triggered by:– An extracellular death-signaling ligand – DNA damage in the nucleus– Protein misfolding in the endoplasmic

reticulum

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

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

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

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

Fig. 11-21

Interdigital tissue 1 mm