Cell Signaling: Communication between cells

Three Stages

05-03-16 Lecture 10

Cell Signaling

Receiving Environmental Signals

•Transporters, channels that transport signal across the membrane

•Receptors bind signals endocytosis

•Receptors :•Mediate cell-cell recognition : tight junctions•ECM - adhesion receptors•Signal receivers

Local and Long-Distance Signaling

•Local Signals: •Paracrine – secreted signal from a neighboring cell. Only nearby cells have receptors – and can respond

•Ex. development, histamines

•Autocrine – signals affect the same cells that make it

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Cell Signaling

Local and Long-Distance Signaling

•Long Distance: •Hormonal (produced by glands): small protein (ex. Insulin) or small molecules that circulate via the bloods

Signals are recognized by specific receptors on outside the cell HOW?

•Interactions with side chain (R-groups) on amino acids

•Sends signal inside cell •Growth

•Replicate DNA and divide

•DIE (Apoptosis)•Programmed cell death – turn on proteases in cell

•Turn on genes to do new things

•Change Metabolism•Create new strutures•Make a different signal – new response

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Cell Signaling

Intracellular Receptors

•Steriods

•cross the plasma membrane and bind nuclear receptors in cytoplasm

•Transported into nuclues through nuclear pore complex

•Turn on genes

Hormone(testosterone)

EXTRACELLULARFLUID

Receptorprotein

DNA

mRNA

NUCLEUS

CYTOPLASM

Plasmamembrane

Hormone-receptorcomplex

New protein

Figure 11.6

hydrophobic - can cross PM

NOTE: Proteins that can enter the nucleus have signals (nuclear import signals).

05-03-16 Lecture 10

Cell Signaling

Three stages of Cell Signaling

•Reception:•signal binds protein receptor on cell causes conformational change signals across membrane.

•Transduction:•Amplify the original signal

•Phosphorylation Cascade•Kinase transfers phosphate from ATP to Proteins

•Serine , Threonine, or Tyrosine•Adds a negative charge onto protein•Causes conformation change•Amplify by phosphorylating many other proteins

•Second Messenger System•Turn on a enzyme•Synthesizes a small molecule•Small molecule acts as a “messenger”

•Binds and allosterically activates “turns on” other proteins

Turn protein on!

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Cell Signaling

Three stages of Cell Signaling

•Response:•Change an activity in nucleus by turning genes on

•Change an activity in cytoplasm•Enzyme turned on•Change cytoskeleton

•Open a channel (e.g. brain)

•Opposite can be true also – turn things off•Receive signal•Amplification•Response: unique (specific) to turn a response off!

Examples

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Cell Signaling

Phosphorylation: Why is it important in signaling?

OHSerineThreonineTyrosine

+ HO P

O

O-

O-

from ATP

H20

Enzyme(Kinase)

O P

O

O-

O-

Big charge changeUsed as a ON/OFF Signal

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Cell Signaling

Three main types of membrane receptors

•Tyrosine Kinases

•G-protein linked

•Ion channels

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Cell Signaling

Tyrosine Kinase receptors

•Transmembrane protein•ligand binds outside surface of cell•Activates kinase inside cell

•Note: inactive without ligand

•Binds ligand conformational change•3˚ 4˚•Mononer dimer•(inactive) (active)

•Kinase phosphorylates many substrates including itself

•Response: ex. turn genes on (development)•Growth hormones use this strategy – signal to divide

To turn OFF: use a phosphatase – removes phosphates from proteins!

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Signalmolecule

Signal-binding sitea

CYTOPLASM

Tyrosines

Signal molecule

TyrTyrTyr

TyrTyr

TyrTyrTyrTyr

TyrTyr

Tyr

TyrTyrTyr

TyrTyr

Tyr TyrTyrTyr

TyrTyr

Tyr

TyrTyrTyr

TyrTyr

Tyr

DimerReceptor tyrosinekinase proteins(inactive monomers)

PPP

PP

P Tyr

TyrTyr

TyrTyr

TyrP

PP

PP

PCellularresponse 1

Inactiverelay proteins

Activatedrelay proteins

Cellularresponse 2

Activated tyrosine-kinase regions(unphosphorylateddimer)

Fully activated receptortyrosine-kinase(phosphorylateddimer)

6 ATP 6 ADP

Figure 11.7

Cell Signaling

Tyrosine Kinase receptors – a schematic

05-03-16 Lecture 10

Cell SignalingCell Signaling

G-protein coupled receptors

•Seven Transmembrane passing protein•Ligand binds outside surface of cell•Binds ligand conformational change•Can now bind “G-protein” insides on membrane

•G-Protein•Able to bind activated G-protein linked receptors•Able to bind GTP

G-protein

GTP

G-protein

GDP

GTP GDP

PiGTP Hydrolysis

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Cell Signaling

G-protein coupled receptors

G-protein-linkedReceptor

Plasma Membrane

EnzymeG-protein(inactive)CYTOPLASM

Cellular response

Activatedenzyme

ActivatedReceptor

Signal moleculeInctivateenzyme

Segment thatinteracts withG proteins

GDP

GDP

GTP

GTP

P i

Signal-binding site

Figure 11.7

GDP

Turn off by hydrolyzing GTP to GDP

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Cell Signaling

ION Channels

•Transmembrane protein (usually a pore or channel)•Closed , waiting for signal•Ligand binds outside surface of cell (neurotransmitter – secreted by neurons)•Binds ligand conformational change•Opens channel for ion (e.g. Na+) to go thru from High to low concentration

•FACLITATED DIFFUSION

•ACTION POTENTIAL – dramatic change in membrane potential (depolarization) due to the rapid influx of Na+ ions!!

•Turns Off: once channel opens and neurotransmitter released and either digested or reabsorbed

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Cellularresponse

Gate open

Gate close

Ligand-gatedion channel receptor

Plasma Membrane

Signalmolecule(ligand)

Figure 11.7

Gate closed Ions

Cell Signaling

ION Channels

ACTION Potential

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Cell Signaling

Phosphorylation Cascade

Signal molecule

Activeproteinkinase

1

Activeproteinkinase

2

Activeproteinkinase

3

Inactiveprotein kinase

1

Inactiveprotein kinase

2

Inactiveprotein kinase

3

Inactiveprotein

Activeprotein

Cellularresponse

Receptor

P

P

P

ATPADP

ADP

ADP

ATP

ATP

PP

PP

PP

Activated relaymolecule

iP

P

i

i

P

Widely used by cells

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Cell Signaling

Second Messenger Signaling

•Cyclic adenosine monophosphate (cAMP)•Produced via G-protein coupled receptor signaling

•Ca2+ influx into the cell•Via channel opening (classic and very important example – ION Channels – via ACTION Potential)

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Cell Signaling

cAMP – a simplified view

ATP

GTP

cAMP

Proteinkinase A

Cellular responses

G-protein-linkedreceptor

AdenylylcyclaseG protein

First messenger(signal moleculesuch as epinephrine)

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Cell Signaling

EXTRACELLULAR

FLUIDPlasma

membrane

ATP

CYTOSOL

ATP Ca2+

pump

Ca2+

pump

Ca2+

pump

Endoplasmic

reticulum (ER)

Nucleus

Mitochondrion

Key High [Ca2+] Low [Ca2+]

Figure 11.11

Ca2+ :

ACTION Potential

Action potential causes Ca2+

to enter cell from outside and from intracellular stores

ON/OFF switch for other proteins

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Cell Signaling – SPECIFITY!

•Many different types of cells•Many signals•Many proteins involved•Many, many responses

•How does the cell accomplish all this?

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Cell Signaling – SPECIFITY!

Response 1

Response 4 Response 5

Response

2

Response

3

Signalmolecule

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 receptorleads to a different response

Activationor inhibition

Receptor

Relaymolecules

Figure 11.15

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