CAMPBELL & REECECHAPTER 11

CELL COMMUNICATION

Cell Messaging

some universal mechanisms of cellular regulation

cells most often communicate with other cells by chemical signals

Evolution of Cell Signaling

Yeast: Saccharomyces cerevisia2 sexes: a & αtype a secrete a signaling molecule

called “a factor” which can bind to receptor proteins on α cells

@ same time α cells secrete “α factor” which binds to receptor proteins on type a cells

Saccharomyces cerevisiae

2 mating factors then cause the 2 yeast cells to grow toward each other & initiate other cell changes

results in fusion or mating of 2 cells of opposite type a/α cell that contains genes of both original cells

this new cell later divides passing this genetic combination to their offspring

Signal Transduction Pathway

series of steps initiated by signal molecule attaching to receptor

mechanism similar in yeasts and mammals & between bacteria and plants

Scientists think signaling mechanisms 1st evolved in ancient prokaryotes & unicellular eukaryotes then adopted for new uses by their multicellular descendants

Communication Among Bacteria

quorum sensing: bacteria release small molecules detected by like bacteria: gives them a “sense” of local density of cells

allows them to coordinate activities only productive when performed by given # in synchrony

ex: forming a biofilm: aggregation of bacteria adhered to a surface: slime on fallen leaves or on your teeth in the morning (they cause cavities)

Biofilm Developing

Biofilm Development

Local Signaling

(eukaryotic cells can also use cell junctions)

secretion of chemicals = messenger molecules from signaling cell

messenger molecules that travel to nearby cells only called: local regulators

Local Regulators

Animals: use 1 class of local regulators: growth factors

many cells in neighborhood respond to growth factor produced by 1 cell

paracrine signaling: secreting cell acts on nearby target cells by discharging local regulator

Paracrine Signaling

Synaptic Signaling

in the animal nervous systemaction potential travels thru cell

membrane of neuron when the electrical signal reaches axon end it triggers exocytosis of neurotransmitter (messenger molecule)

neurotransmitter travels across small space (synapse) attaches to receptors on target cell

Synaptic Signaling

Local Signaling in Plants

not as well understood as in animalsuse hormones (as do animals): long

distance signaling aka endocrine signaling travel target cells (any cell that has

receptor for hormone)Plant hormones aka plant growth

regulatorsmost reach their targets by moving

cell-to-cellsome travel in vessels

Long Distance Signaling

hormones (in some cases)

neurotransmitters: electrical signal travels length of neuron, may go from neuron-to-neuron for long distances

ability for any cell to respond to messenger molecule requires cell to have receptor for that particular molecule

3 Stages of Cell Signaling

1. Reception target cell’s detection of the signal

2. Transduction receptor protein changes converting

signal to a form that can bring about specific cellular response via a signal transduction pathway

3. Response activation of cellular response

Stages of Cell Signaling Response

Reception

cells must have a receptor for the ligand (messenger molecule) to react with

many signal receptors are transmembrane proteins with water-soluble ligandsligands:

usually large hydrophilic

Membrane Receptors

G-Protein-Coupled Receptors

cell-surface transmembrane receptorworks with help of a G protein (protein

that binds to GTP)flexible inherently unstable

difficult to crystallize so can study structure (use x-ray crystallography)

G Protein-Coupled Receptor: 7 α helices

Receptor Tyrosine Kinases

major class of membrane receptors w/enzyme activity

kinase: enzyme that catalyzes addition of phosphate group

cytoplasmic side of receptor has enzyme that: phosphate group from ATP tyrosine (on substrate protein)

Tyrosine

Inactive Monomers of Tyrosine Kinase

When there is no ligand attached to receptor site the kinase receptor protein exists as monomers

Binding of Signaling Molecule: Form Dimers

Tyrosine Kinase Activated by Dimerization

phosphate group added to each tyrosine

Recognition by Relay ProteinsRelay proteins

attach to phosphorylated tyrosine structural change that activates the bound protein

Each activated relay protein triggers different transduction pathway specific cellular response

ION CHANNEL RECEPTORS

Ligand-Gated Ion Channels

Ligand Binds to Receptor Site

ion crosses membrane & enters cytoplasm transduction pathway leading to a response

Ligand Dissociates from Receptor Site

Intracellular Receptors

in cytoplasm or nucleus of target cellshydrophobic or very small ligandsexamplessteroid hormones & thyroid hormones of

animalsNO (nitric oxide), a gas

Turning on Genes

special proteins called transcription factors control which genes are turned on

example:Testosterone (steroid hormone) its activated receptor acts as

transcription factor that turns on specific genes

thus activated receptor carries out transduction of the signal

TRANSDUCTION

when receptors for signaling molecules are membrane proteins the transduction stage is multistep pathway

usually involves inactive/active state by adding/removing phosphate group

benefit of multistep pathway is that possibility of amplification of signal if each step on pathway can transmit signal

to several molecules end up with large # activated molecules @ end of pathway

Signal Transduction Pathway

in most cases original signaling molecule does not enter cell & is not passed along signaling pathway

1st step triggered by signaling molecule binding to receptor

proteins often used as relay molecules (protein interaction a unifying theme of all cellular regulation)

Protein Phosphorylation & Dephosphorylation

protein kinase: enzyme that transfers phosphate groups from ATP protein most act on proteins different than

themselves most act on a.a. serine or threonine

(not tyrosine as in previous example) includes kinases in plants, animals, &

fungi many relay molecules in pathway are

kinases

Phosphorylation Cascade

Protein Phosphatases

enzymes that can rapidly remove phosphate groups from proteins (inactivating them)

also make kinases available to reuse

this phosphorylation/dephosphorylation system acts as molecular “switch” in cell “position of the switch” @ any given time depends on balance between active kinase & active phosphatase molecules

Second Messengers

many signaling pathways involve small, nonprotein, water-soluble molecules or ions known as 2nd messengers

1st messenger is extracellular signaling molecule

2 most widely used 2nd messengers are cAMP & Ca++

Cyclic AMP

epinephrine causes glycogen in hepatocytes to glucose w/out entering cells

search for 2nd messenger that transmits signal from plasma membrane metabolic pathway in cytoplasm

epinephrine binding to receptor followed by elevation of cytosolic concentrations of cAMP

cAMP

ATP cAMP

Adenylyl Cyclase

enzyme embedded in plasma membraneATP cAMP in response to extracellular

signals directly or indirectly(epinephrine one of many)

indirectly: receptor protein changes when signaling molecule attaches activates many adenylyl cyclase possibly thru GTP

GTP

cAMP as 2nd Messenger

1st messenger activates G protein-coup-led receptor adenylyl cyclase ATP to cAMP activates another protein (usually protein kinase A)

Protein Kinase A

serine/threonine kinaseonce activated it will phosphorylate other

proteins (depends on cell type)

Other Regulation Mechanisms

G protein systems inhibit adenylyl cyclase

uses different signaling molecule & receptor

understanding role of cAMP helps to explain how certain microbes cause disease

Vibrio cholerae: causes cholera in contaminated water forms biofilm over small intestines produces a toxin: enzyme that chemically

modifies a G protein involved in regulation of water & salt secretion (GTP --/ GDP so protein stays stuck in active form) high [cAMP] cells secrete large amts salts followed by water (osmosis)

Vibrio cholerae

Calcium Ions

many signaling molecules induce responses in target cell using signal transduction pathways that increase intracellular [Ca++]

more widely used than cAMP as 2nd messenger

Animal Cells Plant Cells

contractionsecretion cell division

pathway that leads to greening in response to light

Effects of Ca++

Ca++ Concentration Gradient

normally, [Ca++] inside cell << than outside

(up to 10,000x higher in extracellular fluid)

pumps used to send Ca++ into SER in muscle fibers (also in mitochondria, chloroplasts)

pathway leading to release of Ca++ from SER involves the 2nd messengers:

1. IP3 (inositol triphosphate)2. DAG (diacylglycerol)

Ca++ Pathway in Tear Production

RESPONSE

can be either nuclear or cytoplasmic responses

in nuclear responses the last kinase enters nucleus activates gene-regulating protein aka a transcription factor gene(s) transcribed mRNA …..

or transcription factor can turn gene offTranscription factors can regulate

several different genes

Nuclear Response thru signal reception transduction (phosphorylation cascade)

gene activation

Cytoplasmic Response

signaling pathway may regulate activity of a pathway (not synthesis of a protein)

open/close ion channelchange cell metabolism by controlling

enzymesregulate cell activities (yeast build

projections toward cell of opposite mating type)

Yeast Reproduction

How do signals induce directional cell growth during mating in yeast?

1. mating factor activates receptor2. G protein binds GTP & becomes

activated3. phosphorylation cascade activates Fus3

which then moves to plasma membrane4. Fus3 (a kinase) phosphorylates formin

this activating it5. formin initiates growth of

microfilamentsw that form shmoo projections

Controlling Response

generally, response controlled @ >1 site (not just either “on” or “off”)

4 aspects of fine-tuning response:1. Signal amplification2. Specificity3. Efficiency4. Termination of signal

Signal Amplification

enzyme cascades amplify the cell’s response to a signal

@ each step the # of activated products much > in preceding step of cascade

amplification happens because activated protein kinase stays in activated form long enuf to process numerous molecules of substrate

as result a small # signal molecules (like epinephrine) can release 100’s of millions of final product (glucose molecules)

Specificity of Cell Signaling & Coordination of the Response

certain cells respond to some signals & have no response to others

2 different cells may have different responses to same signal

different kinds of cells turn on different genes so different kinds of cells have different collections of proteins

What controls responses in cells?

response of a particular cell to a signal depends on its particular collection o

1. signal receptor proteins2. relay proteins3. proteins necessary to carry out the

response

Signaling Efficiency: Scaffolding Proteins & Signaling Complexes

Scaffolding Proteins: type of large relay protein to which several other relay proteins are simultaneously attached increasing the efficiency of signal transduction

Scaffolding Proteins Respond to same Signal

Scaffolding Proteins

some are permanently held together (terminal axons in neurons)

Relay Proteins that are Branch Points

Wiskott-Aldrich Syndrome (WAS) defect in single relay protein leads to:

abnl bleedingeczemapredisposition to:

infections leukemia

Termination of the Signal

ability of cell to respond to new signals depends on reversibility of changes produced by prior signals

binding of signal molecules to receptors is reversible as [signal molecules] decreases fewer

receptor sites occupied by signal those unoccupied: receptor molecule reverts

to its inactive form

Termination of Signal

any particular cell response occurs only when concentration of occupied receptors has reached a certain threshold:

if below threshold the cell response stops relay molecules return to inactive form cAMP AMP phosphorylated kinases lose phosphate

group

Apoptosis integrates multiple cell-signaling pathways

apoptosis: programmed cell deathSteps:1. DNA gets copped up into pieces2. organelles & other cytoplasmic

components fragment 3. cell‘s parts put into vesicles which are

engulfed by phagocyctic cells4. “blebbing” occurs (cell becomes

multilobed)

Apoptosis in Soil Worm C. elegans

2 genes identified Ced4 & Ced3 (ced for cell death)

both encode for proteins essential for cell death

are always present in a cell in inactive form

C. elegans has protein in outer mitochondrial membrane called Ced9 (from gene of same name) which serves as master regulator of apoptosis (has its brake on until “death signal” overrides it)

Signals that Trigger Apoptotic Pathways

capase: group of proteins that mediate apoptosis

several different pathways involving 15 capases identified in mammals

which pathway used depends on type of cell & signal used

1 major pathway involves mitochondrial proteins that form pores in mitochondrial membrane releasing mitochondrial proteins, including cytochrome c, activate capases