chaidir - materi 3 & 4 signal transduction

7/28/2019 Chaidir - Materi 3 & 4 Signal Transduction

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Signal TransductionSignal Transduction

Dr. Chaidir, Apt


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BackgroundComplex unicellular organisms existed on Earth for approximately 2.5 billion

years before the first multicellular organisms appeared.This long period formulticellularity to evolve may be related to difficulties developing theelaborate communication machinery necessary for a multicellular organism.

Cells in a multicellular organism need to be able to produce signals tocommunicate, and respond to signals from other cells in the organism.These signals must govern their own behavior for the benefit of theorganism as

a whole.

Cell communication requires 4 parts:

1. Signal molecules: an extracellular signal molecule is produced by one celland is capable of traveling to neighboring cells, or to cells that may be faraway.

2. Receptor proteins: the cells in an organism must have cell surface receptor

proteins that bind to the signal molecule and communicate its presenceinward into the cell.

3. Intracellular signaling proteins: these distribute the signal to theappropriate parts of the cell.

4. Target proteins: these are altered when a signaling pathway is active andchanges the behavior of the cell.


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1. The signal molecule binds tothe receptor protein (which isgenerally located in theplasma membrane).

2. The receptor activatesintracellular signaling proteinsthat initiate a signaling

cascade (a series of intra-

cellular signaling moleculesthat act sequentially).

3. This signaling cascadeinfluences a target protein,

altering this target protein andthus altering the behavior ofthe cell.

4. This process is often called

signal transduction.Figure 15-1 Molecular Biology of the Cell( Garland Science 2008)

A Simple Signaling Pathway


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Although yeast (unicellular eukaryotes)live independently, they can influencethe behavior of other yeast.

Mating factor: Saccharomycescerevisiae(budding yeast) secrete themating factor peptide that signals yeastof opposite mating types to stopproliferating and prepare to mate.

These two cells (haploid) can then fuseto form a diploid cell which can thenundergo meiosis and sporulate,generating new haploid cells.

The molecules involved in the yeastmating response have relatives insignaling pathways in animal cells,

which have become much moreelaborate.

Normal

Responseto matingfactor

Fig 15-2, 5th Ed

Signal Transduction

in Unicellular Organisms


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Fig. 11-2

Receptor factor

a factor

a

a

Exchange

of matingfactors

Yeast cell,mating type a

Yeast cell,mating type

Mating

New a/cell

a/

1

2

3


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Receptors Types

Cell surface receptors: most signal moleculescannot cross the plasma membrane, andtherefore must bind to receptors in the cellsurface.

Intracellular receptors: Some small signalmolecules can diffuse across the PM and bind toreceptors located in the cytosol or nucleus.These signal molecules are generallyhydrophobic and require carrier proteins to betransported in aqueous solutions (such as the

bloodstream).

Animal cells communicate by using hundreds ofkinds of signal molecules, such as proteins,small peptides, amino acids, steroids, and evengasses and ions.

These signal molecules (called ligands inrelation to their receptor) are often present invery low concentrations (typically 10-8M).

The receptors must have a very high affinity for

these ligands that are in such scarce amounts(K 108).


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Types of cell communication1. Contact-dependent: the signal molecule remains bound to the cell that produced it and,

therefore, will only influence cells that directly contact it.This very local type of signalingis very important in the development of multicellular organisms and in the immune

system.2. Paracrine: a signaling cell produces a signal molecule that is secreted, but only

diffuses a short distance. This signal molecule acts as a local mediator that affectscells only in the immediate environment of the signaling cell. Because paracrine signalmolecules act locally, their diffusion is limited. Factors that limit their diffusion are: rapid

uptake by neighboring target cells, destruction by extracellular enzymes, or byimmobilization in the extracellular matrix.

& 5th Edition


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3. Synaptic: specialized cells called neurons make long processes (axons) that contactcells far away. When a neuron is stimulated, it sends an electrical impulse (actionpotential) along this axon to the target cell. This impulse, once it reaches the end of theaxon, promotes the release of chemical signals called neurotransmitters. Thesediffuse a very short distance to the target cell and activate receptors on it.

4. Endocrine: an endocrine cell secretes a signal molecule called a hormone that entersthe bloodstream and is distributed widely throughout the organism. Endocrine signalscan effect any cell that expresses the receptor to the released hormone.

& 5th Edition


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Autocrine signalingWhen a cell sends a signal to an identical cell type, including themselves.This is common during developmental processes. For example, a cell that has beendirected to adopt a specific fate, may begin to secrete an autocrine signal that activatesreceptors on itself and reinforces this developmental fate.

Autocrine signaling is most effective when it occurs from a group of identical cellssimultaneously. The concentration of the autocrine signal accumulates, thereby activatingreceptors on these same cells. Autocrine signaling is used to encourage groups of cells tomake the same developmental decisions.

Community (cooperative) effects occurs during development; a group of cells can

respond to a fate-inducing signal, but a single isolated cell cannot.


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Fig. 11-5

Local signaling

Target cell

Secretingcell

Secretoryvesicle

Local regulatordiffuses throughextracellular fluid

(a) Paracrine signaling (b) Synaptic signaling

Target cellis stimulated

Neurotransmitterdiffuses across

synapse

Electrical signalalong nerve celltriggers release of

neurotransmitter

Long-distance signaling

Endocrine cell Bloodvessel

Hormone travelsin bloodstreamto target cells

Targetcell

(c) Hormonal signaling


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Extracellular Signaling Response TimesSignal responses such as increased growth and cell divisionthat involve changes in gene expression and synthesis of new proteinsoccur slowly (e.g., hrs) while those that involve changes in cell movement

secretion or metabolism occur rapidly (secs to mins). Synaptic responses

mediated by changes in membrane potential occur in milliseconds.Figure 15-6 Molecular Biology of the Cell Garland Science 2008

Genomicreprogramming


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1. Cells in an organism are exposed to many,

even hundreds, of different extracellularsignals.

2. How cells respond to all of these signals incombination depends on the receptors they

express and on the concentration and timingof these signals: Finger prints for cellsignaling and their choreography

3. Extracellular signals often work incombination. This allows many responsesfrom a limited number of signal molecules.

4. An absence of a signal can also trigger aresponse from a target cell.

5. Most cells in a complex organism areprogrammed to depend upon a specificcombination of signals to survive. If the celldoes not receive this combination of signals,it commits suicide, a process that is known

as programmed cell death, or apoptosis.

Signal Molecules Act

in Combination


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Apoptosis (programmed cell death) integrates multipleApoptosis (programmed cell death) integrates multiple

cellcell--signaling pathwayssignaling pathways

Apoptosis is programmed or controlled celldeath. 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 damagingneighboring cells

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


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Fig. 11-19

2 m


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Apoptosis evolved early in animal evolutionand is essential for the development and

maintenance of all animals Apoptosis may be involved in some diseases

(for example, Parkinsons and Alzheimers);

interference with apoptosis may contributeto some cancers

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


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One signal molecule can have several effectsThe neurotransmitter acetylcholine, for example, has different effects on different

types of cells. This is because:

1. Cell types respond to ligand binding of the same receptor differently. Thesedifferent cells may have different types of intracellular signaling proteins, forexample.

2. Different cells may express different types of receptors that bind the same

ligand. There are different types of acetylcholine receptors, for example.


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Protein Turnover Rates Affect the Cellular ResponseWhat happens when a signal is withdrawn?

In some cases the response is long-lived, sometimes even permanent. Often, theresponse fades when a signal is removed. How rapidly the response

declines depends on how rapidly the affected proteins are turned over.

The intracellular concentration of molecules with rapid turnover rates changemore quickly when their synthesis rate changes.

The concentration of proteins with slow turnover rates change more slowly

when their synthesis rate changes.


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The Three Largest Classes of Cell Surface Receptors1. Ion-channel-linked receptors: These receptors are involved in rapid signaling events

most generally found in neurons. The signal molecule (such as a neurotransmitter) causes

these receptors to either open or close, thereby allowing, or stopping, the movement ofions through its channel. This rapidly changes the excitability of the target cell. Ion-channel-linked receptors constitute a large family of multipass transmembrane proteins.

2. G-protein-linked receptors: These are receptors that, upon ligand binding, activate atrimeric GTP-binding protein (G protein). The activated G protein then affects other

intracellular signaling proteins, or target proteins directly. All G-protein-linked receptorsare 7-pass transmembrane proteins that are a huge family of homologous molecules.

A

B

Alberts, Fig 15-16, 5th Ed


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Fig. 11-7a

Signaling-molecule binding site

Segment that

interacts withG proteins

G protein-coupled receptor


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3. Enzyme-linked receptors: these receptors are either enzymes themselves, or are directlyassociated with the enzymes that they activate. These are single-pass transmembranereceptors, with the enzymatic portion of the receptor being intracellular. The majority ofenzyme-lined receptors are protein kinases, or associate with protein kinases.


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(1st messenger)

2nd

messenger

Second messengers: Small molecules that are

produced in large numbers as a consequence orreceptor activation. These molecules diffusereadily away from their source. Cyclic nucleotidesand diacylglycerol are examples. Firstmessengers are the signal itself.

Relay proteins: pass the signal on to the nextintracellular signaling protein.

Adaptor proteins: link one signaling protein toanother, but do not convey the signal themselves.Critical for the formation of signaling complexes.

Scaffold proteins: proteins that bind multiplesignaling proteins together in a functional complexand often hold them in a specific location.

Amplifier proteins: amplify the signal, often bygenerating second messengers (ion channels and

enzymes).

Anchoring proteins: locate signaling proteins ina precise location in the cell by tethering them tothe membrane or cytoskeleton.Gene regulatory proteins: these are activated atthe cell surface by receptors and translocate intothe nucleus to regulate gene expression

Intracellular Signaling Networks


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Molecular switches: many intracellular proteins act as switches in which theyare converted from an inactive to active state, and can be converted back.

1. Protein phosphorylation: Phosphorylation of the molecular switch (by a proteinkinase) causes the conversion between active and inactive states. Often proteinkinases themselves are molecular switches. Dephosphorylation (by protein

phosphatases) converts the molecular switch back to its starting point. Mostkinases are serine/threonine kinases, with a smaller class phosphorylating tyrosineresidues (tyrosine kinases).

2. GTP-binding proteins: Switch from inactive to active upon binding of GTP. Once

these are activated, they have intrinsic GTPase activity that will eventuallyhydrolyze their GTP to GDP, thus converting them back to an inactive form.

Alberts, Fig 15-18, 5th Ed


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Signal IntegrationCells often require multiple signal proteins coincidentally to trigger a response. Often,

multiple signals require integrator proteins which require more than one input signal to

generate an output signal that propagates a downstream signaling cascade.

Examples:(A) A single protein requires phosphorylation on two different residues, by two independent

signaling pathways, to be activated (proteins such as Y are often called coincidencedetectors).

(B) Two proteins, upon phosphorylation by two different signaling cascades, associatetogether to form an active intracellular signaling molecule.

Fig 15-20 5th Ed.


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SIGNAL TRANSDUCTIONSIGNAL TRANSDUCTION


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MECHANISMS OF SIGNALMECHANISMS OF SIGNAL

TRANSDUCTIONTRANSDUCTION

ProteinPhosphorylation SecondMessengers Gene Transcription& Translation


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THE PHOSPHORYLATIONTHE PHOSPHORYLATION

CASCADECASCADE


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chaidir - materi 3 & 4 signal transduction

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