Signal TransductionSignal Transduction

Dr. Chaidir, Apt

BackgroundComplex unicellular organisms existed on Earth for approximately 2.5 billion

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

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

a whole.

Cell communication requires 4 parts:

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

2. Receptor proteins: the cells in an organism must have cell surface receptor proteins that bind to the signal molecule and communicate its presence inward into the cell.

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

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

1. The signal molecule binds to the receptor protein (which is

generally located in the

plasma membrane).

2. The receptor activates

intracellular signaling proteins that initiate a signaling

cascade (a series of intra-cellular signaling molecules that act sequentially).

3. This signaling cascade

influences a target protein, altering this target protein and

thus altering the behavior of

the cell.

4. This process is often called signal transduction.

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

A Simple Signaling Pathway

Although yeast (unicellular eukaryotes)

live independently, they can influence

the behavior of other yeast.

Mating factor: Saccharomyces

cerevisiae (budding yeast) secrete the mating factor peptide that signals yeast

of opposite mating types to stop

proliferating and prepare to mate.

These two cells (haploid) can then fuse

to form a diploid cell which can then

undergo meiosis and sporulate, generating new haploid cells.

The molecules involved in the yeast mating response have relatives in

signaling pathways in animal cells, which have become much more

elaborate.

Normal

Response to mating

factor

Fig 15-2, 5th Ed

Signal Transduction in Unicellular Organisms

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

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 thebloodstream).

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

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 signaling

is 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 affects

cells only in the immediate environment of the signaling cell. Because paracrine signal

molecules act locally, their diffusion is limited. Factors that limit their diffusion are: rapid

uptake by neighboring target cells, destruction by extracellular enzymes, or by

immobilization in the extracellular matrix.

& 5th Edition

3. Synaptic: specialized cells called neurons make long processes (axons) that contact cells far away. When a neuron is stimulated, it sends an electrical impulse (action potential) along this axon to the target cell. This impulse, once it reaches the end of the axon, promotes the release of chemical signals called neurotransmitters. These diffuse 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 enters the bloodstream and is distributed widely throughout the organism. Endocrine signals can effect any cell that expresses the receptor to the released hormone.

& 5th Edition

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 been directed to adopt a specific fate, may begin to secrete an autocrine signal that activates receptors on itself and reinforces this developmental fate.

Autocrine signaling is most effective when it occurs from a group of identical cells simultaneously. The concentration of the autocrine signal accumulates, thereby activating receptors on these same cells. Autocrine signaling is used to encourage groups of cells to make 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.

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 ofneurotransmitter

Long-distance signaling

Endocrine cell Bloodvessel

Hormone travelsin bloodstreamto target cells

Targetcell

(c) Hormonal signaling

Extracellular Signaling Response TimesSignal responses such as increased growth and cell division

that 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

Genomic reprogramming

1. Cells in an organism are exposed to many, even hundreds, of different extracellular signals.

2. How cells respond to all of these signals in combination depends on the receptors they express and on the concentration and timing of these signals: Finger prints for cell signaling and their choreography

3. Extracellular signals often work in combination. This allows many responses from a limited number of signal molecules.

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

5. Most cells in a complex organism are programmed to depend upon a specific combination of signals to survive. If the cell does 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

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

cellcell--signaling pathwayssignaling pathways

Apoptosis is programmed or controlled cell death. 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 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

Fig. 11-19

2 m

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, Parkinsons and Alzheimers); interference with apoptosis may contribute to some cancers

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

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. These

different cells may have different types of intracellular signaling proteins, for example.

2. Different cells may express different types of receptors that bind the same ligand. There are different types of acetylcholine receptors, for example.

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 slowlywhen their synthesis rate changes.

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 of ions 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 a trimeric GTP-binding protein (G protein). The activated G protein then affects other intracellular signaling proteins, or target proteins directly. All G-protein-linked receptors are 7-pass transmembrane proteins that are a huge family of homologous molecules.

A

B

Alberts, Fig 15-16, 5th Ed

Fig. 11-7a

Signaling-molecule binding site

Segment thatinteracts withG proteins

G protein-coupled receptor

3. Enzyme-linked receptors: these receptors are either enzymes themselves, or are directly associated with the enzymes that they activate. These are single-pass transmembrane

receptors, with the enzymatic portion of the receptor being intracellular. The majority of

enzyme-lined receptors are protein kinases, or associate with protein kinases.

(1st messenger)

2nd

messenger

Second messengers: Small molecules that are produced in large numbers as a consequence or receptor activation. These molecules diffuse readily away from their source. Cyclic nucleotides and diacylglycerol are examples. First messengers are the signal itself.

Relay proteins: pass the signal on to the next intracellular signaling protein.

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

Scaffold proteins: proteins that bind multiple signaling proteins together in a functional complex and often hold them in a specific location.

Amplifier proteins: amplify the signal, often by generating second messengers (ion channels and enzymes).

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

Intracellular Signaling Networks

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

1. Protein phosphorylation: Phosphorylation of the molecular switch (by a protein kinase) causes the conversion between active and inactive states. Often protein kinases themselves are molecular switches. Dephosphorylation (by protein phosphatases) converts the molecular switch back to its starting point. Most kinases are serine/threonine kinases, with a smaller class phosphorylating tyrosine residues (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 eventually hydrolyze their GTP to GDP, thus converting them back to an inactive form.

Alberts, Fig 15-18, 5th Ed

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 togenerate 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 coincidence detectors).

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

Fig 15-20 5th Ed.

SIGNAL TRANSDUCTIONSIGNAL TRANSDUCTION

MECHANISMS OF SIGNAL MECHANISMS OF SIGNAL

TRANSDUCTIONTRANSDUCTION

Protein Phosphorylation

Second Messengers

Gene Transcription & Translation

THE PHOSPHORYLATION THE PHOSPHORYLATION

CASCADECASCADE

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