BIO 402/502 Advanced Cell & Developmental Biology I

Section I: Dr. Berezney

Cell Surface Receptors and Signal Transduction

Lecture 8

BackgroundComplex unicellular organisms existed on Earth for approximately 2.5 billion yearsbefore the first multicellular organisms appeared.

This long period for multicellularity to evolve may be related to difficulties developingthe elaborate 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 the organism asa whole.

Cell communication requires 4 parts:

1. Signal molecules: an extracellular signal molecule is produced by one cell and iscapable 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 receptorproteins that bind to the signal molecule and communicate its presence inward intothe cell.

3. Intracellular signaling proteins: these distribute the signal to the appropriateparts 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 intracellular 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 whole 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

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 a ≥108).

Fig 15-3, 5th Ed

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.

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Types of cell communication3. 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.

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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 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.

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 protein function, 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.

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Signal Molecules Act in Combination

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.

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

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Protein Turnover Rates Affect the Cellular Response What 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.

Fig 15-11, 5th Ed. Fig 15-11, 5th Ed.

Turnover ratesTurnover rates

The Three Largest Classes of Cell Surface Receptors

1. 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

The Three Largest Classes of Cell Surface Receptors

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.

Fig 15-16, 5th Ed

(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

Fig 15-17, 5th Ed

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.