Signal Transduction

Dr. Chaidir, Apt

Background
Complex 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 and changes the behavior of the cell.

. The receptor activates intracellular signaling proteins that initiate a signaling cascade (a series of intracellular signaling molecules that act sequentially). 2. The signal molecule binds to the receptor protein (which is generally located in the plasma membrane).A Simple Signaling Pathway 1. 3. Figure 15-1 Molecular Biology of the Cell (© Garland Science 2008) 4. This signaling cascade influences a target protein. This process is often called signal transduction. altering this target protein and thus altering the behavior of the cell.

Normal 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. which have become much more elaborate. Signal Transduction in Unicellular Organisms Response to mating factor These two cells (haploid) can then fuse to form a diploid cell which can then undergo meiosis and sporulate. Fig 15-2. The molecules involved in the yeast mating response have relatives in signaling pathways in animal cells. 5th Ed . generating new haploid cells.

Fig. mating type a a factor Yeast cell. mating type α 2 Mating a α 3 New a/α cell a/α . 11-2 Receptor α factor 1 Exchange of mating factors a α Yeast cell.

The receptors must have a very high affinity for these ligands that are in such scarce amounts (Kα ≥108). . Intracellular receptors: Some small signal molecules can diffuse across the PM and bind to receptors located in the cytosol or nucleus. and therefore must bind to receptors in the cell surface. Animal cells communicate by using hundreds of kinds of signal molecules. These signal molecules are generally hydrophobic and require carrier proteins to be transported in aqueous solutions (such as the bloodstream). small peptides. and even gasses and ions. amino acids.Receptors Types Cell surface receptors: most signal molecules cannot cross the plasma membrane. steroids. These signal molecules (called ligands in relation to their receptor) are often present in very low concentrations (typically ≤10-8M). such as proteins.

& 5th Edition Types of cell communication 1. 2. Paracrine: a “signaling cell” produces a signal molecule that is secreted. their diffusion is limited. . destruction by extracellular enzymes. Because paracrine signal molecules act locally. but only diffuses a short distance. 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. Factors that limit their diffusion are: rapid uptake by neighboring target cells. Contact-dependent: the signal molecule remains bound to the cell that produced it and. This signal molecule acts as a local mediator that affects cells only in the immediate environment of the signaling cell. or by immobilization in the extracellular matrix.

& 5th Edition 3. Endocrine: an endocrine cell secretes a signal molecule called a hormone that enters the bloodstream and is distributed widely throughout the organism. 4. This impulse. . When a neuron is stimulated. These diffuse a very short distance to the target cell and activate receptors on it. it sends an electrical impulse (action potential) along this axon to the target cell. Endocrine signals can effect any cell that expresses the receptor to the released hormone. promotes the release of chemical signals called neurotransmitters. once it reaches the end of the axon. Synaptic: specialized cells called neurons make long processes (axons) that contact cells far away.

a group of cells can respond to a fate-inducing signal. Community (cooperative) effects occurs during development. thereby activating receptors on these same cells. may begin to secrete an autocrine signal that activates receptors on itself and reinforces this developmental fate. The concentration of the autocrine signal accumulates. but a single isolated cell cannot. Autocrine signaling is most effective when it occurs from a group of identical cells simultaneously.Autocrine signaling When a cell sends a signal to an identical cell type. For example. including themselves. a cell that has been “directed” to adopt a specific fate. This is common during developmental processes. . Autocrine signaling is used to encourage groups of cells to make the same developmental decisions.

11-5 Local signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter Long-distance signaling Endocrine cell Blood vessel Secreting cell Secretory vesicle Neurotransmitter diffuses across synapse Hormone travels in bloodstream to target cells Local regulator diffuses through extracellular fluid (a) Paracrine signaling Target cell is stimulated (b) Synaptic signaling Target cell (c) Hormonal signaling .Fig.

hrs) while those that involve changes in cell movement secretion or metabolism occur rapidly (secs to mins).g. Figure 15-6 Molecular Biology of the Cell © Garland Science 2008 .Genomic reprogramming Extracellular Signaling Response Times Signal responses such as increased growth and cell division that involve changes in gene expression and synthesis of new proteins occur slowly (e. Synaptic responses mediated by changes in membrane potential occur in milliseconds..

or apoptosis. a process that is known as programmed cell death. Cells in an organism are exposed to many. An absence of a signal can also trigger a response from a target cell. even hundreds. . 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. If the cell does not receive this combination of signals. 4. Most cells in a complex organism are “programmed” to depend upon a specific combination of signals to survive. 5. This allows many responses from a limited number of signal molecules. Extracellular signals often work in combination. 2. of different extracellular signals. it commits “suicide”.Signal Molecules Act in Combination 1.

Inc. publishing as Pearson Benjamin Cummings ..Apoptosis (programmed cell death) integrates multiple cell-signaling 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.

Fig. 11-19 2 µm .

publishing as Pearson Benjamin Cummings .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. Inc.. interference with apoptosis may contribute to some cancers Copyright © 2008 Pearson Education. Parkinson’s and Alzheimer’s).

has different effects on different types of cells. for example. Different cells may express different types of receptors that bind the same ligand. 2.One signal molecule can have several effects The neurotransmitter acetylcholine. for example. These different cells may have different types of intracellular signaling proteins. This is because: 1. . Cell types respond to ligand binding of the same receptor differently. There are different types of acetylcholine receptors. for example.

sometimes even permanent. Often. .Protein Turnover Rates Affect the Cellular Response What happens when a signal is withdrawn? In some cases the response is long-lived. How rapidly the response declines depends on how rapidly the affected proteins are turned over. The intracellular concentration of molecules with rapid turnover rates change more quickly when their synthesis rate changes. the response fades when a signal is removed. The concentration of proteins with slow turnover rates change more slowly when their synthesis rate changes.

the movement of ions through its channel. or stopping. or target proteins directly. The signal molecule (such as a neurotransmitter) causes these receptors to either open or close. All G-protein-linked receptors are 7-pass transmembrane proteins that are a huge family of homologous molecules. activate a trimeric GTP-binding protein (G protein). upon ligand binding. G-protein-linked receptors: These are receptors that. The activated G protein then affects other intracellular signaling proteins. . Ion-channel-linked receptors: These receptors are involved in rapid signaling events most generally found in neurons.A B Alberts. Ionchannel-linked receptors constitute a large family of multipass transmembrane proteins. Fig 15-16. This rapidly changes the excitability of the target cell. thereby allowing. 5th Ed The Three Largest Classes of Cell Surface Receptors 1. 2.

11-7a Signaling-molecule binding site Segment that interacts with G proteins G protein-coupled receptor .Fig.

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

but do not convey the signal themselves. 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 . often by generating second messengers (ion channels and enzymes). These molecules diffuse readily away from their source. Scaffold proteins: proteins that bind multiple signaling proteins together in a functional complex and often hold them in a specific location. Critical for the formation of signaling complexes. Relay proteins: pass the signal on to the next intracellular signaling protein. 2nd messenger Adaptor proteins: link one signaling protein to another. First messengers are the signal itself.Intracellular Signaling Networks (1st messenger) Second messengers: Small molecules that are produced in large numbers as a consequence or receptor activation. Cyclic nucleotides and diacylglycerol are examples. Amplifier proteins: amplify the signal.

they have intrinsic GTPase activity that will eventually hydrolyze their GTP to GDP. Once these are activated. Fig 15-18. 1. and can be converted back. Often protein kinases themselves are molecular switches. Protein phosphorylation: Phosphorylation of the molecular switch (by a protein kinase) causes the conversion between active and inactive states. GTP-binding proteins: Switch from inactive to active upon binding of GTP. 5th Ed Molecular switches: many intracellular proteins act as switches in which they are converted from an inactive to active state.Alberts. Most kinases are serine/threonine kinases. 2. . Dephosphorylation (by protein phosphatases) converts the molecular switch back to its starting point. with a smaller class phosphorylating tyrosine residues (tyrosine kinases). thus converting them back to an inactive form.

by two independent signaling pathways. to be activated (proteins such as Y are often called coincidence detectors). associate together to form an active intracellular signaling molecule. . upon phosphorylation by two different signaling cascades. multiple signals require integrator proteins which require more than one input signal to generate an output signal that propagates a downstream signaling cascade.Fig 15-20 – 5th Ed. Examples: (A) A single protein requires phosphorylation on two different residues. Signal Integration Cells often require multiple signal proteins coincidentally to trigger a response. (B) Two proteins. Often.

SIGNAL TRANSDUCTION .

MECHANISMS OF SIGNAL TRANSDUCTION Protein Phosphorylation Second Messengers Gene Transcription & Translation .

THE PHOSPHORYLATION CASCADE .

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