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.
A Simple Signaling Pathway 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. Figure 15-1 Molecular Biology of the Cell ( Garland Science 2008) 4. This process is often called signal transduction.
Normal Response to mating factor Signal Transduction in Unicellular Organisms 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. Fig 15-2, 5 th Ed The molecules involved in the yeast mating response have relatives in signaling pathways in animal cells, which have become much more elaborate.
Fig. 11-2 Receptor α factor 1 Exchange of mating factors a Yeast cell, mating type a a factor α Yeast cell, mating type α 2 Mating a α 3 New a/α cell a/α
Receptors Types Cell surface receptors: most signal molecules cannot cross the plasma membrane, and therefore must bind to receptors in the cell surface. Intracellular receptors: Some small signal molecules can diffuse across the PM and bind to receptors located in the cytosol or nucleus. These signal molecules are generally hydrophobic and require carrier proteins to be transported in aqueous solutions (such as the bloodstream). Animal cells communicate by using hundreds of kinds of signal molecules, such as proteins, small peptides, amino acids, steroids, and even gasses and ions. These signal molecules (called ligands in relation to their receptor) are often present in very low concentrations (typically 10-8 M). The receptors must have a very high affinity for these ligands that are in such scarce amounts (Kα 10 8 ).
& 5 th Edition Types of cell communication 1. 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.
& 5 th 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.
Autocrine signaling When 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 Long-distance signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter 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
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.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
Signal Molecules Act in Combination 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.
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, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-19 2 µm
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, Parkinson s and Alzheimer s); interference with apoptosis may contribute to some cancers Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
One signal molecule can have several effects The 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 Response What happens when a signal is withdrawn? In some cases the response is long-lived, sometimes even permanent. Often, the response 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 change more quickly when their synthesis rate changes. The concentration of proteins with slow turnover rates change more slowly when their synthesis rate changes.
A B Alberts, Fig 15-16, 5th Ed 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. Ionchannel-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.
Fig. 11-7a Signaling-molecule binding site Segment that interacts with G 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.
(1 st messenger) Intracellular Signaling Networks 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. 2 nd messenger 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
Alberts, Fig 15-18, 5 th Ed 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.
Fig 15-20 5 th Ed. Signal Integration Cells 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 coincidence detectors). (B) Two proteins, upon phosphorylation by two different signaling cascades, associate together to form an active intracellular signaling molecule.
SIGNAL TRANSDUCTION
MECHANISMS OF SIGNAL TRANSDUCTION Protein Phosphorylation Second Messengers Gene Transcription & Translation
THE PHOSPHORYLATION CASCADE
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