overview signaltransductionpathways
- 1. Anubha kumari Assistant professor Department of Biotechnology Annada college Hazaribagh jharkhand
- 2. Introduction Cells in multicellular organisms communicate with each other. The process of communication between the cells, in which the signaling cell produces a specific signal molecule that is detected by the target cells described as cell signaling.
- 3. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling • General Principles of Cell Signaling • signaling cell => signaling molecule binds to receptor molecule on target cell • Endocrine • Paracrine • Autocrine • Signaling by PM attached proteins
- 4. • Synaptic signaling • One unique example of paracrine signaling is synaptic signaling, in which nerve cells transmit signals. • This process is named for the synapse, the junction between two nerve cells where signal transmission occurs.
- 5. • Signaling molecules that function within an organism to control metabolism of sugars, fats and amino acids, the growth and differentiation of tissues, the synthesis and secretion of proteins, and the composition of intracellular and extracellular fluids. Animals also respond to many signals from their environment, including light, oxygen, odorants, and testants in food
- 6. • More important in plants and animals are extracellular signaling molecules that function within an organism to control metabolism of sugars, fats and amino acids, the growth and differentiation of tissues, the synthesis and secretion of proteins, and the composition of intracellular and extracellular fluids. Animals also respond to many signals from their environment, including light, oxygen, odorants, and testate in food. • Example -insulin and adrenocorticotropic hormone (ACTH) and small molecules such as the catecholamine (e.g., epinephrine, norepinephrine, and dopamine)
- 7. Copyright © 2005 Pearson Prentice Hall, Inc. 16_06_extracellular_sig.jpg
- 8. Cell Signaling Mechanisms Cell Signalling Biology - Michael J. Berridge - www.cellsignallingbiology.org - 2012 • Typical, molecular signaling pathways are initiated via receptors which perceive the presence of the activating signal. • The signal passes through a series of intracellular transducers and second messengers which may or may not lead to an amplification of the signal. • Ultimately second messenger sensors are activated, modulate of effector molecules which lead cellular responses. • The complexity of cellular signaling results from the “cross-talk” between multiple signaling pathways, and among the specific intracellular aspects of the pathways within each cell type.
- 9. Copyright © 2005 Pearson Prentice Hall, Inc. 16_12_cortisol.jpg
- 10. RECEPTORS • cell-surface receptors that are integral protein on the plasma membranes. Cell-surface receptors generally consist of three discrete segments: 1. a segment on the extracellular surface, 2. a segment that spans the plasma membrane, and 3. a segment facing the cytosol.
- 11. Types of receptors • Receptors come in many types, but they can be divided into two categories: intracellular receptors, which are found inside of the cell (in the cytoplasm or nucleus), and cell surface receptors, which are found in the plasma membrane. • INTRACELLULAR RECEPTOR • EXTRACELLULAR RECEPTOR
- 12. Copyright © 2005 Pearson Prentice Hall, Inc. 16_09_molecules_bind.jpg
- 13. Intracellular receptors • Intracellular receptors are receptor proteins found on the inside of the cell, typically in the cytoplasm or nucleus. In most cases, the ligands of intracellular receptors are small, hydrophobic (water- hating) molecules, since they must be able to cross the plasma membrane in order to reach their receptors. • For example, the primary receptors for hydrophobic steroid hormones, such as the sex hormones estrogen and testosterone, are intracellular
- 14. EXTRACELLULAR RECEPTOR • Cell-surface receptors are membrane-anchored proteins that bind to ligands on the outside surface of the cell. In this type of signaling, the ligand does not need to cross the plasma membrane. So, many different kinds of molecules (including large, hydrophilic or "water- loving" ones) may act as ligands. • There are many kinds of cell-surface receptors, but here we’ll look at three common types: ligand-gated ion channels, G protein-coupled receptors, and receptor tyrosine kinases.
- 15. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling 1. Ligand gated ion channels • (are responsible for the rapid transmission of signals across synapses in the nervous system by allowing a flow of ions across the plasma membrane, which changes the membrane potential, causing an electrical current.) 2. Ion-Channel-Linked Receptors • convert chemical to electrical signals 3. G-protein-linked Receptors • ligand binding => G-Protein activation by exchange bound GDP for GTP • Common structure = 7-trans membrane protein 4.Enzyme-Linked Receptors
- 16. Copyright © 2005 Pearson Prentice Hall, Inc. 16_14_3_basic_classes.jpg
- 17. Ligand-gated ion channels • Ligand-gated ion channels are ion channels that can open in response to the binding of a ligand. To form a channel, this type of cell-surface receptor has a membrane-spanning region with a hydrophilic (water- loving) channel through the middle of it. The channel lets ions to cross the membrane without having to touch the hydrophobic core of the phospholipid bilayer.
- 18. Ligand gated ion channels Fig- Ligand-gated ion channel receptors and their activation by ligands
- 19. Phosphorylation • Proteins can be activated or inactivated in a variety of ways. However, one of the most common tricks for altering protein activity is the addition of a phosphate group to one or more sites on the protein, a process called phosphorylation.
- 21. • Phosphate groups can’t be attached to just any part of a protein. Instead, they are typically linked to one of the three amino acids that have hydroxyl (-OH) groups in their side chains: tyrosine, threonine, and serine. The transfer of the phosphate group is catalyzed by an enzyme called a kinase, and cells contain many different kinases that phosphorylate different targets. • Phosphorylation often acts as a switch, but its effects vary among proteins. • In general, phosphorylation isn’t permanent. To flip proteins back into their non-phosphorylated state, cells have enzymes called phosphatases, which remove a phosphate group from their targets.
- 22. Second messengers • Second messengers, small, non-protein molecules that pass along a signal initiated by the binding of a ligand (the “first messenger”) to its receptor. • Second messengers include Ca2+, cyclic AMP (cAMP), a derivative of ATP; and inositol phosphates, which are made from phospholipids. 1. Calcium ions • For signaling purposes, Ca2+ stored in compartments such as the endoplasmic reticulum.
- 23. Calcium ions (cont) • In pathways that use calcium ions as a second messenger, upstream signaling events release a ligand that binds to and opens ligand-gated calcium ion channels. These channels open and allow the higher levels of Ca2+ that are present outside the cell (or in intracellular storage compartments) to flow into the cytoplasm, raising the concentration of cytoplasmic Ca2+. 2. Cyclic AMP (cAMP) • Another second messenger used in many different cell types is cyclic adenosine monophosphate (cyclic AMP or cAMP), a small molecule made from ATP.
- 24. • In response to signals, an enzyme called adenylyl cyclase converts ATP into cAMP, removing two phosphates and linking the remaining phosphate to the sugar in a ring shape. • Once generated, cAMP can activate an enzyme called protein kinase A (PKA), enabling it to phosphorylate its targets and pass along the signal. Protein kinase A is found in a variety of types of cells, and it has different target proteins in each. This allows the same cAMP second messenger to produce different responses in different contexts.
- 26. 3.Inositol phosphates • Phospholipids called phosphatidylinositols can be phosphorylated and snipped in half, releasing two fragments that both act as second messengers. • One lipid in this group that's particularly important in signaling is called PIP2. In response to a signal, an enzyme called phospholipase C cleaves (chops) PIP2 into two fragments, DAG and IP3. These fragments made can both act as second messengers.
- 27. Hormone receptor • A hormone receptor is a receptor protein on the surface of a cell or in its interior that binds to a specific hormone. The hormone causes many changes that take place in the cell. Binding of hormones to hormone receptors often trigger the start of a biophysical signal that can lead to further signal transduction pathways, or trigger the activation or inhibition of genes.
- 28. Types of Hormone Receptors: • Peptide Hormone Receptors: • Are often trans membrane proteins. They are also called G-protein- coupled receptors, sensory receptors or ionotropic receptors. These receptors generally function via intracellular second messengers, including cyclic AMP (cAMP), inositol 1, 4, 5-triphosphate (IP3) and the calcium (Ca2+)—calmodulin system.
- 29. Steroid Hormone Receptors and Related Receptors: • Are generally soluble proteins that function through gene activation. Their response elements are DNA sequences (promoters) that are bound by the complex of the steroid bound to its receptor. The receptors themselves are zinc-finger proteins. These receptors include those for glucocorticoids, estrogens, androgens, thyroid hormone (T3), calcitriol (the active form of vitamin D), and the retinoids (vitamin A).
- 30. Receptors for Peptide Hormones: Insulin Receptor: • Is a trans membrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors. Two alpha subunits and two beta subunits make up the insulin receptor. The beta subunits pass through the cellular membrane and are linked by disulfide bonds. The alpha and beta subunits are encoded by a single gene (INSR). • Function of insulin receptor-effect of insulin on glucose uptake and metabolism: • Insulin binds to its receptor which in turn starts many protein activation cascades.
- 31. • These include— • i. Translocation of Glut-4 transporter to the plasma membrane and influx of glucose • ii. Glycogen synthesis • iii. Glycolysis and fatty acid synthesis
- 33. • The main activity of activation of the insulin receptor is inducing glucose uptake. For this reason ‘insulin insensitivity’, or a decrease in insulin receptor signaling, leads to diabetes mellitus type 2 – the cells are unable to take up glucose, and the result is hyperglycemia (an increase in circulating glucose). • Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells.
- 35. G protein-coupled receptors • G protein-coupled receptors (GPCRs) are a large family of cell surface receptors that share a common structure and method of signaling. The members of the GPCR family all have seven different protein segments that cross the membrane, and they transmit signals inside the cell through a type of protein called a G protein • A diverse set of ligands bind to this type of receptor, including peptide hormones, neurotransmitters, and odor molecules.
- 36. • 7 TM a Helices are connected by loops of varying length • C-terminus is present inside the cell • 3 loop outside- ligand binding site • 3 loop inside- form binding site for intracellular signaling proteins • H- Helical region • C- Cytosolic region
- 37. G protein • The G protein that transduce the signals from 7 spanning receptors are called heterotrimeric G proteins because they are composed of three different subunits • A subunit • B sununit • G subunit • Heterotrimeric G protein cycle between active and inactive forms, thus acting as molecular swithes
- 39. • 1 Binding of a normal hormonal ligand (e.g., epinephrine) to a G protein coupled receptor changes the conformation of its cytosol- facing loops and enables the receptor to bind to the Ga subunit • This binding releases the bound GDP; thus the activated ligand- bound receptor functions as a guanine nucleotide-exchange factor (GEF) for the Ga subunit • Next GTP rapidly binds to the "empty“ guanine nucleotide site in the Ga subunit, causing a change in the conformation of its switch segment
- 40. • These changes weaken the binding of Ga with both the receptor and the Gby subunit • In most cases, GaGTP which remains anchored in the membrane, then interacts with and activates an associated effector protein. In some cases, GaGTP inhibits the effector.
- 41. • In any case, the active Ga’GTP state is short-lived because the bound GTP is hydrolyzed to GDP in minutes, catalyzed by the intrinsic GTPase activity of the G' subunit. • The conformation of the Ga then switches back to the inactive Ga'GDP state, blocking any further activation of effector proteins.
- 43. Module 1: Figure stimuli for cyclic AMP signalling Cell Signalling Biology - Michael J. Berridge - www.cellsignallingbiology.org - 2012
- 44. Receptor tyrosine kinases • Receptor tyrosine kinases (RTKs) are a class of enzyme-linked receptors found in humans and many other species. A kinase is just a name for an enzyme that transfers phosphate groups to a protein or other target, and an receptor tyrosine kinase transfers phosphate groups to specifically to the amino acid tyrosine.
- 45. How does RTK signaling work? • In a typical example, signaling molecules first bind to the extracellular domains of two nearby receptor tyrosine kinases. The two neighboring receptors then come together, or dimerize. The receptors then attach phosphates to tyrosines in each others' intracellular domains. The phosphorylated tyrosine can transmit the signal to other molecules in the cell. •
- 46. 1. In the resting state, the intrinsic kinase activity of an RTK is very low. 2. In the ligand-bound dimeric receptor, however, the kinase in one subunit phosphorylates one tyrosine residue in the activation lip of the catalytic site in the other subunit. 3. This leads to a conformational change that facilitates binding of ATP in some receptors (e.g., insulin receptor) and binding of protein substrates in other receptors(e.g., FGF receptor). The resulting enhanced kinase activity then phosphorylates additional tyrosine residues in the cytosolic domain of the receptor
- 48. Receptor tyrosine kinases are crucial to many signaling processes in humans. For instance, they bind to growth factors, signaling molecules that promote cell division and survival. Growth factors include platelet- derived growth factor (PDGF), which participates in wound healing, and nerve growth factor (NGF), which must be continually supplied to certain types of neurons to keep them alive. • Because of their role in growth factor signaling, receptor tyrosine kinases are essential in the body, but their activity must be kept in balance: overactive growth factor receptors are associated with some types of cancers.
- 49. Module 1: Figure tyrosine kinase-linked receptors Cell Signalling Biology - Michael J. Berridge - www.cellsignallingbiology.org - 2012
- 50. Types of ligands • Ligands, which are produced by signaling cells and interact with receptors in or on target cells, come in many different varieties. Some are proteins, others are hydrophobic molecules like steroids, and others yet are gases like nitric oxide. Here, we’ll look at some examples of different types of ligands.
- 51. • Ligands that can enter the cell • Small, hydrophobic ligands can pass through the plasma membrane and bind to intracellular receptors in the nucleus or cytoplasm. In the human body, some of the most important ligands of this type are the steroid hormones. • Familiar steroid hormones include the female sex hormone estradiol, which is a type of estrogen, and the male sex hormone testosterone. Vitamin D, a molecule synthesized in the skin using energy from light, is another example of a steroid hormone. Because they are hydrophobic, these hormones don’t have trouble crossing the plasma membrane, but they must bind to carrier proteins in order to travel through the (watery) bloodstream.
- 52. Nitric oxide (NO) is a gas that acts as a ligand. Like steroid hormones, it can diffuse directly across the plasma membrane thanks to is small size. One of its key roles is to activate a signaling pathway in the smooth muscle surrounding blood vessels, one that makes the muscle relax and allows the blood vessels to expand (dilate).
- 53. Module 1: Figure steroid stimuli Cell Signalling Biology - Michael J. Berridge - www.cellsignallingbiology.org - 2012
- 54. Ligands that bind on the outside of the cell • Water-soluble ligands are polar or charged and cannot readily cross the plasma membrane. So, most water-soluble ligands bind to the extracellular domains of cell-surface receptors, staying on the outer surface of the cell. • Peptide (protein) ligands make up the largest and most diverse class of water-soluble ligands. For instance, growth factors, hormones such as insulin, and certain neurotransmitters fall into this category. Peptide ligands can range from just a few amino acids long, as in the pain-suppressing enkephalins, to a hundred or more amino acids in length.
- 55. • As mentioned above, some neurotransmitters are proteins. Many other neurotransmitters, however, are small, hydrophilic (water- loving) organic molecules. Some neurotransmitters are standard amino acids, such as glutamate and glycine, and others are modified or non-standard amino acids.