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r r r Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 1 Module 2 Cell Signalling Pathways Synopsis Cells use a large number of clearly defined signalling pathways to regulate their activity. In this module, attention is focused on the On mechanisms responsible for transmitting information into the cell. These signalling pathways fall into two main groups depending on how they are activated. Most of them are activated by external stimuli and function to transfer information from the cell surface to internal effector systems. However, some of the signalling systems respond to information generated from within the cell, usually in the form of metabolic messengers. For all of these signalling pathways, information is conveyed either through protein--proteininteractions or it is transmitted by diffusible elements usually referred to as second messengers. Cells often employ a number of these signalling pathways, and cross-talk between them is an important feature. In this section, attention is focused on the properties of the major intracellular signalling pathways operating in cells to regulate their cellular activity. During the processes of development, specific cell types select out those signalling systems that are suitable to control their particular functions. One of the aims of this website is to understand how these unique cell-specific signalsomes function to regulate different mammalian cell types. Intracellular signalling pathways 1. Cyclic AMP signalling pathway. One of the first sig- There are a large number of intracellular signalling path- nalling systems to be characterized was the cyclic ways responsible for transmitting information within the AMP signalling pathway, which led to the second mes- cell. They fall into two main categories. The majority re- senger concept that applies to many other signalling spond to external stimuli arriving at the cell surface, usu- systems. The idea is that the external stimulus arriving ally in the form of a chemical signal (neurotransmitter, at the cell surface is the first messenger, which is then hormone or growth factor), which is received by recept- transformed at the cell surface by adenylyl cyclase ors at the cell periphery that function as molecular an- (AC) into a second messenger, cyclic AMP, which is tennae embedded in the plasma membrane. These recept- part of the signalling cascade that then activates down- ors then transfer information across the membrane using stream effectors. a variety of transducers and amplifiers that engage a di- 2. Cyclic ADP-ribose (cADPR) signalling and nicotinic verse repertoire of intracellular signalling pathways (Path- acid–adenine dinucleotide phosphate (NAADP) sig- + ways 1--16 in Module 2: Figure cell signalling pathways). nalling systems function in Ca2 signalling. An ADP-- The phosphoinositide signalling and Ca2 + signalling sys- ribosyl cyclase (ADP-RC) is responsible for generat- tems (Pathways 2--6) have been grouped together because ing these two second messengers. they contain a number of related signalling pathways that 3. Voltage-operated channels (VOCs) contribute to + + often interact with each other. The other categories are Ca2 signals by controlling the entry of external Ca2 the pathways that are activated by signals generated from in excitable cells. within the cell (Pathways 17 and 18). There are a number of 4. Receptor-operated channels (ROCs) contribute to + + metabolic messengers that act from within the cell to initi- Ca2 signals by controlling Ca2 entry in both excit- ate a variety of signalling pathways. GTP-binding proteins able and non-excitable cells. often play a central role in the transduction process re- 5. Stimuli that activate phospholipase C (PLC) to hy- sponsible for initiating many of these signalling pathways. drolyse PtdIns4,5P2 (also known as PIP2) generate a All of these signalling pathways generate an internal number of signalling pathways: 2 + messenger that is responsible for relaying information to • Inositol 1,4,5-trisphosphate (InsP3)/Ca sig- the sensors that then engage the effectors that activate cel- nalling cassette lular responses. The main features of the signalling path- • Diacylglycerol (DAG)/protein kinase C (PKC) sig- ways summarized in Module 2: Figure cell signalling path- nalling cassette ways are outlined below: • PtdIns4,5P2 signalling cassette • Multipurpose inositol polyphosphate signalling Green text indicates links to content within this module; blue text indicates links to content in other modules. pathway Please cite as Berridge, M.J. (2012) Cell Signalling Biology; 6. PtdIns 3-kinase signalling is activated by stimuli doi:10.1042/csb0001002 that stimulate PtdIns 3-kinase to phosphorylate PIP2 C 2012 Portland Press Limited www.cellsignallingbiology.org Licensed copy. Copying is not permitted, except with prior permission and as allowed by law. r r r Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 2 to form the lipid second messenger PtdIns3,4,5P3 ation. The ligand Hedgehog (Hh) acts through the (PIP3). transcription factor GLI. 7. Nitric oxide (NO)/cyclic GMP signalling pathway. 17. Hippo signalling pathway. This pathway has a core Nitric oxide (NO) synthase (NOS) generates the gas protein kinase cascade that has some similarities to the NO that acts both through cyclic GMP and nitrosyla- MAP kinase cascade in that a series of serine/threonine tion reactions. NO has a particularly important role protein kinases function to regulate the transcription in modulating the activity of other pathways such as of a number of genes that function in cell growth, Ca2 + signalling. proliferation and apoptosis. 8. Redox signalling. Many receptors act through 18. Notch signalling pathway. This is a highly conserved NADPH oxidase (NOX) to form reactive oxygen signalling system that functions in developmental pro- −• species, such as the superoxide radical (O2 )and cesses related to cell-fate determination particularly in hydrogen peroxide (H2O2), which act to regulate the stem cells. The notch receptor generates the transcrip- activity of specific signalling proteins such as tyrosine tion factor NICD (Notch intracellular domain). phosphatases, transcription factors and ion channels. 19. Endoplasmic reticulum (ER) stress signalling.Theen- −• The O2 participates in the nitrosylation reaction in doplasmic reticulum (ER) stress signalling pathway Pathway 7. concerns the mechanisms used by the ER to transmit 9. Mitogen-activated protein kinase (MAPK) signalling. information to the nucleus about the state of protein This is a classical example of a protein phosphoryla- processing within the lumen of the ER. tion cascade that often begins with Ras and consists of 20. AMP signalling pathway. This pathway is regulated a number of parallel pathways that function to control by adenosine monophosphate (AMP), which func- many cellular processes and particularly those related tions as a metabolic messenger to activate an important to cell proliferation, cell stress and apoptosis. pathway for the control of cell proliferation. 10. Nuclear factor κB(NF-κB) signalling pathway.This signalling system has a multitude of functions. It is Not included in Module 2: Figure cell signalling path- particularly important in initiating inflammatory re- ways are some additional signalling pathways that have sponses in macrophages and neutrophils as part of an specific functions in regulating various aspects of cell meta- innate immune response to invading pathogens. bolism, such as sterol sensing and cholesterol biosynthesis, 11. Phospholipase D (PLD) signalling pathway.Thisisa that control the level of cholesterol in cell membranes. An- other example is found in the NAD signalling pathways, lipid-based signalling system that depends upon the + hydrolysis of phosphatidylcholine by phospholipase where NAD functions to regulate a number of cellular D (PLD) to give phosphatidic acid (PA), which func- processes, including energy metabolism, gene transcrip- tions as a second messenger to control a variety of tion, DNA repair and perhaps ageing as well. cellular processes. These cassettes then engage a variety of effectors that 12. Sphingomyelin signalling pathway. Certain growth are responsible for activating cellular responses. All of factors and cytokines hydrolyse sphingomyelin to these mechanisms (Module 1: Figure signal transmission generate two second messengers that appear to have mechanisms) depend upon information transfer mechan- opposing effects in the cell. Ceramide seems to pro- isms whereby information is transferred along an orderly mote apoptosis, whereas sphingosine 1-phosphate sequence of events to activate the internal effectors re- (S1P) stimulates cell proliferation. S1P may also re- sponsible for inducing a great variety of cellular responses. lease Ca2 + from internal stores. The action of S1P is complicated in that it is released from the cell, where it can act as a hormone to stimulate external receptors. Cyclic AMP signalling pathway 13. Janus kinase (JAK)/signal transducer and activator of Cyclic AMP is a ubiquitous second messenger that transcription (STAT) signalling pathway.Thisisafast- regulates a multitude of cellular responses. Cyclic track signal transduction pathway for transferring in- AMP formation usually depends upon the activation of formation from cell-surface receptors into the nucleus. G-protein-coupled receptors (GPCRs) that use heterotri- The Janus kinases (JAKs) are tyrosine kinases that meric G proteins to activate
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