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–protein interactions 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 the sensors that then engage the effectors that activate cel- There are a large number of intracellular signalling path- lular responses. The main features of the signalling path- ways responsible for transmitting information within the ways summarized in Module 2: Figure cell signalling path- cell. They fall into two main categories. The majority re- ways are outlined below: spond to external stimuli arriving at the cell surface, usu- ally in the form of a chemical signal (neurotransmitter, 1. Cyclic AMP signalling pathway. One of the first sig- hormone or growth factor), which is received by recept- nalling systems to be characterized was the cyclic ors at the cell periphery that function as molecular an- AMP signalling pathway, which led to the second mes- tennae embedded in the plasma membrane. These recept- senger concept that applies to many other signalling ors then transfer information across the membrane using systems. The idea is that the external stimulus arriving a variety of transducers and amplifiers that engage a di- at the cell surface is the first messenger, which is then verse repertoire of intracellular signalling pathways (Path- transformed at the cell surface by adenylyl cyclase ways 1–16 in Module 2: Figure cell signalling pathways). (AC) into a second messenger, cyclic AMP, which is 2+ The phosphoinositide signalling and Ca signalling sys- part of the signalling cascade that then activates down- tems (Pathways 2–6) have been grouped together because stream effectors. they contain a number of related signalling pathways that 2. Cyclic ADP-ribose (cADPR) signalling and nicotinic often interact with each other. The other categories are acid–adenine dinucleotide phosphate (NAADP) sig- the pathways that are activated by signals generated from nalling systems function in Ca2 + signalling. An ADP– within the cell (Pathways 17 and 18). There are a number of ribosyl cyclase (ADP-RC) is responsible for generat- metabolic messengers that act from within the cell to ini- ing these two second messengers. tiate a variety of signalling pathways. GTP-binding pro- 3. Voltage-operated channels (VOCs) contribute to teins often play a central role in the transduction process Ca2 + signals by controlling the entry of external Ca2 + responsible for initiating many of these signalling path- in excitable cells. ways. 4. Receptor-operated channels (ROCs) contribute to All of these signalling pathways generate an internal Ca2 + signals by controlling Ca2 + entry in both excit- messenger that is responsible for relaying information to able and non-excitable cells. 5. Stimuli that activate phospholipase C (PLC) to hy- drolyse PtdIns4,5P2 (also known as PIP2) generate a number of signalling pathways: • 2+ Please cite as Berridge, M.J. (2014) Cell Signalling Biology; Inositol 1,4,5-trisphosphate (InsP3)/Ca signalling doi:10.1042/csb0001002 cassette C 2014 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 • Diacylglycerol (DAG)/protein kinase C (PKC) sig- 15. Wnt signalling pathways. These pathways play an im- nalling cassette portant role in both development and cell prolifera- • PtdIns4,5P2 signalling cassette tion. • Multipurpose inositol polyphosphate signalling 16. Hedgehog signalling pathway. This pathway re- pathway sembles the Wnt signalling pathway in that it also 6. PtdIns 3-kinase signalling is activated by stimuli that functions to regulate development and cell prolifer- stimulate PtdIns 3-kinase to phosphorylate PIP2 to ation. The ligand Hedgehog (Hh) acts through the form the lipid second messenger PtdIns3,4,5P3 (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. Metabolic messengers. There are a number of meta- a number of parallel pathways that function to control bolites that can function as messengers to regulate a many cellular processes and particularly those related number of different processes. The AMP signalling to cell proliferation, cell stress and apoptosis. pathway is regulated by adenosine monophosphate 10. Nuclear factor κB(NF-κB) signalling pathway.This (AMP), which functions as a metabolic messenger to signalling system has a multitude of functions. It is activate an important pathway for the control of cell particularly important in initiating inflammatory re- proliferation. sponses in macrophages and neutrophils as part of an innate immune response to invading pathogens. Not included in Module 2: Figure cell signalling path- 11. Phospholipase D (PLD) signalling pathway.Thisisa ways are some additional signalling pathways that are re- lipid-based signalling system that depends upon the lated to cellular metabolism. The sterol sensing and cho- hydrolysis of phosphatidylcholine by phospholipase lesterol biosynthesis controls the level of cholesterol in cell membranes. Another example is found in the NAD D (PLD) to give phosphatidic acid (PA), which func- + tions as a second messenger to control a variety of signalling pathways,whereNAD functions to regulate cellular processes. a number of cellular processes, including energy metabol- 12. Sphingomyelin signalling pathway. Certain growth ism, gene transcription, DNA repair and perhaps ageing factors and cytokines hydrolyse sphingomyelin to as well. The gastrotransmitter hydrogen sulphide (H2S), generate two second messengers that appear to have which is released from cysteine, acts to regulate multiple opposing effects in the cell. Ceramide seems to pro- cellular processes (Module 2: Figure H2S generation). mote apoptosis, whereas sphingosine 1-phosphate These cassettes then engage a variety of effectors that (S1P) stimulates cell proliferation. S1P may also re- are responsible for activating cellular responses. All of lease Ca2 + from internal stores. The action of S1P is these mechanisms (Module 1: Figure signal transmission complicated in that it is released from the cell, where mechanisms) depend upon information transfer mech- it can act as a hormone to stimulate external receptors. anisms whereby information is transferred along an or- 13. Janus kinase (JAK)/signal transducer and activator of derly sequence of events to activate the internal effect- transcription (STAT) signalling pathway.Thisisafast- ors responsible for inducing a great variety of cellular re- track signal transduction pathway for transferring