Module 2 Cell Signalling Pathways - Auburn · PDF fileto cell proliferation, cell stress and...
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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 There are a large number of intracellular signalling path- ways responsible for transmitting information within the cell. They fall into two main categories. The majority re- spond to external stimuli arriving at the cell surface, usu- ally in the form of a chemical signal (neurotransmitter, hormone or growth factor), which is received by recept- ors at the cell periphery that function as molecular an- tennae embedded in the plasma membrane. These recept- ors then transfer information across the membrane using a variety of transducers and amplifiers that engage a di- verse repertoire of intracellular signalling pathways (Path- ways 1--16 in Module 2: Figure cell signalling pathways). The phosphoinositide signalling and Ca 2 + signalling sys- tems (Pathways 2--6) have been grouped together because they contain a number of related signalling pathways that often interact with each other. The other categories are the pathways that are activated by signals generated from within the cell (Pathways 17 and 18). There are a number of metabolic messengers that act from within the cell to initi- ate a variety of signalling pathways. GTP-binding proteins often play a central role in the transduction process re- sponsible for initiating many of these signalling pathways. All of these signalling pathways generate an internal messenger that is responsible for relaying information to the sensors that then engage the effectors that activate cel- lular responses. The main features of the signalling path- ways summarized in Module 2: Figure cell signalling path- ways are outlined below: Green text indicates links to content within this module; blue text indicates links to content in other modules. Please cite as Berridge, M.J. (2012) Cell Signalling Biology; doi:10.1042/csb0001002 1. Cyclic AMP signalling pathway. One of the first sig- nalling systems to be characterized was the cyclic AMP signalling pathway, which led to the second mes- senger concept that applies to many other signalling systems. The idea is that the external stimulus arriving at the cell surface is the first messenger, which is then transformed at the cell surface by adenylyl cyclase (AC) into a second messenger, cyclic AMP, which is part of the signalling cascade that then activates down- stream effectors. 2. Cyclic ADP-ribose (cADPR) signalling and nicotinic acid–adenine dinucleotide phosphate (NAADP) sig- nalling systems function in Ca 2 + signalling. An ADP-- ribosyl cyclase (ADP-RC) is responsible for generat- ing these two second messengers. 3. Voltage-operated channels (VOCs) contribute to Ca 2 + signals by controlling the entry of external Ca 2 + in excitable cells. 4. Receptor-operated channels (ROCs) contribute to Ca 2 + signals by controlling Ca 2 + entry in both excit- able and non-excitable cells. 5. Stimuli that activate phospholipase C (PLC) to hy- drolyse PtdIns4,5P 2 (also known as PIP 2 ) generate a number of signalling pathways: • Inositol 1,4,5-trisphosphate (InsP 3 )/Ca 2 + sig- nalling cassette • Diacylglycerol (DAG)/protein kinase C (PKC) sig- nalling cassette • PtdIns4,5P 2 signalling cassette • Multipurpose inositol polyphosphate signalling pathway 6. PtdIns 3-kinase signalling is activated by stimuli that stimulate PtdIns 3-kinase to phosphorylate PIP 2 C 2012 Portland Press Limited www.cellsignallingbiology.org Licensed copy. Copying is not permitted, except with prior permission and as allowed by law.
Transcript of Module 2 Cell Signalling Pathways - Auburn · PDF fileto cell proliferation, cell stress and...
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. Thesesignalling pathways fall into two main groups depending on how they are activated. Most of them areactivated by external stimuli and function to transfer information from the cell surface to internal effectorsystems. However, some of the signalling systems respond to information generated from within thecell, usually in the form of metabolic messengers. For all of these signalling pathways, information isconveyed either through protein--protein interactions or it is transmitted by diffusible elements usuallyreferred to as second messengers. Cells often employ a number of these signalling pathways, andcross-talk between them is an important feature. In this section, attention is focused on the propertiesof 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 aresuitable to control their particular functions. One of the aims of this website is to understand how theseunique cell-specific signalsomes function to regulate different mammalian cell types.
Intracellular signalling pathwaysThere are a large number of intracellular signalling path-ways responsible for transmitting information within thecell. They fall into two main categories. The majority re-spond to external stimuli arriving at the cell surface, usu-ally in the form of a chemical signal (neurotransmitter,hormone or growth factor), which is received by recept-ors at the cell periphery that function as molecular an-tennae embedded in the plasma membrane. These recept-ors then transfer information across the membrane usinga variety of transducers and amplifiers that engage a di-verse repertoire of intracellular signalling pathways (Path-ways 1--16 in Module 2: Figure cell signalling pathways).The phosphoinositide signalling and Ca2 + signalling sys-tems (Pathways 2--6) have been grouped together becausethey contain a number of related signalling pathways thatoften interact with each other. The other categories arethe pathways that are activated by signals generated fromwithin the cell (Pathways 17 and 18). There are a number ofmetabolic messengers that act from within the cell to initi-ate a variety of signalling pathways. GTP-binding proteinsoften play a central role in the transduction process re-sponsible for initiating many of these signalling pathways.
All of these signalling pathways generate an internalmessenger that is responsible for relaying information tothe sensors that then engage the effectors that activate cel-lular responses. The main features of the signalling path-ways summarized in Module 2: Figure cell signalling path-ways are outlined below:
Green text indicates links to content within this module; blue textindicates links to content in other modules.
Please cite as Berridge, M.J. (2012) Cell Signalling Biology;doi:10.1042/csb0001002
1. Cyclic AMP signalling pathway. One of the first sig-nalling systems to be characterized was the cyclicAMP signalling pathway, which led to the second mes-senger concept that applies to many other signallingsystems. The idea is that the external stimulus arrivingat the cell surface is the first messenger, which is thentransformed at the cell surface by adenylyl cyclase(AC) into a second messenger, cyclic AMP, which ispart of the signalling cascade that then activates down-stream effectors.
2. Cyclic ADP-ribose (cADPR) signalling and nicotinicacidadenine dinucleotide phosphate (NAADP) sig-nalling systems function in Ca2 + signalling. An ADP--ribosyl cyclase (ADP-RC) is responsible for generat-ing these two second messengers.
3. Voltage-operated channels (VOCs) contribute toCa2 + signals by controlling the entry of external Ca2 +
in excitable cells.4. Receptor-operated channels (ROCs) contribute to
Ca2 + signals by controlling Ca2 + entry in both excit-able and non-excitable cells.
5. Stimuli that activate phospholipase C (PLC) to hy-drolyse PtdIns4,5P2 (also known as PIP2) generate anumber of signalling pathways: Inositol 1,4,5-trisphosphate (InsP3)/Ca2 + sig-
nalling cassette Diacylglycerol (DAG)/protein kinase C (PKC) sig-
nalling cassette PtdIns4,5P2 signalling cassette Multipurpose inositol polyphosphate signalling
pathway
6. PtdIns 3-kinase signalling is activated by stimulithat stimulate PtdIns 3-kinase to phosphorylate PIP2
C2012 Portland Press Limited www.cellsignallingbiology.orgLicensed copy. Copying is not permitted, except with prior permission and as allowed by law.
http://www.cellsignallingbiology.org/csb/001/csb001.pdf#ON_mechanismshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Mammalian_cell_typeshttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Voltage_operated_channelshttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Receptor_operated_channels
Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 2
to form the lipid second messenger PtdIns3,4,5P3(PIP3).
7. Nitric oxide (NO)/cyclic GMP signalling pathway.Nitric oxide (NO) synthase (NOS) generates the gasNO that acts both through cyclic GMP and nitrosyla-tion reactions. NO has a particularly important rolein modulating the activity of other pathways such asCa2 + signalling.
8. Redox signalling. Many receptors act throughNADPH oxidase (NOX) to form reactive oxygenspecies, such as the superoxide radical (O2 ) andhydrogen peroxide (H2O2), which act to regulate theactivity of specific signalling proteins such as tyrosinephosphatases, transcription factors and ion channels.The O2 participates in the nitrosylation reaction inPathway 7.
9. Mitogen-activated protein kinase (MAPK) signalling.This is a classical example of a protein phosphoryla-tion cascade that often begins with Ras and consists ofa number of parallel pathways that function to controlmany cellular processes and particularly those relatedto cell proliferation, cell stress and apoptosis.
10. Nuclear factor B (NF-B) signalling pathway. Thissignalling system has a multitude of functions. It isparticularly important in initiating inflammatory re-sponses in macrophages and neutrophils as part of aninnate immune response to invading pathogens.
11. Phospholipase D (PLD) signalling pathway. This is alipid-based signalling system that depends upon thehydrolysis of phosphatidylcholine by phospholipaseD (PLD) to give phosphatidic acid (PA), which func-tions as a second messenger to control a variety ofcellular processes.
12. Sphingomyelin signalling pathway. Certain growthfactors and cytokines hydrolyse sphingomyelin togenerate two second messengers that appear to haveopposing effects in the cell. Ceramide seems to pro-mote apoptosis, whereas sphingosine 1-phosphate(S1P) stimulates cell proliferation. S1P may also re-lease Ca2 + from internal stores. The action of S1P iscomplicated in that it is released from the cell, whereit can act as a hormone to stimulate external receptors.
13. Janus kinase (JAK)/signal transducer and activator oftranscription (STAT) signalling pathway. This is a fast-track signal transduction pathway for transferring in-formation from cell-surface receptors into the nucleus.The Janus kinases (JAKs) are tyrosine kinases thatphosphorylate the signal transducers and activatorsof transcription (STATs), which carry the informationinto the nucleus.
14. Smad signalling pathway. This pathway mediates theaction of the transforming growth factor (TGF-)superfamily, which controls transcription through theSmad transcription factors.
15. Wnt signalling pathways. These pathways play an im-portant role in both development and cell prolifera-tion.
16. Hedgehog signalling pathway. This pathway re-sembles the Wnt signalling pathway in that it alsofunctions to regulate development and cell prolifer-
ation. The ligand Hedgehog (Hh) acts through thetranscription factor GLI.
17. Hippo signalling pathway. This pathway has a coreprotein kinase cascade that has some similarities to theMAP kinase cascade in that a series of serine/threonineprotein kinases function to regulate the transcriptionof a number of genes that function in cell growth,proliferation and apoptosis.
18. Notch signalling pathway. This is a highly conservedsignalling system that functions in developmental pro-cesses related to cell-fate determination particularly instem cells. The notch receptor generates the transcrip-tion factor NICD (Notch intracellular domain).
19. Endoplasmic reticulum (ER) stress signalling. The en-doplasmic reticulum (ER) stress signalling pathwayconcerns the mechanisms used by the ER to transmitinformation to the nucleus about the state of proteinprocessing within the lumen of the ER.
20. AMP signalling pathway. This pathway is regulatedby adenosine monophosphate (AMP), which func-tions as a metabolic messenger to activate an importantpathway for the control of cell proliferation.
Not included in Module 2: Figure cell signalling path-ways are some additional signalling pathways that havespecific functions in regulating various aspects of cell meta-bolism, such as sterol sensing and cholesterol biosynthesis,that control the level of cholesterol in cell membranes. An-other example is found in the NAD signalling pathways,where NAD+ functions to regulate a number of cellularprocesses, including energy metabolism, gene transcrip-tion, DNA repair and perhaps ageing as well.
These cassettes then engage a variety of effectors t
