r r r Cell Signalling Biology Michael J. Berridge Module 12 Signalling Defects and Disease 12 1 Module 12 Signalling Defects and Disease Synopsis A large number of diseases are caused by defects in signalling pathways. The nature of these defects and how they are induced varies enormously. Pathogenic organisms and viruses, many of which can interfere with signalling events, can cause some of these defects. There are other diseases that can be traced to defects in the function of cell signalling pathways. The concept of signalsome remodelling and disease provides a framework for considering how defects in signalling pathways can result in disease. It is convenient to separate these defects into phenotypic remodelling of the signalsome and genotypic remodelling of the signalsome. Most of the serious diseases in humans, such as hypertension, heart disease, diabetes and many forms of mental illness, seem to arise from subtle phenotypic modifications of signalling pathways. Such phenotypic remodelling alters the behaviour of cells so that their normal functions are subverted, leading to disease. Since it has proved difficult to clearly establish this relationship between signalsome remodelling and disease, there has been relatively little progress in designing effective treatments. Genotypic modifications resulting from either somatic mutations or germline mutations have been somewhat easier to diagnose, but have also proved difficult to treat as witnessed by the failure of many of the gene therapy strategies. Clearly, there is an urgent need to understand more about all of these disease states in order to design better therapies. The enormous redundancy built into cell signalling mechanisms offers many opportunities for discovering new ways of correcting many disease states. The reversal of Ca2+-dependent neurodegeneration is an example where such a strategy could provide novel therapies for treating some of the major neural diseases in humans such as Alzheimer’s disease and Parkinson’s disease. Pathogenic organisms and viruses • Listeriosis is caused by Listeria monocytogenes,whichis A number of pathogenic organisms and viruses exert their a Gram-positive pathogen that survives in macrophages deleterious effects by modifying the signalling processes by escaping through the phagolysosome membrane. operating in specific cell types: • Peptic ulcers are caused by an excessive production of acid caused by infection of the stomach with Helicobac- • Bacillary dysentery is caused by Shigella flexneri,which ter pylori. acts by interfering with the PtdIns4,5P2 regulation of • Tuberculosis is an example where the pathogen (My- actin remodelling and is also able to activate the PtdIns cobacterium tuberculosis) survives by switching off the 3-kinase signalling pathway. A similar mechanism is em- phagosome maturation process that macrophages use to ployed by Salmonella enterica serotype Typhimurium. kill infectious organisms. • Cholera is caused by the Gram-negative bacterium Vi- brio cholerae, which secretes the cholera toxin (CT) that causes severe water loss, vomiting and muscle Bacillary dysentery cramps. CT activates the cyclic AMP signalling path- Shigella flexneri, which causes bacillary dysentery, modi- way (Module 2: Figure cyclic AMP signalling). fies some of the host cell signalling pathways to facilitate • Chlamydial diseases caused by Chlamydia trachomatis their entry and to boost their virulence. S. flexneri injects also survive by inhibiting the phagocytic processes of the host cell with an effector protein IpgD, which is a phos- macrophages. phoinositide phosphatase that hydrolyses PtdIns4,5P2 to PtdIns5P. Entry of the pathogen into the host is facilit- ated by the decline in the level of PtdIns4,5P2 because of the disruption in the normal PtdIns4,5P2 regulation Please cite as Berridge, M.J. (2014) Cell Signalling Biology; of actin remodelling. In addition, the PtdIns5P formed doi:10.1042/csb0001012 by the hydrolysis may also play a role by activating the 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 12 Signalling Defects and Disease 12 2 PtdIns5P signalling cassette, which can regulate a number ach by developing a number of adaptations that enables of host cell functions. In particular, PtdIns5P can activate it to cope with the highly acidic environment. The bac- the class IA PtdIns 3-kinase to activate the PtdIns 3-k- terium attaches itself to the surface of the epithelial cells inase signalling pathway, and one effect of this will be through a variety of adhesion proteins. Marshall and War- to promote host survival by preventing apoptosis. The ren received the Nobel Prize in Physiology and Medicine hormonal modulation of apoptosis is strongly regulated in 2005 for uncovering the link between H. pylori and by the PtdIns 3-kinase signalling pathway. the onset of peptic ulcer disease. It is now known that most duodenal ulcers and approximately 70% of gast- Cholera ric ulcers are caused by this bacterial infection. In addi- tion, most stomach cancers are associated with infections Cholera is characterized by severe water loss, vomiting and of H. pylori. Eradication of the infection with drugs has muscle cramps. It is caused by infection with the Gram- proved to be a highly effective means of curing peptic negative bacterium Vibrio cholerae, which secretes chol- ulcers. era toxin (CT) that can activate the cyclic AMP signalling H. pylori has an elaborate ’nano-syringe’ that it uses pathway (Module 2: Figure cyclic AMP signalling). CT is to inject proteins such as the cytoxin-associated gene A composed of a catalytic A subunit and five B subunits. The (CagA) directly into the host cell (Module 12: Figure H latter attach the toxin to the surface of the cell, where they pylori nano-syringe). At the tip of this syringe is the pro- function as membrane-penetration subunits that inject the tein cytotoxin-associated gene A ligand (CagL) that has catalytic subunit into the cell. The toxin interacts with a RGD motifs that enables it to bind to the α5β1 integ- GM1 ganglioside on the cell surface of intestinal epithelial rin complex found on the surface of the host cell surface cells, and this enables the A subunit to enter the cell, where (Module 1: Figure integrin receptor). The CagL thus func- it stimulates fluid secretion by activating cyclic AMP form- tions as a stimulus to activate integrin signalling that then ation (Module 7: Figure intestinal secretion). The catalytic creates the conditions for both the injection and the ac- A subunit catalyses the transfer of ADP-ribose from NAD tivation of the oncoprotein cytotoxin-associated gene A to an arginine group on the α subunit of GS (Module 2: (CagA). Figure cyclic AMP signalling). This ADP ribosylation in- Once it enters the epithelial cells, CagA interacts with hibits the ability of GS to hydrolyse GTP, which means resident regulatory proteins to alter both cell structure that this G protein is locked in its active configuration and and cell fate. It disrupts tight junctions by associating thus maintains a persistent activation of cyclic AMP and with proteins such as ZO-1, JAM and the partitioning- intestinal secretion. defective 1 (PAR1)/microtubule affinity-regulating kinase (MARK) family of serine-threonine kinases. The result- Listeriosis ing junctional and polarity defects result in ulcerations, After bacteria have been engulfed, they are normally des- inflammation (gastritis) and can lead to gastric carcino- troyed by a process of phagosome maturation.Inthe genesis. An increase in proliferation is facilitated by the case of the Gram-positive pathogen Listeria monocyto- ability of CagA to induce various signalling pathways to genes, however, the pathogen survives the attention of stimulate transcription factors such as NF-κB, NFAT and macrophages by escaping through the membrane of the SRF. phagolysosome to enter the cytoplasm where they can Just how H. pylori increases in acid secretion that causes replicate and then go on to infect other cells. The bacterial ulcers is still being worked out. There is increasing evid- virulence factor listeriolysin O (LLO) seems to be critical ence to show that the bacterium somehow alters the activ- in that it can oligomerize to form pores in host mem- ity of the cells that regulate the release of gastrin. For branes. One of the functions of these pores is to provide example, there is an increase in the resting rate of gastrin a leak pathway for proteins that prevents the acidification release by the G cells located in the antrum of the stomach of the phagosome that is necessary for it to fuse with the (Module 7: Figure stomach structure). In addition, there lysosomes. In order to lyse the phagosomal membrane to is a decrease in the activity of the D cells that release so- gain access to the cytoplasm, LLO must be reduced and matostatin, which is part of a negative-feedback loop that this is done by making use of the γ-interferon-inducible operates in the control of parietal cell secretion (Module 7: lysosome thiol reductase (GILT), which is a host enzyme Figure HCl secretion). located in the phagosome. The phagosome membrane has NADPH oxidase and nitrogen oxide synthase that gener- Tuberculosis ate the antimicrobial agents reactive oxygen species (ROS) Mycobacterium tuberculosis evades the rapid inflammatory and reactive nitrogen species (RNS) respectively. GILT responses used to attack foreign pathogens as part of the neutralizes the action of ROS and RNS thus enabling Lis- innate immune system. Once such pathogens are taken up teria to escape into the cytoplasm. into the phagosome, they are killed when hydrolytic en- zymes are added during phagosome maturation (Module Peptic ulcers 4: Figure phagosome maturation). M. tuberculosis has de- Peptic ulcers are caused by an excessive production of acid veloped various mechanisms to manipulate the host’s sig- that damages the gastric mucosa. One of the main causes of nalling pathways enabling it to survive and proliferate.