A ll cells must continually sense their surrounding environment and make decisions on the basis of that informa- tion. Single-celled organisms must be able to tell which nutrients are nearby and regulate their metabolic processes accordingly. Cells in multicellular organisms such as ourselves must sense the presence of neighbouring cells and hormones when making decisions such as to whether to proliferate, move or die. These processes all require the transfer of information (Fig. 1) from detection systems referred to as receptors through intermedi- ate molecules within the cell, to cause changes in the expression of genes and the activity of enzymes — the specialized pro- tein machinery that carries out all of a cell’s functions. ‘Signal transduction’, ‘cell sig- nalling’ or simply ‘signalling’ is the study of the mechanisms by which this transfer of biological information comes about. Signalling can be studied at the level of the individual cell or the whole organism. For individual cells, signalling is crucial to deci- sions about division, specialization, death and metabolic control. In more specialized cells it is central to immunity and the trans- mission of nerve impulses, to name but two examples. At the level of whole multicellular organisms, signalling controls growth and development, as well as aspects of metabo- lism and behaviour. Not surprisingly, then, signalling malfunctions underlie many human diseases (Box 1, overleaf). The history of the study of biological signalling can be read in the Nobel Prizes for Physiology or Medicine awarded over the past 30 years, starting with Sutherland in 1971 and culminating with the 2000 prize to Carlsson, Greengard and Kandel for their studies of signal transduction in the nervous system. The work of these and many other scientists has established the outlines of numerous signalling pathways. These vary enormously in their details. Yet despite this diversity, a much simpler underlying logic is beginning to emerge. Here I aim to explore key themes in biological signalling, and to illustrate them with some of the better- understood signalling systems. I hope that the reader will be convinced that signal transduction is not the impenetrable soup of acronyms that it might at first appear to be. NATURE | VOL 411 | 14 JUNE 2001 | www.nature.com 759 news and views feature Signalling nuts and bolts Receptors. Signalling pathways start with receptor proteins that are able to sense a change in the environment outside the cell. Receptors are most commonly found at the cell surface, where they bind to extracellular molecules that cannot penetrate the plasma membrane — the lipid boundary between the cell and the outside world. Receptors on the cell surface can bind to water-soluble sig- nalling proteins such as growth factors and peptide hormones, which may be produced at a distant site in the body (and delivered in the bloodstream) or by neighbouring cells. Receptors can also bind to small water- soluble molecules such as nutrients. As a result of engagement of these receptor proteins by their binding partners (‘ligands’), a signal is transferred across the plasma mem- brane 1 . In most cases, the receptor itself spans the membrane. Ligand binding causes a change in the shape of the protein; this change is transmitted from the extracellular part of the receptor to the part inside the cell. Some- times this involves the formation of dimers of receptor molecules — two receptors bonded together. This tends to occur for receptor pro- teins with amino-acid chains that cross the membrane only once. For receptors that fold up so that they span the membrane several times, ligand binding may cause different parts of the molecule to reorientate them- selves with respect to each other. Inside the cell, the change in the recep- Figure 1 A generic signalling pathway. The grey boxes indicate general components of signalling pathways; the white boxes show specific examples. On the outside of the cell membrane, receptors bind to biologically active ligands such as growth factors. As a result, enzymatic activity associated with the intracellular part of the receptor is altered. This can affect the association of the receptor with intracellular mediators, or the localization or function of those mediators. These in turn alter the activity of ‘effector’ enzymes. Some effectors can move to the nucleus and control gene expression, or they can induce other proteins to do so. Others target small molecules, either generating further signalling mediators (second messengers) or controlling the metabolic state of the cell. Real signalling pathways may bypass entire classes of these molecules, or may have several components in one or more class, working either in series or in parallel. The study of how cells communicate impinges on all aspects of biology, from development to disease. At first glance it’s a horrendously complicated business, but some simple themes are emerging. The ins and outs of signalling Julian Downward © 2001 Macmillan Magazines Ltd