General principles of cellular communication

# 1 Diversity and evolution of cell signalling pathways

Cellular communication encompasses a vast range of extrinsic signals, intracellular signalling pathways and cellular responses. In fact, no two cell types express exactly the same repertoire of signalling components. Rather, cells have signalling systems that suit their physiological function. The main focus of this topic is cellular communication that occurs when extrinsic stimuli bind to receptors on their target cells. Although not all cellular communication relies on the activation of receptors, it is the most common mechanism by which cells sense their environment or communicate with each other. The central signalling paradigm that will be explored in this course is depicted in Figure 1.

Figure 1 Hypothetical cellular communication pathway. The binding of an extrinsic signalling molecule to a specific receptor stimulates an intracellular transduction process that leads to the activation of effector molecule(s) and a cellular response. Cellular responses can be of many different kinds; in this illustration, the effector molecule is a transcription factor, which stimulates the transcription of specific genes.

By activating receptors, extrinsic signals trigger events that relay information within cells and ultimately cause cells to change their behaviour. It is important to remember that receptors are highly selective for their specific (cognate) extrinsic stimuli. In most cases, a particular kind of receptor will only be activated by one type of extrinsic stimulus.

Activated receptors often have pleiotropic actions. That is, they alter the activity of numerous cellular processes simultaneously. These processes could include DNA transcription, protein synthesis or changes in metabolic activity. The overall effect of switching various processes on or off determines the consequent change in cellular behaviour. The fidelity, accuracy and appropriateness of these cellular communication processes are critically important for the cell and for the organism. It is well known that aberrant cellular communication leads to conditions such as cancer, diabetes, heart failure and neurological diseases.

Cells are simultaneously bombarded with numerous extrinsic signals and they make sense of these incoming signals through the activation of specific signalling pathways.

Just a few of the many signalling systems expressed in a typical mammalian cell are depicted in Figure 2. The key point that you should take from this illustration is that cellular communication triggers specific responses by recruiting particular signalling pathways. The activation of receptors following ligand binding is conveyed into a cell by a cascade of signalling proteins or messengers. Note that each pathway can elicit a variety of responses, although only one example is shown for each of the pathways in Figure 2

Figure 2 Some of the cell surface receptor-mediated cellular signalling pathways that operate in eukaryotic cells and some of the responses that these pathways elicit. Key: GPCR, G-protein coupled receptor; IP3, inositol 1,4,5-trisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate

Exactly how a cell will respond to extrinsic stimuli is sometimes hard to predict, even for scientists with considerable experience of studying cellular communication. In part, the response of a cell is determined by the input signals it receives, but there are also many intrinsic factors that determine how cells respond. For example, the age of a cell, its position within the cell cycle and its metabolic status could impact on how it responds to particular extrinsic stimuli. Under some conditions, such as in a nutrient-rich environment, a cell could receive an extrinsic signal that activates anabolic processes and cell division. At another time, when nutrients are depleted, the same signal may trigger catabolism and cell death.

Although cellular signalling pathways are numerous and complex, there are in fact relatively few pathways in comparison to the diversity of cell types and their intricate molecular processes. For example, development in multicellular animals essentially relies on only seven distinct signalling pathways, commonly called hedgehog, wingless-related, transforming growth factor-β, receptor tyrosine kinases, Notch, JAK/STAT and nuclear hormone receptors (names that variously identify a key component, signal, receptor type or function). These seven pathways are used during development to define the size, shape and other characteristics of an animal. How can so few pathways achieve so much? The answer is that signalling pathways can act together to produce outcomes that are different from the outcome of single pathways acting alone. This combinatorial action of pathways may actually allow hundreds of different signalling–response combinations.

In general terms, the number of genes involved in signalling increases with complexity of an organism, with vertebrates (e.g. humans) having many more such genes than invertebrate species (Table 1). Whole genome duplication events, such as those that occurred in the evolution of vertebrates between 550 and 450 million years ago, were responsible for these marked differences. However, the correlation between complexity and number of genes involved in signalling is not a strict one. Thus, while a human generally has many more genes encoding components of the seven developmental signalling pathways than does the nematode worm Caenorhabditis elegans, the latter has many more putative nuclear hormone receptors (Table 1).

Not only have genes encoding signalling components been acquired during evolution, but such genes have also been lost. For example, the nematode C. elegans does not possess genes for the hedgehog signalling pathway that are found in other organisms (insects and other nematodes) that share a close common ancestor.

## Table 1 Numbers of particular ligands and receptors in selected pathways in a variety of eukaryotes
(Note that a ligand is any molecule (or ion) that binds to a protein at a specific binding site.)

| H. sapiens (human) | D. melanogaster (fruitfly) | C. elegans (nematode worm) | S. cerevisiae (yeast)
--- | --- | --- | --- | ---
Ligands |  |  |  |
RTK ligand | 48 | 3 | 4 | 0
TGF-β | 29 | 6 | 4 | 0
Wnt | 18 | 7 | 5 | 0
Notch ligand | 3 | 2 | 2 | 0
Receptor |  |  |  |
RTK | 25 | 6 | 1 | 0
Wnt receptor | 12 | 6 | 5 | 0
NHR | 59 | 25 | 270 | 1

Key: RTK, receptor tyrosine kinase; TGF-β, transforming growth factor-β; Wnt, wingless-related; NHR, nuclear hormone receptor

For many of the cellular communication mechanisms found in animals there are analogous systems in plants, fungi and protists. An example is the mitogen-activated protein kinase (MAP kinase or MAPK) cascade. It is likely that ancestral eukaryotic cells developed complex signalling systems well over two billion years ago, long before multicellular organisms emerged. Indeed, the acquisition of multiple signalling pathways was certainly an essential prerequisite for multicellularity. Prokaryotes also express complex cellular communication systems, as will be discussed below.

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