Introduction

In order to survive, a cell must be able to understand its environment. This is true whether the cell is a single-celled organism or part of a larger, more complex multicellular organism. Cells communicate with their environment through a process called signaling. Cell signaling is how the cell collects information and then responds with an action at the correct time. Signaling is the initial event associated with many key cellular functions, from the correct timing of cell division, to the decision to migrate in a particular direction, and even to whether a cell needs to go through programmed cell death. So many of the cellular events we explore in biology are dependent on signaling to happen correctly. Not only that, but many of the concepts covered in upper-level biology courses are, at their hearts, studies of how the cell receives information and responds to it. For example, developmental biology, sensory perception, endocrinology, and even physiology will make much more sense if you have a foundational understanding of how signaling works.

Thus, our focus in this chapter is to dissect the process of signaling and take a look at the parts of a signaling cascade and some of the commonly recurring themes and patterns. That way, when you encounter any pathway in any context, you will have the ability to “read it” through and identify the patterns within it to correctly interpret the outcomes of that pathway.

Topic 7.1: General Principles of Signaling

Learning Goals

While signaling is a beautiful coordination of cellular events, it also is a very complex process. It can be very confusing to keep track of what the cell is doing at any given time due to the sheer number of signals, the overlap in signaling pathways, and sometimes even the competing signaling events occurring simultaneously. Additionally, a wide range of cellular “behaviors” are mediated through a small set of extracellular signals. Thus, the way that a cell responds to a specific extracellular signal will depend on what genes are being expressed in the cell at that specific moment in time. For example, acetylcholine is an extracellular signal that has different effects in different cell types. It is released at a neuromuscular junction by neurons to promote muscle contraction. In cardiac pacemaker cells, it signals that the heart rate should lower, so the pacemaker cells fire at a decreased rate. Finally, salivary glands also respond to acetylcholine by increasing the synthesis and secretion of saliva by the endomembrane system. Each of these scenarios is the result of different modes of release of the acetylcholine, different receptors receiving it on the cell surface, and also differential expression of the internal components of the acetylcholine pathway.

Our focus for this topic is to lay some groundwork for understanding signaling by looking at the general principles that underlie cell signaling. Then in the next topic, we’ll look at some examples of actual mechanisms that are commonly used in cell signaling. These tools should allow you to interpret any signaling pathway in the future and begin to understand how they mediate a response.

The video below (Video 07-01) gives a quick overview of the mechanism of cell signaling and the terminology you will need to understand this process.

Examples of long distance signaling: neuronal and endocrine

Medium- to Short-Distance Signaling: Paracrine (Diffusion Based), Juxtacrine (Contact Dependent), and Autocrine (Self-)Signaling

In many ways, signaling at closer range is much easier than long-distance signaling, as the signal can be released into the extracellular space and simply left to diffuse. This is one of the most common types of signaling in development. Plants, algae, and fungi don’t really have any long-distance options that are as efficient as the bloodstream or neurons, so for them, almost all signaling is local and diffusion based. In addition, there are a number of examples of cells that release their own signaling molecules and then detect them with receptors. Here we look at the three types of short-range signaling in more detail. They can all be observed in Figure 07-02, below.

Paracrine signaling is considered to be a local signaling mechanism. The ligand is released into the extracellular space, and it diffuses through the extracellular matrix to be picked up by nearby receptors.

Autocrine signaling is when the signal is both released and received by the same cell. It is considered a type of paracrine signaling, since the signal must diffuse to the receptor through the extracellular environment.

Finally, juxtacrine signaling isn’t very common overall compared to the other kinds of signaling. It’s also known as contact-dependent signaling, which gives you an idea of what is involved in this form of signaling. In this case, the cell that receives the signal comes into direct contact with the one that is sending out the signal. Most commonly, this would mean direct cell-to-cell contact, but it may also be an interaction between a cell-surface receptor and a glycoprotein of the extracellular matrix.

The most famous example of cell-to-cell juxtacrine signaling is the Notch-Delta signaling cascade, which is essential to embryonic development in animals. The receptor (Notch) is a plasma membrane protein on one cell, and the ligand (Delta) is on the other. When they bind, the cytosolic side of the Notch receptor is cut off and becomes a transcription factor that then enters the nucleus. As a result, the transcription factor activates gene expression, and the “fate” of this cell is permanently and irreversibly changed. Notch-Delta signaling is extremely important in development, when cells are gaining their identities.

Paracrine, autocrine and juxtacrine signaling schematic

Generic signaling diagram

Here’s a quick explanation of each of the intracellular signaling steps from Figure 07-03. Later, we’ll look at some of the more famous examples of proteins that perform these roles. Remember that not all of these are present in every signaling cascade, and sometimes an individual element could be performing more than one function.