Cell communication is critical in multicellular organisms. At the most basic level, extracellular signals determine whether a cell lives or dies, whether it remains quiescent, or whether it is stimulated to perform a specific function. Intercellular signaling is important in the developing embryo, in maintaining tissue organization, and in ensuring that tissues respond in an adaptive and effective fashion to various threats, such as local tissue trauma or a systemic infection. Loss of cellular communication and the “social controls” that maintain normal relationships of cells can variously lead to unregulated growth (cancer) or an ineffective response to an extrinsic stress (as in shock).
An individual cell is constantly exposed to a remarkable cacophony of signals, which must be “interpeted” and integrated into responses that benefit the organism as a whole. Some signals may induce a given cell type to differentiate, others may stimulate proliferation, and yet others may direct the cell to perform a specialized function. Multiple signals received in combination may trigger yet another totally unique response. Many cells require certain inputs just to continue living; in the absence of appropriate exogenous signals, they die by apoptosis.
The sources of the signals that most cells respond to can be classified into several groups:
Pathogens and damage to neighboring cells. Many cells have an innate capacity to sense and respond to damaged cells (danger signals), as well as foreign invaders such as microbes. The receptors that generate these danger signals are discussed in Chapters 3 and 5.
Cell-cell contacts, mediated through adhesion molecules and/or gap junctions. As mentioned previously, gap junction signaling is accomplished between adjacent cells via hydrophilic connexons that permit the movement of small ions (e.g., calcium), various metabolites, and potential second messenger molecules such as cAMP.
Cell-ECM contacts, mediated through integrins, which are discussed in Chapter 3 in the context of leukocyte attachment to other cells during inflammation.
Secreted molecules. The most important secreted molecules include growth factors, discussed later; cytokines, a term reserved for mediators of inflammation and immune responses (also discussed in Chapters 3 and 5); and hormones, which are secreted by endocrine organs and act on different cell types (Chapter 20).
Signaling pathways also can be classified into different types based on the spatial relationships between the sending and receiving cells:
Paracrine signaling. Cells in just the immediate vicinity are affected. Paracrine signaling may involve trans-membrane “sending” molecules that activate receptors on adjacent cells or secreted factors that diffuse for only short distances. In some instances, the latter is achieved by having secreted factors bind tightly to ECM.
Autocrine signaling occurs when molecules secreted by a cell affect that same cell. This can serve as a means to entrain groups of cells undergoing synchronous differentiation during development, or it can be used to amplify (positive feedback) or dampen (negative feedback) a response.
Synaptic signaling. Activated neurons secrete neurotransmitters at specialized cell junctions (synapses) onto target cells.
Endocrine signaling. A hormone is released into the bloodstream and acts on target cells at a distance.
Regardless of the nature of an extracellular stimulus (paracrine, synaptic, or endocrine), the signal it conveys is transmitted to the cell via a specific receptor protein. Signaling molecules (ligands) bind their respective receptors and initiate a cascade of intracellular events culminating in the desired cellular response. Ligands usually have high affinities for receptors and at physiologic concentrations bind receptors with exquisite specificity. Receptors may be present on the cell surface or located within the cell (
Fig. 1.12