For many cytokine receptors, ligand binding causes dimerization or clustering of individual receptor molecules, bringing the associated kinases together and enabling them to phosphorylate the cytoplasmic tail of adjacent receptors— thus initiating an intracellular signal. In the case of the lymphocyte antigen receptors, association with cytoplasmic tyrosine kinases occurs after ligand binding but is unlikely to be due to a simple clustering mechanism. Instead, the actions of co-receptors are required: these bring cytoplasmic tyrosine kinases into proximity with the cytoplasmic regions of the antigen receptor, a complex process that we will describe later.
Signaling is usually not a simple ‘on or off’ switch. Depending on the affinity of the receptor for the ligand, the abundance of the ligand, the concentrations of intracellular signaling components, and a complex network of positiveand negative-feedback pathways, receptor activation and downstream signaling occur when a minimum threshold determined by all of these factors is exceeded. These features are often merged into the simple term ‘signal
These receptors activate a protein kinase on the cytoplasmic side of the membrane to convey the information that a ligand has bound to their extracellular portion. Receptor tyrosine kinases (top panels) contain the kinase activity as part of the receptor itself. Ligand binding results in clustering of the receptor, activation of catalytic activity, and the consequent phosphorylation (denoted by red dots) of the receptor tails and other substrates, transmitting the signal onward. Receptors that lack intrinsic kinase activity associate with nonreceptor kinases (bottom panels). Receptor dimerization or clustering after ligand binding activates the associated enzyme. in all receptors of these types encountered in this chapter, the enzyme is a tyrosine kinase.
strength.’ It is important to keep in mind that variations in signal strength will determine the magnitude of cellular responses—some will be all-or-nothing, whereas others will increase as the strength of signaling increases.
The role of protein kinases in cell signaling is not confined to receptor activation, as they act at many different stages in intracellular signaling pathways. Protein kinases figure largely in cell signaling because phosphorylation and dephosphorylation—the removal of a phosphate group—are the means of regulating the activity of many enzymes, transcription factors, and other proteins. Equally important to the workings of signaling pathways is the fact that phosphorylation generates sites on proteins to which other signaling proteins can bind.
Phosphate groups are removed from proteins by a large class of enzymes called protein phosphatases. Different classes of protein phosphatases remove phosphate groups from phosphotyrosine or from phosphoserine/ phosphothreonine, or both (as in dual-specificity phosphatases). Specific dephosphorylation by phosphatases is one important means of regulating signaling pathways by resetting a protein to its original state and thus switching signaling off. Dephosphorylation does not always inhibit a protein’s activity. In many instances the removal of a particular phosphate group by a specific phosphatase is needed to activate an enzyme. In other cases, the extent of phosphorylation of an enzyme determines its activity, and represents a balance between the activity of kinases and phosphatases.
Fig. 7.2 Signaling proteins interact with each other and with lipid signaling molecules via modular protein domains. a few of the most common protein domains used by immune-system signaling proteins are listed, together with some proteins that contain them and the general class of ligand bound by the interaction domain. The right-hand column lists specific examples of a protein motif (in single-letter amino acid code) or, for the phosphoinositide-binding domains, the particular phosphoinositide that they bind. all these domains are used in many other nonimmune signaling pathways as well.
7-2 Intracellular signal propagation is mediated by large multiprotein signaling complexes.