Many cells are regulated by ligands that bind to cell-surface receptors with a single transmembrane domain, but without intrinsic enzyme activities in their cytoplasmic domains. While there are numerous examples of such receptors, these systems are best characterized by the cytokine receptor superfamily . Signaling by these receptors depends upon their interaction with cytoplasmic tyrosine kinases, which utilize a series of protein-protein interactions similar to those employed by the receptor tyrosine kinases.
1. Interactions of Cytokine Receptors
Interferons, many of the interleukins, growth hormone, and numerous other molecules bind to the cytokine family of receptors (1). These receptors are characterized by (i) a single transmembrane domain with large extracellular regions and (ii) a shorter intracellular domain that does not contain any tyrosine kinase activity. In most cases, these receptors initiate signaling pathways by interacting directly with other signaling proteins, usually tyrosine kinases that are predominately cytoplasmic. In fact, the receptors characteristically have discrete binding domains for these kinases, as well as a number of tyrosine-phosphorylation sites for interaction with SH2-containing proteins.
Although the activation of src family kinases by cytokines has been extensively studied, these enzymes are not activated by most cytokines. In contrast, cytokine binding to its receptor does lead to the activation of the JAK family of tyrosine kinases. They can couple cytokine receptors to a variety of downstream signaling pathways, but are specific for activation of a unique family of transcription factors, known as STATs (see JAK/STAT Signaling).
