Chapter 16: Signaling Pathways That Control Gene Expression

16.2 Cytokine Receptors and the JAK/STAT Signaling Pathway

In this section and the next, we discuss two large classes of receptors that activate protein tyrosine kinases. Protein tyrosine kinases, of which there are about 90 in the human genome, phosphorylate specific tyrosine residues on target proteins, usually in the context of a specific linear sequence of amino acids in which the tyrosine is embedded. The phosphorylated target proteins can then activate one or more signaling pathways. These pathways are noteworthy because they regulate most aspects of cell proliferation, differentiation, survival, and metabolism.

There are two broad categories of receptors that activate tyrosine kinases: (1) those in which the tyrosine kinase enzyme is an intrinsic part of the receptor’s polypeptide chain, called the receptor tyrosine kinases (RTKs), which we discuss in Section 16.3, and (2) those, such as cytokine receptors, in which the receptor and kinase are separate polypeptides, encoded by different genes, yet are bound tightly together. In cytokine receptors, the tightly bound kinase is known as a JAK kinase. Both classes of receptors activate similar intracellular signal transduction pathways (Figure 16-6). We begin with the cytokine receptors, since they mainly employ a short signal transduction pathway called the JAK/STAT pathway: a STAT transcription factor binds to the activated receptor, becomes phosphorylated by the JAK kinase, moves to the nucleus, and directly activates transcription.

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FIGURE 16-6 Overview of signal transduction pathways triggered by receptors that activate protein tyrosine kinases. Both receptor tyrosine kinases (RTKs) and cytokine receptors activate multiple signal transduction pathways that ultimately regulate transcription of genes. (a) In the most direct pathway, mainly employed by cytokine receptors, a STAT transcription factor binds to the activated receptor, becomes phosphorylated, moves to the nucleus, and directly activates transcription. (b) Binding of one type of adapter protein (GRB2 or Shc) to an activated receptor leads to activation of the Ras/MAP kinase pathway (see Section 16.4). (c, d) Two phosphoinositide pathways are triggered by recruitment of phospholipase Cγ and PI-3 kinase to the membrane (see Section 16.4). Elevated levels of Ca²⁺ and activated protein kinase B modulate the activity of transcription factors as well as of cytosolic proteins that are involved in metabolic pathways or cell movement or shape.