Another type of cytoplasmic tyrosine kinase associates with integrins, the main receptors that cells use to bind to the extracellular matrix (discussed in Chapter 19). The binding of matrix components to integrins activates intracellular signaling pathways that influence the behavior of the cell. When integrins cluster at sites of matrix contact, they help trigger the assembly of cell–matrix junctions called focal adhesions. Among the many proteins recruited into these junctions is the cytoplasmic tyrosine kinase called focal adhesion kinase (FAK), which binds to the cytosolic tail of one of the integrin subunits with the assistance of other proteins. The clustered FAK molecules phosphorylate each other, creating phosphotyrosine docking sites where the Src kinase can bind. Src and FAK then phosphorylate each other and other proteins that assemble in the junction, including many of the signaling proteins used by RTKs. In this way, the two tyrosine kinases signal to the cell that it has adhered to a suitable substratum, where the cell can now survive, grow, divide, migrate, and so on.
The largest and most diverse class of receptors that rely on cytoplasmic tyrosine kinases to relay signals into the cell is the class of cytokine receptors, which we consider next.
Cytokine Receptors Activate the JAK–STAT Signaling Pathway
The large family of cytokine receptors includes receptors for many kinds of local mediators (collectively called cytokines), as well as receptors for some hormones, such as growth hormone and prolactin (Movie 15.8). These receptors are stably associated with cytoplasmic tyrosine kinases called Janus kinases (JAKs) (after the two-faced Roman god), which phosphorylate and activate transcription regulators called STATs (signal transducers and activators of transcription). STAT proteins are located in the cytosol and are referred to as latent transcription regulators because they migrate into the nucleus and regulate gene transcription only after they are activated.
Although many intracellular signaling pathways lead from cell-surface receptors to the nucleus, where they alter gene transcription (see Figure 15–55), the JAK–STAT signaling pathway provides one of the more direct routes. Cytokine receptors are dimers or trimers and are stably associated with one or two of the four known JAKs (JAK1, JAK2, JAK3, and Tyk2). Cytokine binding alters the arrangement so as to bring two JAKs into close proximity so that they phosphorylate each other, thereby increasing the activity of their tyrosine kinase domains. The JAKs then phosphorylate tyrosines on the cytoplasmic tails of cytokine receptors, creating phosphotyrosine docking sites for STATs (Figure 15–56). Some adaptor proteins can also bind to some of these sites and couple cytokine receptors to the Ras–MAP-kinase signaling pathway discussed earlier, but these will not be discussed here.