Some Enzyme-Coupled Receptors Associate with Cytoplasmic Tyrosine Kinases
Many cell-surface receptors depend on tyrosine phosphorylation for their activity and yet lack a tyrosine kinase domain. These receptors act through cytoplasmic tyrosine kinases, which are associated with the receptors and phosphorylate various target proteins, often including the receptors themselves, when the receptors bind their ligand. These tyrosine-kinase-associated receptors thus function in much the same way as RTKs, except that their kinase domain is encoded by a separate gene and is noncovalently associated with the receptor polypeptide chain. A variety of receptor classes belong in this category, including the receptors for antigen and interleukins on lymphocytes (discussed in Chapter 24), integrins (discussed in Chapter 19), and receptors for various cytokines and some hormones. As with RTKs, many of these receptors are either preformed dimers or are cross-linked into dimers by ligand binding.
Some of these receptors depend on members of the largest family of mammalian cytoplasmic tyrosine kinases, the Src family (see Figures 3–10 and 3–64), which includes Src, Yes, Fgr, Fyn, Lck, Lyn, Hck, and Blk. These protein kinases all contain SH2 and SH3 domains and are located on the cytoplasmic side of the plasma membrane, held there partly by their interaction with transmembrane receptor proteins and partly by covalently attached lipid chains. Different family members are associated with different receptors and phosphorylate overlapping but distinct sets of target proteins. Lyn, Fyn, and Lck, for example, are each associated with different sets of receptors on lymphocytes. In each case, the kinase is activated when an extracellular ligand binds to the appropriate receptor protein. Src itself, as well as several other family members, can also bind to activated RTKs; in these cases, the receptor and cytoplasmic kinases mutually stimulate each other’s catalytic activity, thereby strengthening and prolonging the signal (see Figure 15–51). There are even some G proteins (Gs and Gi) that can activate Src, which is one way that the activation of GPCRs can lead to tyrosine phosphorylation of intracellular signaling proteins and effector proteins.
Figure 15–55 Five parallel intracellular signaling pathways activated by GPCRs, RTKs, or both. In this simplified example, the five kinases (shaded yellow) at the end of each signaling pathway phosphorylate target proteins (shaded red), many of which are phosphorylated by more than one of the kinases. The phospholipase C activated by the two types of receptors is different: GPCRs activate PLCβ, whereas RTKs activate PLCγ (not shown). Although not shown, some GPCRs can also activate Ras, but they do so independently of Grb2, via a Ras-GEF that is activated by Ca2+ and diacylglycerol.