region) or, less commonly, PTB domains (for phosphotyrosine-binding). By recognizing specific phosphorylated tyrosines, these small interaction domains enable the proteins that contain them to bind to activated RTKs, as well as to many other intracellular signaling proteins that have been transiently phosphorylated on tyrosines (Figure 15–46). As discussed previously, many signaling proteins also contain other interaction domains that allow them to interact specifically with other proteins as part of the signaling process. These domains include the SH3 domain, which binds to proline-rich motifs in intracellular proteins (see Figure 15–11).
Not all proteins that bind to activated RTKs via SH2 domains help to relay the signal onward. Some act to decrease the signaling process, providing negative feedback. One example is the c-Cbl protein, which can dock on some activated receptors and catalyze their ubiquitylation, covalently adding one or more ubiquitin molecules to specific sites on the receptor. This promotes the endocytosis and degradation of the receptors in lysosomes—an example of receptor down-regulation (see Figure 15–20). Endocytic proteins that contain ubiquitininteraction motifs (UIMs) recognize the ubiquitylated RTKs and direct them into clathrin-coated vesicles and, ultimately, into lysosomes (discussed in Chapter 13). Mutations that inactivate c-Cbl-dependent RTK down-regulation cause prolonged RTK signaling and thereby promote the development of cancer.
As is the case for GPCRs, ligand-induced endocytosis of RTKs does not always decrease signaling. In some cases, RTKs are endocytosed with their bound signaling proteins and continue to signal from endosomes or other intracellular compartments. This mechanism, for example, allows nerve growth factor (NGF) to bind to its specific RTK (called TrkA) at the end of a long nerve cell axon and signal to the cell body of the same cell a long distance away. Here, signaling endocytic
Figure 15–46 The binding of SH2containing intracellular signaling proteins to an activated RTK.