The hundreds of different protein kinases in a eukaryotic cell are organized into complex networks of signaling pathways that help to coordinate the cell’s activities, drive the cell cycle, and relay signals into the cell from the cell’s environment. Many of the extracellular signals involved need to be both integrated and amplified by the cell. Individual protein kinases (and other signaling proteins) serve as input–output devices, or “microprocessors,” in the integration process. An important part of the input to these signal-processing proteins comes from the control that is exerted by phosphates added and removed from them by protein kinases and protein phosphatases, respectively.
The Src family of protein kinases (see Figure 3–10) exhibits such behavior. The Src protein (pronounced “sarc” and named for the type of tumor, a sarcoma, that its deregulation can cause) was the first tyrosine kinase to be discovered. It is now known to be part of a subfamily of nine very similar protein kinases, which are found only in multicellular animals. As indicated by the evolutionary tree in Figure 3–62, sequence comparisons suggest that tyrosine kinases as a group were a relatively late innovation that branched off from the serine/threonine kinases, with the Src subfamily being only one subgroup of the tyrosine kinases created in this way.
The Src protein and its relatives contain a short N-terminal region that becomes covalently linked to a strongly hydrophobic fatty acid, which anchors the kinase at the cytoplasmic face of the plasma membrane. Next along the linear sequence of
Figure 3–62 an evolutionary tree of selected protein kinases. A higher eukaryotic cell contains hundreds of such enzymes, and the human genome codes for more than 500. Note that only some of these, those discussed in this book, are shown.
Figure 3–64 The activation of a Src-type protein kinase by two sequential events. As described in the text, the requirement for multiple upstream events to trigger these processes allows the kinase to serve as a signal integrator (Movie 3.11). (Adapted from S.C. Harrison et al., Cell 112:737–740, 2003. With permission from Elsevier.)
Figure 3–65 How a Src-type protein kinase acts as a signal-integrating device. A disruption of the inhibitory interaction illustrated for the SH3 domain (green) occurs when its binding to the indicated orange linker region is replaced with its higher-affinity binding to an activating ligand.
change that inactivates the protein. The three-dimensional structure of a prototypical member of this family, the monomeric GTPase called Ras, is shown in Figure 3–67.
The Ras protein has an important role in cell signaling (discussed in Chapter 15). In its GTP-bound form, it is active and stimulates a cascade of protein phosphorylations in the cell. Most of the time, however, the protein is in its inactive, GDP-bound form. It becomes active when it exchanges its GDP for a GTP molecule in response to extracellular signals, such as growth factors, that bind to receptors in the plasma membrane (see Figure 15–47).
Regulatory Proteins GAP and GEF Control the Activity of GTP-Binding Proteins by Determining Whether GTP or GDP Is Bound