Key Concepts of Section 16.4

• Ras is an intracellular GTPase switch protein that acts downstream from most RTKs and cytokine receptors. Like G_α, Ras cycles between an inactive GDP-bound form and an active GTP-bound form. Ras cycling requires the assistance of two proteins: a guanine nucleotide exchange factor (GEF) and a GTPase-activating protein (GAP).

• RTKs are linked indirectly to Ras via two proteins: GRB2, an adapter protein, and Sos, which has GEF activity (see Figure 16-21).

• The SH2 domain in GRB2 binds to a phosphotyrosine in activated RTKs, while its two SH3 domains bind Sos, thereby bringing Sos close to membrane-bound Ras·GDP and activating its GEF activity.

• Binding of Sos to inactive Ras causes a large conformational change that permits release of GDP and binding of GTP, forming active Ras (see Figure 16-23).

• Activated Ras triggers a kinase cascade in which Raf, MEK, and MAP kinase are sequentially phosphorylated and thus activated. Activated MAP kinase then translocates to the nucleus (see Figure 16-24).

• Activation of MAP kinase following stimulation of a growth-factor receptor leads to phosphorylation and activation of two transcription factors, which associate into a trimeric complex that promotes transcription of various early response genes (see Figure 16-26).

• Different extracellular signals induce activation of different MAP kinase pathways, which regulate diverse cellular processes by phosphorylating different sets of transcription factors.

• The kinase components of each MAP kinase cascade assemble into a large pathway-specific complex stabilized by a scaffold protein (see Figure 16-27). This ensures that activation of one MAP kinase pathway by a particular extracellular signal does not lead to activation of other pathways containing shared components.