BOX 1.

The RTK/Ras/MAP kinase signaling cascade. Activation of the epidermal growth factor receptor (EGFR) and other RTKs on the cell surface promotes recruitment of guanine‐nucleotide exchange factors that induce loading of RAS with GTP. GTP‐bound RAS recruits RAF‐family kinases to the membrane (there are three Raf isoforms, ARAF, BRAF, and CRAF/RAF‐1), where they are activated by dimerization. Once activated, they phosphorylate their only known substrates, MEK1 and MEK2. Active, phosphorylated MEK1/2 in turn phosphorylates ERK1 and ERK2, which have multiple targets for phosphorylation, including other kinases and transcription factors that control gene expression. Somatic mutations in each of the nodes in this pathway can lead to cancer; oncogenic activation of EGFR, K‐Ras, and BRAF is common, while activating mutations in MEK1/2 and ERK1/2 are relatively rare. The SHP2 tyrosine phosphatase (not illustrated) is also an important contributor to this pathway