The MAPK pathway. Once activated, tyrosine kinase (TK) receptors activate the monomeric G protein RAS (pathway I), which in turn binds the serine-threonine kinase BRAF by inducing a conformational change that allows its activation (pathway I) and hence activation of the MAPK pathway. The activation of the MAPK pathway results in DNA synthesis in response to the external mitogenic stimulus (pathway I). When the RET/PTC (pathway II) or the BRAF (pathway II) oncogenes are generated through chromosomal rearrangements, activation of the MAPK pathway becomes constitutive, and cells become able to proliferate indefinitely, to grow in an anchorage-independent manner, and to induce tumors after injection into athymic mice (pathway II). MEK, MAPK/ERK kinase; L, ligand.