RAS is the most commonly mutated oncogene in human tumors. Approximately 30% of all human tumors contain mutated RAS genes, and the frequency is even higher in some specific cancers (e.g., pancreatic adenocarcinoma). RAS is a member of a family of small G proteins that bind guanosine nucleotides (guanosine triphosphate [GTP] and guanosine diphosphate [GDP]). Signaling by RAS involves the following sequential steps: • Normally, RAS flips back and forth between an excited signal-transmitting state and a quiescent state. RAS is inactive when bound to GDP; stimulation of cells by growth factors such as EGF and PDGF leads to exchange of GDP for GTP and subsequent conformational changes
Activation of transcription
Fig. 6.18 Model for action of RAS. When a normal cell is stimulated through a growth factor receptor, inactive (GDP-bound) RAS is activated to a GTP-bound state. Activated RAS transduces proliferative signals to the nucleus along two pathways: the so-called “RAF/ERK/MAP kinase pathway” and the PI3 kinase/AKT pathway. GDP, Guanosine diphosphate; GTP, guanosine triphosphate; MAP, mitogen-activated protein; PI3, phosphatidylinositol-3.
Fig. 6.18 ). This excited signal-emitting state is short-lived, however, because the intrinsic guanosine triphosphatase (GTPase) activity of RAS hydrolyzes GTP to GDP, releasing a phosphate group and returning the protein to its quiescent GDP-bound state. The GTPase activity of activated RAS is magnified dramatically by a family of GTPase-activating proteins (GAPs), which act as molecular brakes that prevent uncontrolled RAS activation by favoring hydrolysis of GTP to GDP.
• Activated RAS stimulates downstream regulators of proliferation by several interconnected pathways that converge on the nucleus and alter the expression of genes that regulate growth, such as MYC. While details of the signaling cascades (some of which are illustrated in
Fig. 6.18 ) downstream of RAS are not discussed here, an important point is that mutational activation of these signaling intermediates mimics the growth promoting effects of activated RAS. For example, BRAF, which lies in the so-called “RAF/ERK/MAP kinase pathway” is mutated in more than 60% of melanomas and is associated with unregulated cell proliferation. Mutations of phosphatidly inositol-3 kinase (PI3 kinase) in the PI3K/AKT pathway also occur with high frequency in some tumor types, with similary consequences.
RAS most commonly is activated by point mutations in amino acid residues that are either within the GTP-binding pocket or in the enzymatic region that carries out GTP hydrolysis. Both kinds of mutations interfere with breakdown of GTP, which is essential to inactivate RAS. RAS is thus trapped in its activated, GTP-bound form, and the cell is forced into a continuously proliferating state. It follows from this scenario that the consequences of activating mutations in RAS should be mimicked by loss-offunction mutations in GAPs, which would lead to a failure to simulate GTP hydrolysis and thereby restrain RAS. Indeed, the GAP neurofibromin-1 (NF1) is mutated in the cancer-prone familial disorder neurofibromatosis type 1 (Chapter 22) and is a bona fide tumor suppressor. Similarly, another important tumor suppressor called PTEN is a negative inhibitor of PI3 kinase and is frequently mutated in carcinomas, certain leukemias, and other cancers as well.