Signal Transduction

The mitogenic signals that a cell receives are transmitted through receptor-associated tyrosine kinases (RTKs) to RAS, which in turn activates a multitude of cellular pathways leading to cell growth and proliferation. Therefore, a broad class of oncogenic mutations that occur in signal transduc-tion pathways can generally be considered RAS pathway activators. Oncogenic mutations in the RAS pathway can occur upstream of RAS, downstream of RAS, or in RAS itself. Activated mutants of all three RAS proteins can promote onco-genesis, and, although their functions are not entirely overlapping, a generic RAS signaling pathway is described next (Figure 16.4).16

The RAS proteins are small, farnesylated GTPases. Far-nesylation, the attachment of a 15-carbon lipophilic chain, is required for proper localization of RAS to the cell membrane in close proximity to RTKs.16,17 When mitogens bind to an

RTK, the receptor dimerizes and becomes autophosphory-lated, allowing the SH2 domain of an adapter protein known as growth factor receptor-bound protein 2 (GRB2) to bind, which in turn recruits the son of sevenless (SOS) protein to the cell membrane, where RAS is anchored.17 SOS functions as a guanine nucleotide exchange factor (GEF), facilitating the ability of inactive RAS to become active RAS by exchanging bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP). RAS in the GTP bound state remains active until a GTPase-activating protein (GAP) allows the hydrolysis of GTP to GDP.17

GTP-bound RAS can activate a multitude of pathways, but two are particularly relevant to our understanding of cancer. First, RAS activates the serine/threonine kinase RAF, which subsequently activates the mitogen-activated protein kinase (MAPK) pathway.17 The end effect of the activation of this pathway is the activation of c-Fos and c-Jun by phos-phorylation, resulting in the upregulation of gene expression required for the G1 phase of the cell cycle, including the D-type cyclins. A second pathway activated by RAS is the phos-phatidylinositol 3-kinase (PI-3) pathway.17 Activated PI-3 kinase phosphorylates phosphatidylinositol 4,5-bisphosphate to produce the second messenger phosphatidylinositol 3,4,5-triphosphate. This second messenger lipid can activate numerous other proteins including the kinase Akt. Phospho-rylation by Akt promotes growth by inactivating many proapoptotic proteins such as Bad and the forkhead family of transcription factors. The PI-3 kinase pathway also affects levels of the Cip/Kip protein p27, most likely through upreg-ulation of the proteins required for p27 degradation. Finally, the functions of the PI-3 kinase pathway are antagonized by the phosphatase and tensin homologue (PTEN) protein that

Figure 16.4. The RAS pathway. Mitogenic stimuli from growth factors are transmitted through receptor tyrosine kinases (RTKs) to RAS, which becomes active by exchanging guanosine diphosphate (GDP) for guanosine triphosphate (GTP). GTP-bound RAS can activate many pathways, including the RAF and phosphatidylinositol 3-kinase (PI-3) kinase pathways.

Figure 16.4. The RAS pathway. Mitogenic stimuli from growth factors are transmitted through receptor tyrosine kinases (RTKs) to RAS, which becomes active by exchanging guanosine diphosphate (GDP) for guanosine triphosphate (GTP). GTP-bound RAS can activate many pathways, including the RAF and phosphatidylinositol 3-kinase (PI-3) kinase pathways.

removes a phosphorylation from the PI-3 kinase-generated secondary messengers.

The RAS pathway and various subpathways are subject to activation at many points in cancer. Activating mutations in the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Kit, and FMS-like tyrosine kinase 3 (FLT3). RTKs are common in cancer, as well as simple overexpression of normal proteins.18-21 Mutations in RAS that maintain the GTP-bound state are also found in tumors, and the inactivation of RAS GAPs, such as the NF1 tumor suppressor, can lead to RAS activation through decreased rates of hydrolysis of GTP.16 Additionally, several downstream RAS effectors have links to cancer. BRAF activations have been observed in many patients, and the PTEN tumor suppressor is also subject to inactivation in multiple cancers. Finally, RTKs are not the only RAS activators. Other tyrosine kinases such as the translocation product BCR-Abl can bind GRB2 and activate RAS. BCR-Abl is the oncogene found on the Philadelphia chromosome, and activation of RAS by BCR-Abl is required for its oncogenic function.22

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