Deregulated Cytosolic Signaling Pathways

For additional information on this topic, see Chapter 7.08.

7.01.8.2.1 The Ras-Raf-MEK-MAPK pathway

Different growth factors and cytokines transduce their growth-promoting signals through the activation of the small G protein Ras (Figure 4). This leads to activation of members of the Raf family of serine/threonine kinases (c-Raf, A-Raf, and B-Raf) and its downstream effector, the mitogen-activated protein kinase (MAPK) kinase (MEK). This protein then phosphorylates and activates MAPK, the so-called extracellular signal-regulated kinase (ERK). The Ras-Raf-MEK-MAPK pathway controls the growth and survival of a broad spectrum of cancers. Thus, it has been shown by the expression of dominant negative or activated forms of MEK that the expression of cyclin D1, which leads to transition from G1 to S phase, is controlled by MEK signaling.287 Activating mutations in Ras and Raf are present in a large percentage of solid tumors. For example, the Ras oncogene is found mutated in its oncogenic form in 15% of human cancers, with subsequent activation of the MAPK pathway.288 The MEK and ERK kinases are rarely found constitutively activated in human tumors; however, B-Raf is often mutated and activated in certain human tumors such as melanoma (66%), ovarian (30%), or papillary thyroid (35-70%). All the mutations are within the kinase domain, either in the P loop or in the activation segment adjacent to the Asp-Phe-Gly (DFG) motif. Interestingly, roughly 90% of the activating mutations involve the replacement of the hydrophobic valine residue in the activation loop by glutamic acid, which due to its negative charge seems to mimic the phosphorylation of activation loop.289 Ras and B-Raf activating mutations are generally mutually exclusive in human, showing that activation of the MAPK pathway at the Ras or the B-Raf level is probably equivalent.290

7.01.8.2.2 The phosphatidylinositol-3-kinase-PDK1-protein kinase B pathway

The phosphatidylinositol-3-kinase (PI3K)-protein kinase B (PKB) pathway (Figure 5) regulates fundamental cellular functions (e.g., transcription, translation, proliferation, growth or survival), and it is often deregulated in a wide range of tumor types.291,292 Activation of the PI3K-PKB survival pathway can begin with the stimulation of growth factor receptor tyrosine kinases, followed by the recruitment of PI3K to the plasma membrane. Once localized to the plasma membrane, PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) at the 3'-OH position of the

MEK1, MEK2

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