Review Volume 3, Issue 3 pp 192—222

Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging

Figure 4. Dysregulated Expression of Upstream Receptors and Kinases Can Result in Activation of the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR Pathways. Sometimes dysregulated expression of growth factor receptors occurs by either increased expression or genomic amplifications (e.g., VEGFR, EGFR, HER2, IGF1R). Mutations have been detected in EGFR, FLT3, KIT, PDGFR, PIK3CA, RAS, BRAF, MEK1/MEK2, SOS, PTPN11 (indicated in red ovals), and PTEN (indicated in a purple square) . Akt and Rheb are overexpressed in certain cancers. Other signaling molecules which may be overexpressed (e.g., IGF-1R, VEGF-R, ERK, mTOR, p70S6K) but not necessarily mutated or amplified are indicated in yellow ovals. The MDM2 ubiquitin ligase is indicated in a green oval. The p53 tumor suppressor is one of the most frequently inactivated genes in human cancer and has multiple effects on these pathways and is indicated in a purple oval. Amplifications of HER2 and EGFR are detected in certain cancer types. The BCRABL chromosomal translocation is present in virtually all chronic myeloid leukemias (CMLs) and some acute lymphatic leukemias (ALLs). Many of these mutations and chromosomal translocations result in the activation of the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR cascades. These pathways can also be activated by autocrine growth stimulation, the genetic basis of which is frequently unknown. Deregulated expression of these pathways can result in cancer as well as premature aging.