Figure 1
Diagrammatic representation of the MAPK and the PTEN/PI3K/AKT/mTOR pathways and their potential interactions in transformed cells.
Growth factor and other survival signals are transduced through receptor tyrosine kinases via adaptor proteins (such as GRB2 and the guanine-nucleotide exchange factor SOS) and activate Ras and its downstream targets, Raf and MEK1/2, which results in the activation of ERK1/2. ERK1/2 activation leads to perturbations in downstream targets that promote survival, i.e., downregulation of Bim and Bad and upregulation of myeloid cell leukemia sequence 1 (Mcl-1). Growth factor survival signaling proceeds through the PI3K pathway, a process that is amplified in cells deficient in the PTEN phosphatase. PI3K activates pyruvate dehydrogenase kinase isozyme 1 (PDK1) and AKT, which either directly or indirectly (i.e, via forkhead box O [FOXO]) inactivate proapoptotic molecules such as Bim and Bad. AKT also activates mTORC1/regulatory-associated protein of mTOR (RAPTOR) by relieving it of the inhibitory influence of the tuberous sclerosis 1/2 (TSC1/2) complex. It is postulated that pharmacologic inhibition of mTOR (e.g., by rapamycin or RAD001) leads, via an S6K1- and PI3K-dependent process, to activation of Ras and MEK/ERK, which promotes cell survival in the face of mTOR inhibition. Inhibition of mTOR may also provoke an autophagic response. Conversely, interruption of the MAPK pathway (i.e., by MEK1/2 inhibitors such as PD0325901) in the setting of mTOR inhibition promotes cell death through a Bim-dependent mechanism. 4EBP, EIF4E-binding protein; EIF4E, eukaryotic translation initiation factor 4E; GRB2, growth factor receptor–bound protein 2; PIP1, phosphatidylinositol 3-phosphate; PIP3, phosphatidylinositol-3,4,5-triphosphate.
