Figure 1.

Schematic representation of common proliferative signalling pathways. An overview of proliferative signal transduction through classical Ras-Raf-MEK-ERK/MAPK and PI3K-AKT-mTOR pathways is presented here. Receptor tyrosine kinases (RTKs) such as epidermal growth factor (EGRF) dimerise upon ligand activation (such as through EGF) and recruit proteins containing Src homology (SH) 2 domains such as GRB2 and SHC [32]. In the Raf axis, son of sevenless (SOS) activates Ras through guanine triphosphate (GTP) exchange [33], which subsequently recruits Raf to the plasma membrane where it becomes activated [34]. Raf initiates a signalling cascade by phosphorylating MEK1/2, which in turn phosphorylates ERK (also known as mitogen activated kinase; MAPK) [35]. ERK/MAPK translocates to the nucleus where it activates transcription factors (e.g., c-MYC, c-JUN, and c-FOS), which increase the transcription of cyclin D mRNA [36]. In the AKT axis, RTK dimerization activates PI3K, which stimulates the production of phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 production recruits AKT to the plasma membrane where phosphorylation events by PDK1 and mechanistic target of rapamycin complex (mTORC) 2 result in its activation [37,38]. AKT is able to activate mTORC1 and inhibit the action of TSC2, which is a negative regulator of mTORC 1. mTORC1 inhibits 4E-BP, which is a negative regulator of translation [39]. These events result in the production of cyclin D, which complexes with cyclin dependent kinases (CDKs) 4 and 6 to inhibit retinoblastoma (RB) protein and allow E2F transcription factors to produce cyclin E [40,41]. Cyclin E production drives the cell through the G₁/S transition of the cell cycle towards G₂ and mitosis [42].