The ERK pathway plays an important role of integrating external signals from the presence of mitogens such as epidermal growth factor (EGF) into signaling events promoting cell growth and proliferation in many mammalian cell types. In a simplified model, the presence of mitogens and growth factors trigger the activation of canonical receptor tyrosine kinases such as EGFR leading to their dimerization and subsequent activation of the small GTPase Ras. This then leads to a series of phosphorylation events downstream in the MAPK cascade (Raf-MEK-ERK) ultimately resulting in the phosphorylation and activation of ERK. The phosphorylation of ERK results in an activation of its kinase activity and leads to phosphorylation of its many downstream targets involved in regulation of cell proliferation. In most cells, some form of sustained ERK activity is required for cells to activate genes that induce cell cycle entry and suppress negative regulators of the cell cycle. Two such important targets include Cyclin D complexes with Cdk4 and Cdk6 (Cdk4/6) which are both phosphorylated by ERK. The transition from G1 to S phase is coordinated by the activity of Cyclin D-Cdk4/6, which increases during late G1 phase as cells prepare to enter S-phase in response to mitogens. Cdk4/6 activation contributes to hyper-phosphorylation and the subsequent destabilization of retinoblastoma protein (Rb). Hypo-phosphorylated Rb, is normally bound to transcription factor E2F in early G1 and inhibits its transcriptional activity, preventing expression of S-phase entry genes including Cyclin E, Cyclin A2 and Emi1. ERK1/2 activation downstream of mitogen induced Ras signaling is necessary and sufficient to remove this cell cycle block and allow cells to progress to S-phase in most mammalian cells.