Growth and mitogen signals are transmitted downstream of the ERK pathway are incorporated into multiple positive feedback loops to generate a bistable switch at the level of E2F activation. This occurs due to three main interactions during late G1 phase. The first is a result of mitogen stimulation though the ERK leading to the expression of the transcription factor Myc, which is a direct activator of E2F. The second pathway is a result of ERK activation leading to the accumulation of active complexes of Cyclin D and Cdk4/6 which destabilize Rb via phosphorylation and further serve to activate E2F and promote expression of its targets. Finally, these interactions are all reinforced by an additional positive feedback loop by E2F on itself, as its own expression leads to production of the active complex of Cyclin E and CDK2, which further serves to lock in a cell's decision to enter S-phase. As a result, when serum concentration is increased in a gradual manner, most mammalian cells respond in a switch-like manner in entering S-phase. This mitogen stimulated, bistable E2F switch is exhibits hysteresis, as cells are inhibited from returning to G1 even after mitogen withdrawal post E2F activation.