Restriction Point - Restriction-point Mechanism

Restriction-point Mechanism

Signals from extracellular growth factors are transduced in a typical manner. Growth factor binds to receptors on the cell surface, and a variety of phosphorylation cascades result in Ca2+ uptake and protein phosphorylation. Phosphoprotein levels are counterbalanced by phosphatases. Ultimately, transcriptional activation of certain target genes occurs. Extracellular signaling must be maintained, and the cell must also have access to sufficient nutrient supplies to support rapid protein synthesis. Accumulation of cyclin D's are essential.

Cyclin D-bound cdk’s 4 and 6 are activated by cdk-activating kinase and drive the cell towards the restriction point. Cyclin D, however has a high turnover rate (t_1/2<25 min). It is because of this quick turnover rate that the cell is extremely sensitive to mitogenic signaling levels, which not only stimulate cycin D production, but also help to stabilize cyclin D within the cell. In this way, cyclin D acts as a mitogenic signal sensor. Cdk inhibitors (CKI), such as the Ink4 proteins and p21, help to prevent improper cyclin-cdk activity.

Active Cyclin D-cdk complexes phosphorylated Retinoblastoma protein (pRb) in the nucleus. pRb acts as an inhibitor of G₁ by preventing E2F-mediated transcription. Once phosphorylated, E2F activates the transcription of cyclins E and A. Active cyclin E-cdk begins to accumulate and completes pRb phosphorylation, as shown in the figure.