Growth factors (GFs) trigger certain signaling cascades that lead to the activation of cyclin D/CDK4 complexes. Active CDK4 phosphorylates (thereby deactivating) the retinoblastoma protein (pRb) which inhibits entry into S phase due mainly to inhibitory binding with E2F transcription factors; these factors induce many of the genes required for S phase (such as members of the pre-replication complex, cyclin E, cyclin A, Cdc25A, etc.). Synthesis of cyclins E and A leads to activation of CDK2 which further phosphorylates (thereby deactivates) pRb. Another transcription factor, namely Myc, also contributes to the G1-S transition, but this protein's regulation is not shown. Arrows mean “activate,” and hammerheads mean “inhibit.” The dashed arrows signify the totality of gene expression steps (transcription and translation). Interactions numbered 1 to 10 form a minimal model that can account for the R point behavior.

Also shown are the known detailed mechanistic steps corresponding to the qNET shown in the upper panel (shaded grey). “a” refers to active, and “i” to inactive. Note that the network in the lower figure uses the chemist's convention of representing reaction steps; also, dashed arrows mean that the protein where the arrow originates from induces or catalyzes the reaction step that the arrow points to.

The lower panel shows the position of the R point (R) which subdivides the G1 phase into G1-pm (post-mitosis) and G1-ps (pre-S-phase). Quiescent or non-dividing cells have to be exposed to continuous growth-factor stimulation up until the R point in order to commit to entry into S-phase. After R and a finite induction period, cyclin E/CDK2 activity increases (shown by the dashed curve labelled E) as reported by Ekholm et al. [6].